VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Schwartz’s Principles of Surgery Tenth Edition VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. 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VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Schwartz’s Principles of Surgery Tenth Edition David L. Dunn, MD, PhD, FACS Editor-in-Chief F. Charles Brunicardi, MD, FACS Moss Foundation Chair in Gastrointestinal and Personalized Surgery Professor and Vice Chair Surgical Services Chief of General Surgery, UCLA Santa Monica Medical Center Department of Surgery David Geffen School of Medicine at UCLA Los Angeles, California Executive Vice President for Health Affairs Professor of Surgery, Microbiology, and Immunology University of Louisville Louisville, Kentucky John G. Hunter, MD, FACS Mackenzie Professor and Chair Department of Surgery Oregon Health & Science University Portland, Oregon Jeffrey B. Matthews, MD, FACS Associate Editors Dana K. Andersen, MD, FACS Program Director Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland Timothy R. Billiar, MD, FACS George Vance Foster Professor and Chairman Department of Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Surgeon-in-Chief and Chairman Department of Surgery Dallas B. Phemister Professor of Surgery The University of Chicago Chicago, Illinois Raphael E. Pollock, MD, PhD, FACS Professor and Director Division of Surgical Oncology Department of Surgery Chief of Surgical Services, Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute The Ohio State University Wexner Medical Center Columbus, Ohio New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Copyright © 2015 by McGraw-Hill Education. All rights reserved. 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VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Stephen Lowry, MD, MBA (1947-2011) Photograph used with permission johnemersonphotography.com The tenth edition of Schwartz’s Principles of Surgery is dedicated to the late Dr. Stephen Lowry, consummate surgeon-scientist, educator, colleague, mentor, and longtime contributor to Schwartz’s Principles of Surgery. At the time of his death, Dr. Lowry served as Richard Harvey Professor and Chair of the Department of Surgery and Senior Associate Dean for Education at the RutgersRobert Wood Johnson Medical School (RWJMS) in New Brunswick, New Jersey. He was the inaugural holder of the Richard Harvey Professorship at RWJMS, which honors excellence in innovative teaching and exemplified his absolute dedication to medical education. Dr. Lowry’s dedicated and distinguished surgical career produced valuable contributions to both scientific knowledge and patient care, including his seminal investigations utilizing the human endotoxemia model that defined important aspects of the host inflammatory response following injury. His investigations had been supported by continuous National Institute of Health (NIH) funding for more than 25 years and were recognized by the coveted Method to Extend Research in Time (MERIT) award from the NIH. He authored more than 400 scientific publications and was the recipient of numerous honors that recognized his academic achievements. Although Dr. Lowry received many accolades and awards throughout his career, he was first and foremost an enthusiastic teacher and sincere supporter of people, their goals, and their lives. Dr. Lowry genuinely enjoyed listening, learning, and sharing his knowledge and did so with a depth of feeling that inspired and encouraged those around him. As his wife Susette wrote, “Steve knew he would be remembered for his professional accomplishments, but never imagined he would be honored and missed for his personality and style that set him apart from the rest. The world really was a better place with Steve in it!” The loss of his warmth, professionalism, intellect, and enthusiasm for medical education will be greatly missed. Siobhan Corbett, MD, and the editors of Schwartz’s Principles of Surgery, Tenth edition VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Robert S. Dorian, MD, MBA (1954-2014) Photo provided by Saint Barnabas Medical Center. Used with permission. The Editors of Schwartz’s Principles of Surgery wish to dedicate this tenth edition to the memory of Dr. Robert S. Dorian, the sole author of the “Anesthesia” chapter in the last three editions. Dr. Dorian was born in Philadelphia and grew up in Livingston, New Jersey where his father was a prominent gynecologist. He received his undergraduate degree in Physics and Music from Tufts University in Boston while at the same time studying piano at the New England Conservatory of Music. Bob received his medical education at Rutgers Medical School in Piscataway, New Jersey. After completing an internship in surgery at Downstate Medical Center in Brooklyn, he trained in anesthesiology at Weill Cornell Medical College and New York Hospital in New York City. He completed a fellowship in pediatric anesthesiology at Boston Children’s Hospital and Harvard Medical School. After his training, Bob established practice at the St. Barnabas Medical Center and rose to become the Chairman of the Department of Anesthesiology, a position he held for 14 years until his death. He was highly respected on both a national and international basis as an outstanding chairman. Bob was a consummate anesthesiologist, educator, mentor, and wonderful friend. He was the greatest of clinical anesthesiologists and was dedicated to providing the highest level of care to his patients. He was an extraordinary teacher and as the Program Director of the St. Barnabas anesthesia residency program for ten years, he trained scores of residents. His residents adored him because of the tremendous amount of attention he gave to each resident to assure they were highly trained in their craft and that they were placed in the top fellowships around the nation. Bob was also an incredibly gifted musician, scholar, and thinker. His intellect, humanity, and humor were inspiring to everyone who knew him. Bob was respected on an international basis for his humanitarian work with frequent medical missions to underserved populations around the world. In this endeavor, he was often accompanied by his wife, Linda, and their daughters, Rose and Zoe. Dr. Dorian had a most special gift and that was to bring out the best in every person that he met and make them feel very special. He lit up every room and made each encounter an occasion to remember. Having a conversation with Bob was one of life’s great pleasures. Colleagues, nurses, and patients would look forward to his arrival because he would make them laugh and brighten their day. He was loved by all and will be sorely missed. Bob’s memory and legacy will live on in the thousands of patients that he cared for, in the academic programs that he fostered, in the generations of anesthesiologists that he trained, and in his remarkable family. His words and intellect will be preserved in this textbook of surgery. James R. Macho, MD, FACS, and the editors of Schwartz’s Principles of Surgery, Tenth edition VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Contents Contributors/ix 14. Minimally Invasive Surgery, Robotics, Natural Orifice Transluminal Endoscopic Surgery, and Single-Incision Laparoscopic Surgery..........415 Acknowledgments/xix Foreword/xxi Donn H. Spight, John G. Hunter, and Blair A. Jobe 15. Molecular and Genomic Surgery........................443 Preface/xxiii Xin-Hua Feng, Xia Lin, Juehua Yu, John Nemunaitis, and F. Charles Brunicardi Preface to the First Edition/xxv Part I Basic Considerations 1 1. Fundamental Principles of Leadership Training in Surgery.......................................................... 3 Amy L. Hill, James Wu, Mark D. Girgis, Danielle Hsu, Areti Tillou, James Macho, Vishad Nabili, and F. Charles Brunicardi 2. Systemic Response to Injury and Metabolic Support............................................................13 Siobhan A. Corbett 3. Fluid and Electrolyte Management of the Surgical Patient.................................................65 G. Tom Shires III 4. Hemostasis, Surgical Bleeding, and Transfusion.................................................85 Bryan Cotton, John B. Holcomb, Matthew Pommerening, Kenneth Jastrow, and Rosemary A. Kozar 5. Shock.............................................................109 Brian S. Zuckerbraun, Andrew B. Peitzman, and Timothy R. Billiar 6. Surgical Infections..........................................135 Greg J. Beilman and David L. Dunn 7. Trauma...........................................................161 Clay Cothren Burlew and Ernest E. Moore 8. Burns.............................................................227 Jonathan Friedstat, Fred W. Endorf, and Nicole S. Gibran 9. Wound Healing................................................241 Adrian Barbul, David T. Efron, and Sandra L. Kavalukas 10. Oncology........................................................273 Funda Meric-Bernstam and Raphael E. Pollock 11. Transplantation...............................................321 Angelika C. Gruessner, Tun Jie, Klearchos Papas, Marian Porubsky, Abbas Rana, M. Cristy Smith, Sarah E. Yost, David L. Dunn, and Rainer W.G. Gruessner 12. Patient Safety.................................................365 Catherine L. Chen, Michol A. Cooper, Mark L. Shapiro, Peter B. Angood, and Martin A. Makary 13. Physiologic Monitoring of the Surgical Patient...............................................399 Louis H. Alarcon and Mitchell P. Fink Part II Specific Considerations 471 16. The Skin and Subcutaneous Tissue....................473 Sajid A. Khan, Jonathan Bank, David H. Song, and Eugene A. Choi 17. The Breast......................................................497 Kelly K. Hunt, John F.R. Robertson, and Kirby I. Bland 18. Disorders of the Head and Neck........................565 Richard O. Wein, Rakesh K. Chandra, C. René Leemans, and Randal S. Weber 19. Chest Wall, Lung, Mediastinum, and Pleura......................................................605 Katie S. Nason, Michael A. Maddaus, and James D. Luketich 20. Congenital Heart Disease.................................695 Tara Karamlou, Yasuhiro Kotani, and Glen A. Van Arsdell 21. Acquired Heart Disease....................................735 Shoichi Okada, Jason O. Robertson, Lindsey L. Saint, and Ralph J. Damiano, Jr. 22. Thoracic Aneurysms and Aortic Dissection.............................................785 Scott A. LeMaire, Raja R. Gopaldas, and Joseph S. Coselli 23. Arterial Disease .............................................827 Peter H. Lin, Mun Jye Poi, Jesus Matos, Panagiotis Kougias, Carlos Bechara, and Changyi Chen 24. Venous and Lymphatic Disease.........................915 Jason P. Jundt, Timothy K. Liem, and Gregory L. Moneta 25. Esophagus and Diaphragmatic Hernia................941 Blair A. Jobe, John G. Hunter, and David I. Watson 26. Stomach.......................................................1035 Yuko Kitagawa and Daniel T. Dempsey 27. The Surgical Management of Obesity...............1099 Philip R. Schauer and Bruce Schirmer 28. Small Intestine.............................................1137 Ali Tavakkoli, Stanley W. Ashley, and Michael J. Zinner 29. Colon, Rectum, and Anus...............................1175 Kelli M. Bullard Dunn and David A. Rothenberger 30. The Appendix................................................1241 Mike K. Liang, Roland E. Andersson, Bernard M. Jaffe, and David H. Berger VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ viii 31. Liver............................................................1263 Elaine Y. Cheng, Ali Zarrinpar, David A. Geller, John A. Goss, and Ronald W. Busuttil 41. Gynecology...................................................1671 Chad Hamilton, Michael Stany, W. Thomas Gregory, and Elise C. Kohn 32. Gallbladder and the Extrahepatic Biliary System...............................................1309 Thai H. Pham and John G. Hunter Contents 33. Pancreas.......................................................1341 William E. Fisher, Dana K. Andersen, John A. Windsor, Ashok K. Saluja, and F. Charles Brunicardi 34. Spleen..........................................................1423 Adrian E. Park, Eduardo M. Targarona, and Igor Belyansky 35. Abdominal Wall, Omentum, Mesentery, and Retroperitoneum...........................................1449 Neal E. Seymour and Robert L. Bell 42. Neurosurgery................................................1709 Casey H. Halpern and M. Sean Grady 43. Orthopedic Surgery........................................1755 Bert J. Thomas, Freddie H. Fu, Bart Muller, Dharmesh Vyas, Matt Niesen, Jonathan Pribaz, and Klaus Draenert 44. Surgery of the Hand and Wrist........................1787 Scott D. Lifchez and J. Alex Kelamis 45. Plastic and Reconstructive Surgery..................1829 Joseph E. Losee, Michael L. Gimbel, J. Peter Rubin, Christopher G. Wallace, and Fu-Chan Wei 46. Anesthesia for the Surgical Patient.................1895 Robert S. Dorian 36. Soft Tissue Sarcomas.....................................1465 Janice N. Cormier, Alessandro Gronchi, and Raphael E. Pollock 47. Surgical Considerations in the Elderly.............1923 Rosemarie E. Hardin and Michael E. Zenilman 37. Inguinal Hernias...........................................1495 Justin P. Wagner, F. Charles Brunicardi, Parviz K. Amid, and David C. Chen 38. Thyroid, Parathyroid, and Adrenal...................1521 Geeta Lal and Orlo H. Clark 39. Pediatric Surgery...........................................1597 David J. Hackam, Tracy Grikscheit, Kasper Wang, Jeffrey S. Upperman, and Henri R. Ford 48. Ethics, Palliative Care, and Care at the End of Life...................................1941 Daniel E. Hall, Peter Angelos, Geoffrey P. Dunn, Daniel B. Hinshaw, and Timothy M. Pawlik 49. Global Surgery...............................................1955 Raymond R. Price and Catherine R. deVries Index/1983 40. Urology........................................................1651 Karim Chamie, Jeffrey La Rochelle, Brian Shuch, and Arie S. Belldegrun VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Contributors Louis H. Alarcon, MD Associate Professor of Surgery and Critical Care Medicine, Medical Director, Trauma Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 13, Physiologic Monitoring of the Surgical Patient Parviz K. Amid, MD, FACS, FRCS Clinical Professor of Surgery, David Geffen School of Medicine at UCLA, Director Lichtenstein Amid Hernia Clinic at UCLA, Los Angeles, California Chapter 37, Inguinal Hernias Dana K. Andersen, MD, FACS Program Director, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland Chapter 33, Pancreas Roland E. Andersson, MD, PhD Associate Professor, Department of Surgery, County Hospital Ryhov, Jönköping, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden Chapter 30, The Appendix Peter Angelos, MD, PhD, FACS Linda Kohler Anderson Professor of Surgery and Surgical Ethics, Chief, Endocrine Surgery, Associate Director, MacLean Center for Clinical Medical Ethics, The University of Chicago Medicine, Chicago, Illinois Chapter 48, Ethics, Palliative Care, and Care at the End of Life Peter B. Angood, MD, FRCS(C), FACS, MCCM President and Chief Executive Officer, American College of Physician Executives, Tampa, Florida Chapter 12, Patient Safety Stanley W. Ashley, MD Frank Sawyer Professor of Surgery, Department of Surgery, Brigham & Women’s Hospital, Boston, Massachusetts Chapter 28, Small Intestine Jonathan Bank, MD Department of Surgery, The University of Chicago Medicine & Biological Sciences, Chicago, Illinois Chapter 16, The Skin and Subcutaneous Tissue Adrian Barbul, MD, FACS Vice-Chair, Department of Surgery, Surgical Director, Washington Hospital Center, Washington DC Chapter 9, Wound Healing Carlos Bechara, MD Assistant Professor of Surgery, Division of Vascular Surgery & Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Greg J. Beilman, MD Frank B. Cerra Professor of Critical Care Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 6, Surgical Infections Robert L. Bell, MD, MA, FACS Assistant Professor of Clinical Surgery, Columbia University College of Physicians and Surgeons, Summit Medical Group, Berkeley Heights, New Jersey Chapter 35, Abdominal Wall, Omentum, Mesentery, and Retroperitoneum Arie S. Belldegrun, MD, FACS Director, Institute of Urologic Oncology, Professor & Chief of Urologic Oncology, Roy and Carol Doumani Chair in Urologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 40, Urology Igor Belyansky, MD Director of Abdominal Wall Reconstruction Program, Department of General Surgery, Anne Arundel Medical Center, Annapolis, Maryland Chapter 34, Spleen David H. Berger, MD, FACS Professor of Surgery, Vice President and Chief Medical Officer, Baylor College of Medicine, Houston, Texas Chapter 30, The Appendix VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ x Timothy R. Billiar, MD, FACS David C. Chen, MD Kirby I. Bland, MD Elaine Y. Cheng, MD George Vance Foster Professor and Chairman, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 5, Shock Contributors Professor and Chair, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama Chapter 17, The Breast F. Charles Brunicardi, MD, FACS Moss Foundation Chair in Gastrointestinal and Personalized Surgery, Professor and Vice Chair, Surgical Services, Chief of General Surgery, UCLA Santa Monica Medical Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Chapter 15, Molecular and Genomic Surgery Chapter 33, Pancreas Chapter 37, Inguinal Hernias Clay Cothren Burlew, MD, FACS Director, Surgical Intensive Care Unit, Department of Surgery, Denver Health Medical Center, Associate Professor of Surgery, University of Colorado School of Medicine, Denver, Colorado Chapter 7, Trauma Ronald W. Busuttil, MD, PhD Professor and Executive Chairman, Department of Surgery, University of California-Los Angeles, Los Angeles, California Chapter 31, Liver Clinical Director, Lichtenstein Amid Hernia Clinic at UCLA, Physician, General Surgery, UCLA Center for Esophageal Disorders, Los Angeles, California Chapter 37, Inguinal Hernias Fellow in Abdominal Transplant Surgery, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California-Los Angeles, Los Angeles, California Chapter 31, Liver Eugene A. Choi, MD Assistant Professor of Surgery, Department of Surgery, The University of Chicago Medicine & Biological Sciences, Chicago, Illinois Chapter 16, The Skin and Subcutaneous Tissue Orlo H. Clark, MD, FACS Professor, Surgery, University of California, San Francisco, California Chapter 38, Thyroid, Parathyroid, and Adrenal Michol A. Cooper, MD, PhD General Surgery Resident, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland Chapter 12, Patient Safety Siobhan A. Corbett, MD Associate Professor, Department of Surgery, Rutgers-Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, New Brunswick, New Jersey Chapter 2, Systemic Response to Injury and Metabolic Support Karim Chamie, MD, MSHS Janice N. Cormier, MD, MPH Rakesh K. Chandra, MD Joseph S. Coselli, MD Assistant Professor of Urology, Institute of Urologic Oncology, Department of Urology, University of California, Los Angeles, California Chapter 40, Urology Associate Professor of Otolaryngology, Chief, Rhinology & Skull Base Surgery, Department of Otolaryngology-Head & Neck Surgery, Vanderbilt University, Nashville, Tennessee Chapter 18, Disorders of the Head and Neck Catherine L. Chen, MD, MPH Resident Physician, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California Chapter 12, Patient Safety Changyi Chen, MD, PhD Professor of Surgery, Division of Vascular Surgery & Endovascular Therapy, Vice Chairman of Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Professor, Departments of Surgical Oncology and Biostatistics and Biomathematics, The University of Texas MD Anderson Cancer Center, Houston, Texas Chapter 36, Soft Tissue Sarcomas Professor and Chief, Cullen Foundation Endowed Chair, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Chief, Adult Cardiac Surgery, Texas Heart Institute, Chief, Adult Cardiac Surgery Section and, Associate Chief, Cardiovascular Service, Baylor St. Luke’s Medical Center, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection Bryan A. Cotton, MD, MPH Associate Professor of Surgery, University of Texas Health Science Center at Houston, Center for Translational Injury Research, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding and Transfusion VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Xin-Hua Feng, PhD Daniel T. Dempsey, MD, FACS Mitchell P. Fink, MD John M. Schoenberg Professor of Surgery, Chief of Cardiac Surgery, Vice Chairman, Department of Surgery, Barnes-Jewish Hospital, Washington University School of Medicine, St Louis, Missouri Chapter 21, Acquired Heart Disease Professor of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Chapter 26, Stomach Catherine R. deVries, MD Director, Center for Global Surgery, Professor, Department of Surgery, Associate Professor, Department of Family and Preventive Medicine, Division of Public Health, University of Utah, Salt Lake City, Utah Chapter 49, Global Surgery Robert S. Dorian, MD Chairman, Department of Anesthesiology, Saint Barnabas Medical Center, Livingston, New Jersey Chapter 46, Anesthesia for the Surgical Patient Klaus Draenert, MD Zentrum fur Orthopadische, Wissenschaften, Gabriel-Max-Strasse 3, Munchen, Germany Chapter 43, Orthopaedic Surgery David L. Dunn, MD, PhD, FACS Executive Vice President for Health Affairs, Professor of Surgery, Microbiology and Immunology, University of Louisville, Louisville, Kentucky Chapter 6, Surgical Infections Chapter 11, Transplantation Kelli M. Bullard Dunn, MD, FACS, FASCRS Senior Associate Dean for Statewide Initiatives and Outreach, Associate Director for Clinical Programs, James Graham Brown Cancer Center, Professor of Surgery, University of Louisville, Louisville, Kentucky Chapter 29, Colon, Rectum, and Anus Geoffrey P. Dunn, MD Medical Director, Department of Surgery, Hamot Medical Center, Erie, Pensylvania Chapter 48, Ethics, Palliative Care, and Care at the End of Life David T. Efron, MD, FACS Associate Professor of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Chapter 9, Wound Healing Fred W. Endorf, MD Clinical Associate Professor, Department of Surgery, University of Minnesota, St. Paul, Minnesota Chapter 8, Burns Professor of Molecular Cell Biology, Michael E. DeBakey Department of Surgery, and Department of Molecular & Cellular Biology Baylor College of Medicine, Houston, Texas Chapter 15, Molecular and Genomic Surgery Professor-in-Residence, Departments of Surgery and Anesthesiology, Vice Chair, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California Chapter 13, Physiologic Monitoring of the Surgical Patient xi Contributors Ralph J. Damiano, MD William E. Fisher, MD, FACS Professor and Chief, Division of General Surgery, George L. Jordan, M.D. Chair of General Surgery, Director, Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 33, Pancreas Henri R. Ford, MD Vice President and Chief of Surgery, Children’s Hospital Los Angeles, Vice-Dean, Medical Education, Professor and Vice Chair for Clinical Affairs, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Jonathan Friedstat, MD Clinical Instructor, Harborview Medical Center, Seattle, Washington Chapter 8, Burns Freddie H. Fu, MD, DSc (Hon), DPs (Hon) Distinguished Service Professor, University of Pittsburgh, David Silver Professor and Chairman, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Head Team Physician, University of Pittsburgh Department of Athletics, Pittsburgh, Pennsylvania Chapter 43, Orthopaedic Surgery David A. Geller, MD Richard L. Simmons Professor of Surgery, Co-Director, UPMC Liver Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 31, Liver Nicole S. Gibran, MD, FACS Professor, Department of Surgery, Director, Medicine Regional Burn Center, Harborview Medical Center, Seattle, Washington Chapter 8, Burns Michael L. Gimbel, MD Assistant Professor of Surgery, Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Brunicardi_FM_pi-xxvi.indd 11 4/17/14 12:18 PM xii Mark D. Girgis, MD Clinical Instructor, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Contributors Raja R. Gopaldas, MD Assistant Professor, Division of Cardiothoracic Surgery, Hugh E. Stephenson, Jr., MD, Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri Chapter 22, Thoracic Aneurysms and Aortic Dissection John A. Goss, MD Professor and Chief, Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 31, Liver M. Sean Grady, MD, FACS Charles Harrison Frazier Professor, Chairman, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Chapter 42, Neurosurgery W. Thomas Gregory, MD Associate Professor, Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon Chapter 41, Gynecology Tracy Grikscheit, MD Assistant Professor of Surgery, Department of Pediatric Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Alessandro Gronchi, MD Department of Surgery - Sarcoma Service, Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian, Milan, Italy Chapter 36, Soft Tissue Sarcomas Angelika C. Gruessner, PhD Daniel E. Hall, MD, MDiv, MHSc Core Investigator, Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania and Associate Professor, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 48, Ethics, Palliative Care, and Care at the End of Life Casey H. Halpern, MD Chief Resident, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania Chapter 42, Neurosurgery Chad Hamilton, MD Chief, Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, Maryland Chapter 41, Gynecology Rosemarie E. Hardin, MD Practice of Breast Oncology, Wheeling, West Virginia Chapter 47, Surgical Considerations in the Elderly Amy L. Hill, MD Clinical Instructor, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Daniel B. Hinshaw, MD Professor, Department of Surgery, University of Michigan, Ann Arbor, Michigan Chapter 48, Ethics, Palliative Care, and Care at the End of Life John B. Holcomb, MD, FACS Vice Chair and Professor of Surgery, Chief, Division of Acute Care Surgery, University of Texas Health Science Center at Houston, Center for Translational Injury Research, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding and Transfusion Danielle Hsu, MD Professor of Public Health, University of Arizona, Tucson, Arizona Chapter 11, Transplantation Clinical Instructor, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Rainer W.G. Gruessner, MD, FACS Kelly K. Hunt, MD, FACS Professor of Surgery and Immunology, Chairman, Department of Surgery, University of Arizona, Tucson, Arizona Chapter 11, Transplantation David J. Hackam, MD, PhD Roberta Simmons Associate Professor of Pediatric Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 39, Pediatric Surgery Hamill Foundation Distinguished Professorship in Honor of Dr. Richard G. Martin, Sr., Chief, Surgical Breast Oncology, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas Chapter 17, The Breast VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ John G. Hunter, MD, FACS Bernard M. Jaffe, MD Professor Emeritus, Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana Chapter 30, The Appendix Kenneth Jastrow, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding and Transfusion Tun Jie, MD, MS, FACS Interim Chief, Division of Abdominal Transplant Surgery, Assistant Professor of Surgery, Department of Surgery, University of Arizona, Tucson, Arizona Chapter 11, Transplantation Blair A. Jobe, MD, FACS Chair of Surgery, Western Pennsylvania Hospital, Director, Institute for the Treatment of Esophageal and Thoracic Disease, Allegheny Health Network, Pittsburgh, Pennsylvania Chapter 14, Minimally Invasive Surgery, Robotics, Natural Orifice Transluminal Endoscopic Surgery and Single Incision Laparoscopic Surgery Chapter 25, Esophagus and Diaphragmatic Hernia Jason P. Jundt, MD Vascular Resident, Division of Vascular Surgery, Department of Surgery and Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon Chapter 24, Venous and Lymphatic Disease Tara Karamlou, MD, MSc Assistant Professor of Surgery, Division of Pediatric Cardiac Surgery, Benioff Children’s Hospital University of California, San Francisco, California Chapter 20, Congenital Heart Disease Sandra L. Kavalukas, MS Penn State College of Medicine, Hershey, Pennsylvania Chapter 9, Wound Healing J. Alex Kelamis, MD xiii Assistant Professor of Surgery, Department of Surgery, Section of Surgical Oncology, Yale University School of Medicine, New Haven, Connecticut Chapter 16, The Skin and Subcutaneous Tissue Yuko Kitagawa, MD, PhD, FACS Professor and Chairman, Department of Surgery, Vice President, Keio University Hospital, Director of Keio Cancer Center, School of Medicine, Keio University, Tokyo, Japan Chapter 26, Stomach Elise C. Kohn, MD Senior Investigator, Head, Molecular Signaling Section, Head, Medical Ovarian Cancer Clinic, Medical Oncology Branch, Center for Cancer Research National Cancer Institute, Bethesda, Maryland Chapter 41, Gynecology Yasuhiro Kotani, MD, PhD Clinical Fellow, Cardiovascular Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario Chapter 20, Congenital Heart Disease Panagiotis Kougias, MD Assistant Professor of Surgery, Division of Vascular Surgery & Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Rosemary A. Kozar, MD, PhD Vice Chair of Research and Academic Development, “Red” Duke Professor of Surgery, University of Texas Health Science Center at Houston, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding and Transfusion Jeffrey La Rochelle, MD Department of Urology, Oregon Health and Science University, Portland, Oregon Chapter 40, Urology Geeta Lal, MD, MSc, FRCS(C), FACS Associate Professor, Surgery, University of Iowa, Iowa City, Iowa Chapter 38, Thyroid, Parathyroid, and Adrenal C. René Leemans, MD, PhD Professor and Chairman, Department of OtolaryngologyHead & Neck Surgery, VU University Medical Center, Amsterdam, Netherlands Chapter 18, Disorders of the Head and Neck Senior Resident, Department of Plastic and Reconstructive Surgery, Johns Hopkins University, University of Maryland Medical Center, Baltimore, Maryland Chapter 44, Surgery of the Hand and Wrist VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Contributors Professor and Chairman, Department of Surgery, Oregon Health & Science University, Portland, Oregon Chapter 14, Minimally Invasive Surgery, Robotics, Natural Orifice Transluminal Endoscopic Surgery and Single Incision Laparoscopic Surgery Chapter 25, Esophagus and Diaphragmatic Hernia Chapter 32, Gallbladder and the Extrahepatic Biliary System Sajid A. Khan, MD xiv Scott A. LeMaire, MD Contributors Professor and Director of Research, Division of Cardiothoracic Surgery, Vice Chair for Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Texas Heart Institute, Professional Staff, Department of Cardiovascular Surgery, Baylor St. Luke’s Medical Center, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection Mike K. Liang, MD Assistant Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 30, The Appendix Timothy K. Liem, MD, FACS Michael A. Maddaus, MD Professor of Surgery, Department of Surgery, Division of General Thoracic and Foregut Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 19, Chest Wall, Lung, Mediastinum, and Pleura Martin A. Makary, MD, MPH Associate Professor of Surgery, Johns Hopkins University School of Medicine, Associate Professor of Health Policy & Management, Johns Hopkins Bloomberg School of Public Health, Director, Surgical Quality & Safety, Johns Hopkins Hospital, Baltimore, Maryland Chapter 12, Patient Safety Associate Professor of Surgery, Vice-Chair for Quality, Department of Surgery, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon Chapter 24, Venous and Lymphatic Disease Jeffrey B. Matthews, MD, FACS Scott D. Lifchez, MD, FACS Jesus Matos, MD Xia Lin, PhD Funda Meric-Bernstam, MD Peter H. Lin, MD Gregory L. Moneta, MD, FACS Joseph E. Losee, MD Ernest E. Moore, MD, FACS, MCCM James D. Luketich, MD Vishad Nabili, MD, FACS Assistant Professor, Department of Plastic and Reconstructive Surgery, Johns Hopkins University, Director of Hand Surgery, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Chapter 44, Surgery of the Hand and Wrist Associate Professor of Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 15, Molecular and Genomic Surgery Professor of Surgery, Chief, Division of Vascular Surgery & Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Ross H. Musgrave Professor of Pediatric Plastic Surgery, Executive Vice-Chair, Department of Plastic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Henry T. Bahnson Professor of Cardiothoracic Surgery, Chief, The Heart, Lung, and Esophageal Surgery Institute, Department of Surgery, Division of Thoracic and Foregut Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 19, Chest Wall, Lung, Mediastinum, and Pleura James R. Macho, MD, FACS Emeritus Professor of Surgery, UCSF School of Medicine, Director of Surgical Critical Care, Saint Francis Memorial Hospital, San Francisco, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Surgeon-in-Chief and Chairman, Department of Surgery, Dallas B. Phemister Professor of Surgery, The University of Chicago, Chicago, Illinois Assistant Professor of Surgery, Division of Vascular Surgery & Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Professor, Dept. of Surgical Oncology, Medical Director, Institute of Personalized Cancer Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 10, Oncology Professor and Chief, Division of Vascular Surgery, Department of Surgery and Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon Chapter 24, Venous and Lymphatic Disease Professor and Vice Chairman of Research, Department of Surgery, University of Colorado Denver, Editor, Journal of Trauma and Acute Care Surgery, Denver, Colorado Chapter 7, Trauma Associate Professor and Residency Program Director, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Katie S. Nason, MD, MPH Assistant Professor, Division of Thoracic Surgery, Department of General Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 19, Chest Wall, Lung, Mediastinum, and Pleura VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ John Nemunaitis, MD Director, Mary Crowley Cancer Research Center, Dallas, Texas Chapter 15, Molecular and Genomic Surgery Matt Niesen, MD Shoichi Okada, MD Department of Surgery, Washington University School of Medicine, St. Louis, Missouri Chapter 21, Acquired Heart Disease Klearchos Papas, PhD Professor of Surgery, Scientific Director of the Institute for Cellular Transplantation, University of Arizona, Tucson, Arizona Chapter 11, Transplantation Adrian E. Park, MD, FRCSC, FACS, FCS(ECSA) Chair, Department of Surgery, Anne Arundel Medical Center, Professor of Surgery, PAR, Johns Hopkins University, Annapolis, Maryland Chapter 34, Spleen Timothy M. Pawlik, MD, MPH, PhD, FACS Professor of Surgery and Oncology, John L. Cameron M.D. Professor of Alimentary Tract Diseases, Chief, Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, Maryland Chapter 48, Ethics, Palliative Care, and Care at the End of Life Andrew B. Peitzman, MD Mark M. Ravitch Professor and Vice Chairman, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 5, Shock Thai H. Pham, MD, FACS Assistant Professor of Surgery, Surgical Services, North Texas Veterans Affairs Medical Center and University of Texas Southwestern School of Medicine, Dallas, Texas Chapter 32, Gallbladder and the Extrahepatic Biliary System Mun Jye Poi, MD Professor and Director, Division of Surgical Oncology, Department of Surgery, Chief of Surgical Services, Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, College of Medicine, Columbus, Ohio Chapter 10, Oncology Chapter 36, Soft Tissue Sarcomas Matthew Pommerening, MD Resident, Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding and Transfusion Marian Porubsky, MD Assistant Professor, Department of Surgery, Division of Adominal Transplantation, University of Arizona, Tucson, Arizona Chapter 11, Transplantation Jonathan Pribaz, MD Resident in Orthopaedic Surgery, UCLA Department of Orthopaedic Surgery, Santa Monica, California Chapter 43, Orthopaedic Surgery Raymond R. Price, MD Director Graduate Surgical Education, Intermountain Healthcare, Associate Director Center for Global Surgery, Adjunct Associate Professor, Department of Surgery, Adjunct Associate Professor, Department of Family and Preventive Medicine, Division of Public Health, University of Utah, Salt Lake City, Utah Chapter 49, Global Surgery Abbas Rana, MD Assistant Professor of Surgery, Department of Surgery, University of Arizona, Tucson, Arizona Chapter 11, Transplantation John F.R. Robertson, MD, ChB, BSc, FRCS(Glasg) Professor of Surgery, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK Chapter 17, The Breast Jason O. Robertson, MD, MS Assistant Professor of Surgery, Division of Vascular Surgery & Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Department of Surgery, Washington University School of Medicine, St. Louis, Missouri Chapter 21, Acquired Heart Disease David A. Rothenberger, MD Jay Phillips Professor and Chairman, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 29, Colon, Rectum, and Anus VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ xv Contributors Resident in Orthopaedic Surgery, UCLA Department of Orthopaedic Surgery, Santa Monica, California Chapter 43, Orthopaedic Surgery Raphael E. Pollock, MD, PhD, FACS xvi J. Peter Rubin, MD UPMC Endowed Professor and Chair, Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Contributors Lindsey L. Saint, MD Clinical Instructor, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri Chapter 21, Acquired Heart Disease Ashok K. Saluja, PhD Eugene C & Gail V Sit Chair in Pancreatic & Gastrointestinal Cancer Research, Professor & Vice Chair of Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 33, Pancreas Philip R. Schauer, MD Professor of Surgery, Lerner College of Medicine, Director, Bariatric and Metabolic Institute Cleveland Clinic, Cleveland, Ohio Chapter 27, The Surgical Management of Obesity Bruce D. Schirmer, MD, FACS Stephen H. Watts Professor of Surgery, University of Virginia Health System, Charlottesville, Virginia Chapter 27, The Surgical Management of Obesity Neal E. Seymour, MD Professor, Department of Surgery, Tufts University School of Medicine, Chief of General Surgery, Baystate Medical Center, Springfield, Massachusetts Chapter 35, Abdominal Wall, Omentum, Mesentery, and Retroperitoneum Mark L. Shapiro, MD, FACS Chief, Acute Care Surgery, Associate Director, Trauma, Duke University Medical Center, Durham, North Carolina Chapter 12, Patient Safety G. Tom Shires III, MD, FACS John P. Thompson Chair, Surgical Services, Texas Health Presbyterian Hospital Dallas, Dallas, Texas Chapter 3, Fluid and Electrolyte Management of the Surgical Patient Brian Shuch, MD Assistant Professor, Department of Urology, Yale School of Medicine, New Haven, Connecticut Chapter 40, Urology M. Cristy Smith, MD Associate Director of Mechanical Circulatory Support, Cardiothoracic Surgery, Peacehealth St. Joseph Medical Center, Bellingham, Washington Chapter 11, Transplantation David H. Song, MD Cynthia Chow Professor of Surgery, Chief, Section of Plastic and Reconstructive Surgery, Vice Chairman, Department of Surgery, The University of Chicago Medicine & Biological Sciences, Chicago, Illinois Chapter 16, The Skin and Subcutaneous Tissue Donn H. Spight, MD,FACS Assistant Professor of Surgery, Department of Surgery, Oregon Health & Science University, Portland, Oregon Chapter 14, Minimally Invasive Surgery, Robotics, Natural Orifice Transluminal Endoscopic Surgery and Single Incision Laparoscopic Surgery Michael Stany, MD Gynecologic Oncologist, Walter Reed National Military Medical Center, Assistant Professor, Uniformed Services University of the Health Sciences, Bethesda, Maryland Chapter 41, Gynecology Eduardo M. Targarona, MD, PhD, FACS Chief of the Unit of Gastrointestinal and Hematological Surgery, Hospital Sant Pau, Professor of Surgery, Autonomous University of Barcelona, Barcelona, Spain Chapter 34, Spleen Ali Tavakkoli, MD Assistant Professor of Surgery, Department of Surgery, Brigham & Women’s Hospital, Boston, Massachusetts Chapter 28, Small Intestine Bert J. Thomas, MD Chief, Joint Replacement Service, Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 43, Orthopaedic Surgery Areti Tillou, MD, FACS Associate Professor and Vice Chair for Education, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Jeffrey S. Upperman, MD Associate Professor of Surgery, Director of Trauma, Pediatric Surgery, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Glen A. Van Arsdell, MD Head, Cardiovascular Surgery, The Hospital for Sick Children, Professor of Surgery, University of Toronto, Toronto, Ontario Chapter 20, Congenital Heart Disease Justin P. Wagner, MD Clinical Instructor, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California Chapter 37, Inguinal Hernias VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Christopher G. Wallace, MD, MS, FRCS (Plast) Microsurgical Fellow, Department of Plastic Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan Chapter 45, Plastic and Reconstructive Surgery Kasper S. Wang, MD David I. Watson, MBBS, MD, FRACS Professor & Head, Department of Surgery, Flinders University of South Australia, Adelaide, South Australia, Australia Chapter 25, Esophagus and Diaphragmatic Hernia Randal S. Weber, MD, FACS Professor and Chairman, Director of Surgical Services, Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas Chapter 18, Disorders of the Head and Neck Fu-Chan Wei, MD, FACS Professor, Department of Plastic Surgery, Chang Gung Memorial Hospital, Chang Gung University and Medical College, Taipei, Taiwan Chapter 45, Plastic and Reconstructive Surgery Richard O. Wein, MD, FACS Associate Professor, Department of OtolaryngologyHead & Neck Surgery, Tufts Medical Center, Boston, Massachusetts Chapter 18, Disorders of the Head and Neck John A. Windsor, BSc MD, FRACS, FACS Professor of Surgery, Department of Surgery, University of Auckland, Auckland, New Zealand Chapter 33, Pancreas James Wu, MD Clinical Instructor, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 1, Fundamental Principles of Leadership Training in Surgery Sarah E. Yost, PharmD, BCPS Clinical Pharmacist in Abdominal Transplant, Department of Pharmacy, The University of Arizona Medical Center, Tucson, Arizona Chapter 11, Transplantation Juehua Yu, PhD Postdoctoral Fellow, Department of Surgery, University of California, Los Angeles, Los Angeles, California Chapter 15, Molecular and Genomic Surgery Assistant Professor of Surgery, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, California Chapter 31, Liver Michael E. Zenilman, MD Professor and Vice-Chair of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, Director, National Capital Region, Johns Hopkins Medicine, Visiting Professor, SUNY Downstate School of Public Health, Brooklyn, New York, Surgeon-inChief, Johns Hopkins Suburban Hospital, Bethesda, Maryland Chapter 47, Surgical Considerations in the Elderly Michael J. Zinner, MD Moseley Professor and Chairman, Department of Surgery, Brigham & Women’s Hospital, Boston, Massachusetts Chapter 28, Small Intestine Brian S. Zuckerbraun, MD, FACS Associate Professor of Surgery, Henry T. Bahnson Professor of Surgery, University of Pittsburgh, Chief, Trauma and Acute Care Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 5, Shock VIDEO CONTRIBUTORS Yolanda T. Becker, MD, FACS Professor of Surgery, Director, Kidney and Pancreas Transplant Program, Surgical Director of Perioperative Services, University of Chicago Medical Center, Chicago, Illinois Kidney Transplant Janet M. Bellingham, MD Assistant Professor, Department of Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin Kidney Transplant F. Charles Brunicardi, MD, FACS Moss Foundation Chair in Gastrointestinal and Personalized Surgery, Professor and Vice Chair, Surgical Services, Chief of General Surgery, UCLA Santa Monica Medical Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California Laparoscopic Cholecystectomy, Laparoscopic Inguinal Hernia Repair Sally E. Carty, MD Division Chief, Endocrine Surgery, Professor, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Thyroidectomy VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ xvii Contributors Associate Professor of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Ali Zarrinpar, MD, PhD xviii Giselle G. Hamad, MD Jamal J. Hoballah, MD, MBA Michael J. Rosen, MD, FACS Seon-Hahn Kim, MD Associate Professor of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Laparoscopic Incisional Hernia Repair Contributors Professor of Surgery, Case Western Reserve University, Director, Case Comprehensive Hernia Center, Cleveland, Ohio Open Posterior Component Separation Konstantin Umanskiy, MD, FACS Assistant Professor of Surgery, The University of Chicago Medicine, Chicago, Illinois Right Colectomy, Sigmoid Colectomy INTERNATIONAL ADVISORY BOARD Gaurav Agarwal, MS (Surgery), FACS Professor and Chairman, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon Professor and Chairman, Department of Surgery, Korea University College of Medicine, Seoul, South Korea Yuko Kitagawa, MD, PhD, FACS Professor and Chairman, Department of Surgery, Vice President, Keio University Hospital, Director of Keio Cancer Center, School of Medicine, Keio University, Tokyo, Japan Miguel Angel Mercado Diaz, MD Professor and Chairman, Department of General Surgery, National Institute of Medical Science and Nutrition, Mexico DF, Mexico Professor, Department of Endocrine and Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Gerald C. O’Sullivan, MD, FRCSI, FACS (Hon) Claudio Bassi, MD, FRCS, FACS, FEBS John F. Thompson, MD Professor of Surgery, Surgical and Oncological Department, University of Verona, Pancreas Institute, Verona, Italy Mordechai Gutman, MD Head, Department of Surgery, Sheba Medical Center, Tel-Hashomer, Israel Serafin C. Hilvano, MD, FPCS, FACS, American Surgical Association(Hon.) Professor Emeritus, Department of Surgery, College of Medicine, University of the Philippines Manila, Manila, Philippines Professor of Surgery, University College Cork, Mercy University Hospital, Cork, Ireland Melanoma Institute Australia, Royal Prince Alfred and Mater Hospitals, Sydney, Australia, Discipline of Surgery, The University of Sydney, Sydney, Australia John A. Windsor, BSc MD, FRACS, FACS Professor of Surgery, Department of Surgery, University of Auckland, Auckland, New Zealand Liwei Zhu, MD Department of Surgery, Tianjin Medical University Hospital, Tianjin, China VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Acknowledgments The Editors would like to thank the following authors of the previous edition (9th) for their contributions. Portions of their work may have been revised, reconfigured, and/or serve as a foundation for chapters in the tenth edition: Badar V. Jan, Ernest A. Gonzalez, Walter L. Biffl, Abhinav Humar, Patrick Cole, Lior Heller, Jamal Bullocks, Lisa A. Newman, Edward M. Copeland III, Karl F. Welke, Ross M. Ungerleider, Charles F. Schwartz, Gregory A. Crooke, Eugene A. Grossi, Aubrey C. Galloway, Kapil Sharma, Catherine Cagiannos, Tam T. Huynh, Jeffrey H. Peters, Allan Tsung, Richard H. Bell Jr., Carlos D. Godinez Jr., Vadim Sherman, Kurt D. Newman, Joanna M. Cain, Wafic ElMasri, Michael L. Smith, Joel A. Bauman, Michael H. Heggeness, Francis H. Gannon, Jacob Weinberg, Peleg Ben-Galim, Charles A. Reitman, and Subhro K. Sen. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Foreword The adjective “tenth” connotes a milestone, and, in the case of a “tenth edition” of a textbook, it is evidence of readership acceptability. This continued reader response would evoke parental pride from those who generated the original publication more than 45 years ago. I can still vividly recall the meeting in New York City at which John DeCarville, an editor at McGraw-Hill, brought together David M. Hume, Richard C. Lillehei, G. Thomas Shires, Edward H. Storer, Frank C. Spencer, and me to create a new surgical textbook. The new surgical publication was to serve as a companion to Harrison’s recently introduced medical textbook. The favorable reception of the first edition was most encouraging. The consistency of style and the deliberate inclusion of 52 chapters to allow for review of one chapter a week throughout the year were particularly appealing. Subsequent to the initial publication and following the tragic and premature deaths of Dr. Lillehei, Dr. Hume, and Dr. Storer, Dr. Shires, Dr. Spencer, and I were privileged to shepherd six additional editions over the ensuing 35 years. Under the direction of Dr. F. Charles Brunicardi and his associate editors, a new vitality was infused over the three most recent editions. The ten editions, as they are considered in sequence, serve as a chronicle of the dramatic evolution that has occurred in surgery over the past half century. Those, who have been charged with providing current information to the readership, have had to filter and incorporate extraordinary and unanticipated scientific breakthroughs and technical innovations. At the time of the genesis of the first edition, success had not been achieved in cardiac, hepatic, or intestinal transplantation. Adjuvant therapy for a broad variety of malignancies was in its infancy. Minimally invasive surgery would not become a reality for two decades. On the other side of the spectrum, operative procedures that occupied the focus of symposia have slipped into obscurity. Vagotomy for peptic ulcer has become a rarity, as a consequence of an appreciation of the role of Helicobacter pylori and the efficacy of proton pump inhibitors. Surgical procedures to decompress portal hypertension in the treatment of bleeding esophagogastric varices have essentially disappeared from the operating room schedule. They have been replaced by transjugular intrahepatic portosystemic shunt (TIPS) and the liberal application of hepatic transplantation. As Bob Dylan pointed out, “The Times They Are A-changin.” And they most assuredly will continue to change, and at an unanticipated rate. The scientific basis for the practice of surgery is increasing at an ever accelerating pace, and the technologic improvements and breakthroughs are equally extraordinary. The dissemination of the expansion of knowledge has resulted in a shrinking of the globe, necessitating an extension or adaptation of the more modern approaches to underdeveloped nations and underprivileged populations. Global medicine has become a modern concern. The importance of internationalism is manifest in the clinical trials and data acquisition provided by our surgical colleagues on the other sides of the oceans that surround us. It is therefore appropriate that a more international flavor has been developed for Principles of Surgery related both to citations and contributors. A distinct consideration of global medicine and, also, the qualities of leadership in surgery that must be nurtured are evidence of the editorial credo of “maintaining modernization” and “anticipating the future.” As the editors and contributors continue to provide the most up-to-date information with a clarity that facilitates learning, it is the hope that the seed, which was planted almost a half century ago, will continue to flourish and maintain the approval of its audience. Seymour I. Schwartz, MD, FACS Distinguished Alumni Professor of Surgery University of Rochester School of Medicine and Dentistry VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Preface Each new edition of this book is approached by the editorial team with a dual vision keeping a dedicated eye affixed to the foundations of surgery while bringing into sharper focus on new and emerging elements. We are entering into a spectacular era of surgery in which the highest quality of care is merging with minimally invasive surgery, robotic surgery, the use of supercomputers, and personalized genomic surgery, all designed to improve the outcomes and quality of life for our patients. With these advances in mind, several new chapters have been added and all previous chapters have been updated with an emphasis on evidence-based, state-of-the-art surgical care. While this tried-and-true method remains the basis for upholding and maintaining the superb efforts and achievements of Dr. Seymour Schwartz and previous coeditors and contributors, this edition expands its vision to see beyond the operating theater and takes a look at the making of a surgeon as a whole, with the addition of the chapter, Fundamental Principles of Leadership Training in Surgery. Surely excellence in craft must be mastered and equal importance must also be given to the nontechnical training of what it means to be a leader of a surgical team. To this effort, the editors were keen to include as the first chapter in this edition a comprehensive review of leadership methods and ideologies as well as underscoring the importance of instituting a formal leadership-training program for residents that emphasizes mentoring. Our own paths as surgeons have been defined by the mentoring relationship and we have undoubtedly benefitted greatly from the efforts of our mentors; we sincerely hope that those with whom we have entered into this time-honored tradition have reaped the benefit as well. Simply stated, leadership skills can and should be taught to surgical trainees and in doing so this will help them improve quality of care. The editors are thankful that this text is a reliedon source for training and crafting surgeons on a global basis. This is due in large part to the extraordinary efforts of our contributors, the leaders in their fields, who not only do so to train up-and-coming surgeons, but to impart their knowledge and expertise to the benefit of patients worldwide. The recent inclusion of many international authors to the chapters within is ultimately a testament to mentorship, albeit on a broader scale, and we thank them all, both near and far. To our fellow editorial board members who have tirelessly devoted their time and knowledge to the integrity and excellence of their craft and this textbook, we extend our gratitude and thanks. We are to thankful to Brian Belval, Christie Naglieri, and all at McGraw-Hill for the continued belief in and support of this textbook. We wish to thank Katie Elsbury for her dedication to the organization and editing of this textbook. Last, we would like to thank our families who are the most important contributors of all. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ F. Charles Brunicardi, MD, FACS This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Preface to the First Edition The raison d’être for a new textbook in a discipline which has been served by standard works for many years was the Editorial Board’s initial conviction that a distinct need for a modern approach in the dissemination of surgical knowledge existed. As incoming chapters were reviewed, both the need and satisfaction became increasingly apparent and, at the completion, we felt a sense of excitement at having the opportunity to contribute to the education of modern and future students concerned with the care of surgical patients. The recent explosion of factual knowledge has emphasized the need for a presentation which would provide the student an opportunity to assimilate pertinent facts in a logical fashion. This would then permit correlation, synthesis of concepts, and eventual extrapolation to specific situations. The physiologic bases for diseases are therefore emphasized and the manifestations and diagnostic studies are considered as a reflection of pathophysiology. Therapy then becomes logical in this schema and the necessity to regurgitate facts is minimized. In appreciation of the impact which Harrison’s Principles of Internal Medicine has had, the clinical manifestations of the disease processes are considered in detail for each area. Since the operative procedure represents the one element in the therapeutic armamentarium unique to the surgeon, the indications, important technical considerations, and complications receive appropriate emphasis. While we appreciate that a textbook cannot hope to incorporate an atlas of surgical procedures, we have provided the student a single book which will satisfy the sequential demands in the care and considerations of surgical patients. The ultimate goal of the Editorial Board has been to collate a book which is deserving of the adjective “modern.” We have therefore selected as authors dynamic and active contributors to their particular fields. The au courant concept is hopefully apparent throughout the entire work and is exemplified by appropriate emphasis on diseases of modern surgical interest, such as trauma, transplantation, and the recently appreciated importance of rehabilitation. Cardiovascular surgery is presented in keeping with the exponential strides recently achieved. There are two major subdivisions to the text. In the first twelve chapters, subjects that transcend several organ systems are presented. The second portion of the book represents a consideration of specific organ systems and surgical specialties. Throughout the text, the authors have addressed themselves to a sophisticated audience, regarding the medical student as a graduate student, incorporating material generally sought after by the surgeon in training and presenting information appropriate for the continuing education of the practicing surgeon. The need for a text such as we have envisioned is great and the goal admittedly high. It is our hope that this effort fulfills the expressed demands. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Seymour I. Schwartz, MD, FACS This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Part Basic Considerations VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ I This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 1 Fundamental Principles of Leadership Training in Surgery chapter Introduction Definitions of Leadership Fundamental Principles of Leadership Amy L. Hill, James Wu, Mark D. Girgis, Danielle Hsu, Areti Tillou, James Macho, Vishad Nabili, and F. Charles Brunicardi 3 3 Vision / 3 Willingness / 4 Time Management / 7 3 Leadership Styles INTRODUCTION The field of surgery has evolved greatly from its roots, and surgical practice now requires the mastery of modern leadership principles and skills as much as the acquisition of medical knowledge and surgical technique. Historically, surgeons took sole responsibility for their patients and directed proceedings in the operating room with absolute authority, using a commandand-control style of leadership. Modern surgical practice has now evolved from single provider–based care toward a teambased approach, which requires collaborative leadership skills. Surgical care benefits from the collaboration of surgeons, anesthesiologists, internists, radiologists, pathologists, radiation oncologists, nurses, pharmacists, social workers, therapists, hospital staff, and administrators. Occupying a central role on the healthcare team, surgeons1 have the potential to improve patient outcomes, reduce medical errors, and improve patient satisfaction through their leadership of the multidisciplinary team. in the landscape of modern healthcare systems, it is 1 Thus, imperative that surgical training programs include formal instruction on leadership principles and skills to cultivate their trainees’ leadership capabilities. Many medical and surgical communities, including residency training programs, acknowledge the need for improved physician leadership.2 Surgical trainees identify leadership skills as important, but report themselves as “not competent” or “minimally competent” in this regard.2,3 While a small number of surgical training programs have implemented formal curriculum focused on teaching leadership principles, it is now imperative that all surgical training programs teach these important skills to their trainees.4,5 Interviews of academic chairpersons identified several critical leadership success factors,6 including mastery of visioning, communication, change management, emotional intelligence, team building, business skills, personnel management, and systems thinking. These chairpersons stated that the ability of emotional intelligence was “fundamental to their success and its absence the cause of their failures,” regardless of medical knowledge.6 Thus, training programs need to include leadership training to prepare trainees for success in modern healthcare delivery. In the United States, the Accreditation Council for Graduate Medical Education (ACGME) has established six Formal Leadership Training Programs in Surgery 9 Mentoring / 10 9 Conclusion 11 core competencies—patient care, medical knowledge, practicebased learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice (Table 1-1)4—that each contain principles of leadership. The ACGME has mandated the teaching of these core competencies but has not established a formal guide on how to teach the leadership skills described within the core competencies. Therefore, this chapter offers a review of fundamental principles of leadership and an introduction of the concept of a leadership training program for surgical trainees. DEFINITIONS OF LEADERSHIP Many different definitions of leadership have been described. Former First Lady Rosalynn Carter once observed that, “A leader takes people where they want to go. A great leader takes people where they don’t necessarily want to go, but where they ought to be.” Leadership does not always have to come from a position of authority. Former American president John Quincy Adams stated, “If your actions inspire others to dream more, learn more, do more, and become more, you are a leader.” Another definition is that leadership is the process of using social influence to enlist the aid and support of others in a common task.7 FUNDAMENTAL PRINCIPLES OF LEADERSHIP Clearly, leadership is a complex concept. Surgeons should strive to adopt leadership qualities that provide the best outcomes for their patients, based on the following fundamental principles. Vision The first and most fundamental principle of leadership is to establish a vision that people can live up to, thus providing direction and purpose to the constituency. Creating a vision is a declaration of the near future that inspires and conjures motivation.8 A 2 classic example of a powerful vision that held effective impact is President Kennedy’s declaration in 1961 that “. . . this nation should commit itself to achieving the goal, before this decade is out, of landing a man on the moon and returning him safely to the earth.” Following his declaration of this vision with a timeline to achieve it, the United Sates mounted a remarkable unified effort, and by the end of the decade, Neil Armstrong VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 5 Effective surgical leadership improves patient care. A fundamental principle of leadership is to provide a vision that people can live up to, thereby providing direction and purpose to the constituency. Surgical leaders have the willingness to lead through an active and passionate commitment to the vision. Surgical leaders have the willingness to commit to lifelong learning. Surgical leaders have the willingness to communicate effectively and resolve conflict. took his famous walk and the vision had been accomplished (Fig. 1-1). On a daily basis, surgeons are driven by a powerful vision: the vision that our surgical care will improve patients’ lives. The great surgical pioneers, such as Hunter, Lister (Fig. 1-2), Halsted, von Langenbeck, Billroth, Kocher (Fig. 1-3), Carrel, Gibbon, Blalock, Wangensteen, Moore, Rhoads, Huggins, Murray, Kountz, Longmire, Starzl, and DeBakey (Fig. 1-4), each possessed visions that revolutionized the field of surgery. In the nineteenth century, Joseph Lister changed the practice of surgery with his application of Pasteur’s germ theory. He set a young boy’s open compound leg fracture, a condition with a 90% mortality rate at that time, using carbolic acid dressings and aseptic surgical technique. The boy recovered, and Lister gathered nine more patients. His famous publication on the use of aseptic technique introduced the modern era of sterile technique. Emil Theodor Kocher was the first to master the thyroidectomy, thought to be an impossible operation at the time, and went on to perform thousands of thyroidectomies with a mortality of less than 1%. He was awarded the Nobel Prize in Physiology or Medicine in 1909 for describing the thyroid’s physiologic role in metabolism. Michael E. DeBakey’s powerful vision led to the development of numerous groundbreaking procedures that helped pioneer the field of cardiovascular surgery. For example, envisioning an artificial 6 7 8 9 Surgical leaders must practice effective time management. Different leadership styles are tools to use based on the team dynamic. Surgical trainees can be taught leadership principles in formal leadership training programs to enhance their ability to lead. Mentorship provides wisdom, guidance, and insight essential for the successful development of a surgical leader. artery for arterial bypass operations, Dr. DeBakey invented the Dacron graft, which has helped millions of patients suffering from vascular disease and enabled the development of endovascular surgery. Dr. Frederick Banting, the youngest recipient of the Nobel Prize in Physiology or Medicine, had a vision to discover the biochemical link between diabetes and glucose homeostasis. His vision and perseverance led to the discovery of insulin.9 In retrospect, the power and clarity of their visions were remarkable, and their willingness and dedication were inspiring. By studying their careers and accomplishments, surgical trainees can appreciate the potential impact of a welldeveloped vision. Leaders must learn to develop visions to provide direction for their team. The vision can be as straightforward as providing quality of care or as lofty as defining a new field of surgery. One can start developing their vision by brainstorming the answers to two simple questions: “Which disease needs to be cured?” and “How can it be cured?”10 The answers represent a vision and should be recorded succinctly in a laboratory notebook or journal. Committing pen to paper enables the surgical trainee to define their vision in a manner that can be shared with others. Willingness The Willingness Principle represents the active commitment of the leader toward their vision. A surgical leader must be willing Table 1-1 Accreditation Council for Graduate Medical Education core competencies Core Competency Description Patient care To be able to provide compassionate and effective healthcare in the modern-day healthcare environment Medical knowledge To effectively apply current medical knowledge in patient care and to be able to use medical tools (i.e., PubMed) to stay current in medical education Practice-based learning and improvement To critically assimilate and evaluate information in a systematic manner to improve patient care practices Interpersonal and communication skills To demonstrate sufficient communication skills that allow for efficient information exchange in physician-patient interactions and as a member of a healthcare team Professionalism To demonstrate the principles of ethical behavior (i.e., informed consent, patient confidentiality) and integrity that promote the highest level of medical care Systems-based practice To acknowledge and understand that each individual practice is part of a larger healthcare delivery system and to be able to use the system to support patient care 4 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 5 CHAPTER 1 to lead, commit to lifelong learning, communicate effectively, and resolve conflict. To Lead. A key characteristic of all great leaders is the willingness to serve as the leader. Dr. Martin Luther King, Jr., who championed the civil rights movement with a powerful vision of equality for all based on a commitment to nonviolent methods,11 did so at a time when his vocalization of this vision ensured harassment, imprisonment, and threats of violence against himself, his colleagues, and his family and friends (Fig. 1-5). King, a young, highly educated pastor, had the security of employment and family, yet was willing to accept enormous responsibility and personal risk and did so in order to lead a nation toward his vision of civil rights, for which he was awarded the Nobel Peace Prize in 1964. Steve Jobs, co-founder of Apple Inc., chose to remain in his position as chief executive officer (CEO) to pursue his vision of perfecting the personal computer at great personal expense. He described this experience as “. . . rough, really rough, the worst time in my life . . . . I would go to work at 7 a.m. and I’d get back at 9 at night, and the kids would be in bed. And I couldn’t speak, I literally couldn’t, I was so exhausted . . . . It got close Figure 1-2. Joseph Lister directing use of carbolic acid spray in one of his earliest antiseptic surgical operations, circa 1865. (Copyright Bettmann/Corbis/AP Images.) Figure 1-3. Emil Theodor Kocher. (Courtesy of the National Library of Medicine.) to killing me.”12 Both individuals demonstrated a remarkable tenacity and devotion to their vision. Willingness to lead is a necessity in any individual who desires to become a surgeon. By entering into the surgical theater, a surgeon accepts the responsibility to care for and operate on patients despite the risks and burdens involved. They do so, believing fully in the improved quality of life that can be achieved. Surgeons must embrace the responsibility of leading surgical teams that care for their patients, as well as leading surgical trainees to become future surgeons. A tremendous sacrifice is required for the opportunity to learn patient care. Surgical trainees accept the hardships of residency with its Figure 1-4. Michael E. DeBakey. (Reproduced with permission from AP Photo/David J. Phillip. © 2014 The Associated Press.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fundamental Principles of Leadership Training in Surgery Figure 1-1. Apollo 11 Lunar Module moon walk. Astronaut Edwin “Buzz” Aldrin walks by the footpad of the Apollo 11 Lunar Module, July 1969. (Reproduced with permission from AP Photo/NASA. © 2014 The Associated Press.) 6 PART I BASIC CONSIDERATIONS Figure 1-5. Dr. Martin Luther King, Jr. acknowledges the crowd at the Lincoln Memorial for his “I Have a Dream” speech during the March on Washington, D.C., August 28, 1963. (Reproduced with permission from AP Photo. © 2014 The Associated Press.) accompanying steep learning curve, anxiety, long work hours, and time spent away from family and friends. The active, passionate commitment to excellent patient care reflects a natural willingness to lead based on altruism and a sense of duty toward those receiving care. Thus, to ensure delivery of the utmost level of care, surgical trainees should commit to developing and refinleadership skills. These skills include a commitment 3 ing to lifelong learning, effective communication, and conflict resolution. To Learn. Surgeons and surgical trainees, as leaders, must possess willingness to commit to continuous learning. Modern surgery is an ever-changing field with dynamic and evolving healthcare systems and constant scientific discovery and innovation. Basic and translational science relating to surgical care is growing at an exponential rate. The sequencing of the human genome and the enormous advances in molecular biology and signaling pathways are leading to the transformation of personalized medicine and surgery in the twenty-first century (see Chap. 15).13 Performing prophylactic mastectomies with immediate reconstruction for BRCA1 mutations and thyroidectomies with thyroid hormone replacement for RET proto-oncogene mutations are two of many examples of genomic information guiding surgical care. Technologic advances in minimally invasive surgery and robotic surgery as well as electronic records and other information technologies are revolutionizing the craft of surgery. The expansion of minimally invasive and endovascular surgery over the past three decades required surgeons to retrain in new techniques using new skills and equipment. In this short time span, laparoscopy and endovascular operations are now recognized as the standard of care for many surgical diseases, resulting in shorter hospital stay, quicker recovery, and a kinder and gentler manner of practicing surgery. Remarkably, during the last century, the field of surgery has progressed at an exponential pace and will continue to do so with the advent of using genomic analyses to guide personalized surgery, which will transform the field of surgery this century. Therefore, surgical leadership training should emphasize and facilitate the continual pursuit of knowledge. Fortunately, surgical organizations and societies provide surgeons and surgical trainees a means to acquire new knowledge on a continuous basis. There are numerous local, regional, national, and international meetings of surgical organizations that provide ongoing continuing medical education credits, also required for the renewal of most medical licenses. The American Board of Surgery requires all surgeons to complete meaningful continuing medical education to maintain certification.14 These societies and regulatory bodies enable surgeons and surgical trainees to commit to continual learning, and ensure their competence in a dynamic and rapidly 4 growing field. Surgeons and trainees now benefit from the rapid expansion of web-based education as well as mobile handheld technology. These are powerful tools to minimize nonproductive time in the hospital and make learning and reinforcement of medical knowledge accessible. Currently web-based resources provide quick access to a vast collection of surgical texts, literature, and surgical videos. Surgeons and trainees dedicated to continual learning should be well versed in the utilization of these information technologies to maximize their education. The next evolution of electronic surgical educational materials will likely include simulation training similar to laparoscopic and Da Vinci device training modules. The ACGME, acknowledging the importance of lifelong learning skills and modernization of information delivery and access methods, has included them as program requirements for residency accreditation. To Communicate Effectively. The complexity of modern healthcare delivery systems requires a higher level and collaborative style of communication. Effective communication directly impacts patient care. In 2000, the U.S. Institute of Medicine published a work titled, To Err Is Human: Building a Safer Health System, which raised awareness concerning the magnitude of medical errors. This work showcased medical errors as the eighth leading cause of death in the United States with an estimated 100,000 deaths annually.15 Subsequent studies examining medical errors have identified communication errors as one of the most common causes of medical error.16,17 In fact, the Joint Commission identifies miscommunication as the leading cause of sentinel events. Information transfer and communication errors cause delays in patient care, waste surgeon and staff time, and cause serious adverse patient events.18 Effective communication between surgeons, nurses, ancillary staff, and patients is not only a crucial element to improved patient outcomes, but it also leads to less medical litigation.19-21 A strong correlation exists between communication and 5 patient outcomes. Establishing a collaborative atmosphere is important since communication errors leading to medical mishaps are not simply failures to transmit information. Communication errors “are far more complex and relate to hierarchical differences, concerns VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Time Management It is important for leaders to practice effective time management. Time is the most precious resource, as it cannot be bought, saved, or stored. Thus, management of time is essential for a productive and balanced life for those in the organization. The effective use of one’s time is best done through a formal time management program to improve one’s ability to lead by setting priorities and making choices to achieve goals. The efficient use of one’s time helps to improve both productivity and quality of life. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 7 Fundamental Principles of Leadership Training in Surgery To Resolve Conflict. Great leaders are able to achieve their vision through their ability to resolve conflict. During the pursuit of any vision, numerous conflicts arise on a daily basis; numerous conflicts arise on a daily basis when surgeons and surgical trainees provide high-quality care. Therefore, the techniques for conflict resolution are essential for surgical leaders. To properly use conflict resolution techniques, it is important for the surgeon and surgical trainee to always remain objective and seek personal flexibility and self-awareness. The gulf between self-perception and the perception of others can be profound; in a study of cooperation and collaboration among operating room staff, the quality of their own collaboration was rated at 80% by surgeons, yet was rated at only 48% by operating room nurses.26 Systematic inclusion of modern conflict resolution methods that incorporate the views of all members of a multidisciplinary team help maintain objectivity. Reflection is often overlooked in surgical residency training but is a critical component of learning conflict resolution skills. Introspection allows the surgeon to understand the impact of his or her actions and biases. Objectivity is the basis of effective conflict resolution, which can improve satisfaction among team members and help deliver optimal patient care. Modern conflict resolution techniques are based on objectivity, willingness to listen, and pursuit of principlebased solutions.27 For example, an effective style of conflict resolution is the utilization of the “abundance mentality” model, which attempts to achieve a solution that benefits all involved and is based on core values of the organization, as opposed to the utilization of the traditional fault-finding model, which identifies sides as right or wrong.28 Application of the abundance mentality in surgery elevates the conflict above the affected parties and focuses on the higher unifying goal of improved patient care. Morbidity and mortality (M&M) conferences are managed in this style and have the purpose of practice improvement and improving overall quality of care within the system, as opposed to placing guilt or blame on the surgeon or surgical trainees for the complication being reviewed. The traditional style of command-and-control technique based on fear and intimidation is no longer welcome in any healthcare system and can lead to sanctions, lawsuits, and removal of hospital privileges or position of leadership. Another intuitive method that can help surgical trainees learn to resolve conflict is the “history and physical” model of conflict resolution. This model is based on the seven steps of caring for a surgical patient that are well known to the surgical trainee.29 (1) The “history” is the equivalent of gathering subjective information from involved parties with appropriate empathy and listening. (2) The “laboratory/studies” are the equivalent of collecting objective data to validate the subjective information. (3) A “differential diagnosis” is formed of possible root causes of the conflict. (4) The “assessment/plan” is developed in the best interest of all involved parties. The plan, including risks and benefits, is openly discussed in a compassionate style of communication. (5) “Preoperative preparation” includes the acquisition of appropriate consultations for clearances, consideration of equipment and supplies needed for implementation, and the “informed consent” from the involved parties. (6) The “operation” is the actual implementation of the agreed-upon plan, including a time-out. (7) “Postoperative care” involves communicating the operative outcome, regular postoperative follow-up, and the correction of any complications that arise. This seven-step method is an example of an objective, respectful method of conflict resolution. Practicing different styles of conflict resolution and effective communication in front of the entire group of surgical trainees attending the leadership training program is an effective means of teaching conflict resolution techniques. CHAPTER 1 with upward influence, conflicting roles and role ambiguity, and interpersonal power and conflict.”17,22 Errors frequently originate from perceived limited channels of communication and hostile, critical environments. To overcome these barriers, surgeons and surgical trainees should learn to communicate in an open, universally understood manner and remain receptive to any team member’s concerns. A survey of physicians, nurses, and ancillary staff identified effective communication as a key element of a successful leader.23 As leaders, surgeons and surgical trainees who facilitate an open, effective, collaborative style of communication reduce errors and enhance patient care. A prime example is that successful communication of daily goals of patient care from the team leader improves patient outcomes. In one recent study, the modest act of explicitly stating daily goals in a standardized fashion significantly reduced patient length of intensive care unit stay and increased resident and nurse understanding of goals of care.24 Implementing standardized daily team briefings in the wards and preoperative units led to improvements in staff turnover rates, employee satisfaction, and prevention of wrong site surgery.22 In cardiac surgery, improving communication in the operating room and transition to the postanesthesia care unit was an area identified to decrease risk for adverse outcomes.25 Behaviors associated with ineffective communication, including absence from the operating room when needed, playing loud music, making inappropriate comments, and talking to others in a raised voice or a condescending tone, were identified as patient hazards; conversely, behaviors associated with effective collaborative communication, such as time outs, repeat backs, callouts, and confirmations, resulted in improved patient outcomes. One model to ensure open communication is through standardization of established protocols. A commonly accepted protocol is the “Time Out” that is now required in the modern operating room. During the Time Out protocol, all team members introduce themselves and state a body of critical information needed to safely complete the intended operation. This same standardization can be taught outside the operating room. Within the Kaiser system, certain phrases have been given a universal meaning: “I need you now” by members of the team is an understood level of urgency and generates a prompt physician response 100% of the time.22 As mentioned earlier, standardized forms can be useful tools in ensuring universally understood communication during sign-out. The beneficial effect of standardized communication further demonstrates how effective communication can improve patient care and is considered a vital leadership skill. 8 Time-Motion Study High service 0 High education 0 High education 10 5 PART I Category 4 Category 2 Low education, low service value High education, low Eg.) Waiting during mandatory in-house call service value Eg.) Teaching conferences 5 BASIC CONSIDERATIONS High service Category 3 Category 1 Low education, high service value High education, high service value Eg.) Performing H & Ps Eg.) Operating room 10 It is important for surgeons and surgical trainees to learn and use a formal time management program. There are demands placed on surgeons and surgi6 ever-increasing cal trainees to deliver the highest quality care in highly regulated environments. Furthermore, strict regulations on limitation of work hours demand surgical trainees learn patient care in a limited amount of time.30 All told, these demands are enormously stressful and can lead to burnout, drug and alcohol abuse, and poor performance.30 A time-motion study of general surgery trainees analyzed residents’ self-reported time logs to determine resident time expenditure on educational/ service-related activities (Fig. 1-6).31 Surprisingly, senior residents were noted to spend 13.5% of their time on low-service, low-educational value activities. This time, properly managed, could be used to either reduce work hours or improve educational efficiency in the context of new work hour restrictions. It is therefore critical that time be used wisely on effectively achieving one’s goals. Parkinson’s law, proposed in 1955 by the U.K. political analyst and historian Cyril Northcote Parkinson, states that work expands to fill the time available for its completion, thus leading individuals to spend the majority of their time on insignificant tasks.32 Pareto’s 80/20 principle states that 80% of goals are achieved by 20% of effort and that achieving the final 20% requires 80% of their effort. Therefore, proper planning of undertaking any goal needs to include an analysis of how much effort will be needed to complete the task.32 Formal time management programs help surgeons and surgical trainees better understand how their time is spent, enabling them to increase productivity and achieve a better balanced lifestyle. Various time allocation techniques have been described.32 A frequently used basic technique is the “prioritized list,” also known as the ABC technique. Individuals list and assign relative values to their tasks. The use of the lists and categories serves solely as a reminder, thus falling short of aiding the user in allocating time wisely. Another technique is the “time management matrix technique.”28 This technique plots activities on two axes: importance and urgency, yielding four quadrants (Fig. 1-7). Congruous with the Pareto’s 80/20 principle and Parkinson’s law, the time management matrix technique channels efforts into quadrant II (important but nonurgent) activities. The activities in this quadrant are high yield and include planning, creative activity, building relationships, and maintaining productivity. Too often, surgeons spend a majority of their time attending to Figure 1-6. Surgery resident time-motion study. H & P = history and physical examination. quadrant I (important and urgent) tasks. Quadrant I tasks include emergencies and unplanned or disorganized situations that require intensive and often inefficient effort. While most surgeons and surgical trainees have to deal with emergencies, they often develop the habit of inappropriately assigning activities into quadrant I; excess time spent on quadrant I tasks leads to stress or burnout for the surgeon and distracts from long-term goals. Efficient time management allows surgeons and surgical trainees to be proactive about shifting energy from quadrant I tasks to quadrant II, emphasizing preplanning and creativity over always attending to the most salient issue at hand, depending on the importance and not the urgency. Finally, “the six areas of interest” is an alternative effective time management model that can help surgeons and surgical trainees achieve their goals, live a better balanced lifestyle, and improve the quality of their lives.32 The process begins by performing a time-motion study in which the activities of 6-hour increments of time over a routine week are chronicled. At the end of the week, the list of activities is analyzed to determine how the 168 hours in 1 week have been spent. The surgical trainee then selects six broad categories of areas of interest (i.e., family, clinical care, education, health, community service, hobbies, etc.), and sets a single activity goal in each category every day and monitors whether those goals are achieved. This technique is straightforward and improves one’s quality of life by setting and achieving a balanced set of goals of personal interest, while eliminating time-wasting activities. A formal time management program is essential for modern leadership. The practice and use of time management strategies can help surgeons and surgical trainees achieve and maintain their goals of excellent clinical care for their patients, while maintaining a more balanced lifestyle. Time Management Matrix Important Quadrant I Quadrant II Non-important Quadrant III Quadrant IV Urgent Non-urgent Figure 1-7. Time management. (From Covey S. The Seven Habits of Highly Effective People. New York: Simon & Schuster; 1989.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ LEADERSHIP STYLES Since it has been shown that effective leadership can improve patient outcomes, leadership principles and skills should be taught to surgical trainees using formal leadership training programs. The importance of teaching leadership skills is reflected by the ACGME mandated core competencies (see Table 1-1). However, surgical trainees, most notably chief residents, find themselves in various leadership roles without ever having experienced formalized leadership training, which has been shown to result in a self-perceived lack of leadership ability.23 When surveyed on 18 core leadership skills (Table 1-2), 92% of residents rated all 18 skills as important, but over half rated themselves as “minimally” or “not competent” in 10 out of 18 skills.2 It has been documented that trainees are requesting leadership training and wish to close the gap between perceived need for training and the implementation of formal leadership training programs.34–37 A number of leadership workshops have been created. Extracurricular leadership programs have been designed mostly for physicians with an MBA or management background but have not been incorporated into the core residency training program.38 Also, there are many institutions that have published experiences with leadership retreats or seminars for residents or young physicians.39–42 The ACGME hosts multiple leadership skills workshops for chief residents, mostly targeted toward pediatricians, family practitioners, and psychiatrists.43 Similarly, the American College of Surgeons leads an annual 3-day leadership conference focusing on leadership attributes, consensus development, team building, conflict resolution, and translation of leadership principles into clinical practice.44 These programs were all received well by participants and represent a call for a formal leadership program for all surgical trainees. An innovative leadership curriculum first implemented in 1999 taught general surgery trainees collaborative leadership skills, at a time when the traditional command-and-control leadership style predominated.45 Surgical residents participated in 18-hour-long modules based on the leadership principles and skills listed in Table 1-2, taught by the surgical faculty. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fundamental Principles of Leadership Training in Surgery FORMAL LEADERSHIP TRAINING PROGRAMS IN SURGERY 9 CHAPTER 1 The principles of leadership can be practiced in a variety of styles. Just as there are many definitions of leadership, many classifications of styles exist as well. A landmark study by Daniel Goleman in Harvard Business Review identified six distinct leadership styles, based on different components of emotional intelligence.33 Emotional intelligence is the ability to recognize, understand, and control the emotions in others and ourselves. By learning different styles, surgeons and trainees can recognize their own leadership style and the effect on the team dynamic. Furthermore, it teaches when the situation may demand change in style for the best outcome. The six leadership styles identified are Coercive, Authoritative, Affiliative, Democratic, Pacesetting, and Coaching. The Coercive leader demands immediate compliance. This style reflects the command and control style that has historically dominated surgery. Excessive coercive leadership erodes team members’ sense of responsibility, motivation, sense of participation in a shared vision, and ultimately, performance. However, it is effective in times of crisis to deliver clear, concise instruction. This style should be used sparingly and is best suited for emergencies. The Authoritative leader embodies the phrase “Come with me,” focusing on mobilizing the team toward a common, grand vision. This type of leader allows the team freedom to innovate, experiment, and devise its own means. Goleman’s research indicates this style is often the most effective. These leaders display self-confidence, empathy, and proficiency in initiating new ideas and leading people in a new direction. This is best used when a shift in paradigm is needed. The Affiliative leader creates harmony and builds emotional bonds. This requires employment of empathy, building relationships, and emphasis on communication. An affiliative leader frequently gives positive feedback. This style can allow poor performance to go uncorrected if too little constructive/ critical advice is given. Affiliative leadership is most useful when motivating people during stressful circumstances or healing rifts in a team. The Coaching style of leadership focuses on developing people for the future. Coaching is leadership through mentorship. The coach gives team members challenging tasks, counsels, encourages, and delegates. Unlike the affiliative leader who focuses on positive feedback, the coach helps people identify their weaknesses and improve their performance, and ties their work into their long-term career aspirations. This leadership style builds team capabilities by helping motivated learners improve. However, this style does not work well when team members are defiant and unwilling to change or learn, or if the leader lacks proficiency. The Democratic leader forges consensus through participation. This leadership style listens to and values each member’s input. It is not the best choice in an emergency situation, when time is limited, or when teammates cannot contribute informed guidance to the leader. It can also be exasperating if a clear vision does not arise from the collaborative process. This style is most appropriate when it is important to obtain team consensus, quell conflict, or create harmony. The Pacesetter leader sets high standards for performance and exemplifies them. These leaders identify poor performers and demand more from them. However, unlike the coach, the pacesetter does not build the skills of those who are not keeping up. Rather, a pacesetter will either take over the task himself or delegate the task to another team member. This leadership style works well when it is important to obtain high-quality results and there is a motivated, capable team. However, pacesetters can easily become micromanagers who have difficulty delegating tasks to team members, which leads to burn out on the part of the leader. Additionally, team members can feel overwhelmed and demoralized by the demands for excellence without an empathic counter balance. Each of the above styles of leadership has strengths and weakness. Importantly, leaders who are the most successful do not rely only on one leadership style alone. They use several of them seamlessly depending on the situation and the team 7 members at hand. Therefore, the more styles a leader has mastered, the better, with particular emphasis on the Authoritative, Affiliative, Democratic, and Coaching styles. Each leadership style is a tool that is ultimately employed to guide a team to realizing a vision or goal. Thus, leadership training programs should teach the proper use of all leadership styles while adhering to the principles of leadership. 10 be taught to surgical trainees, and there are many validated tools 8 to measure outcomes. Table 1-2 18 leadership training modules PART I BASIC CONSIDERATIONS Importance Mean Score Competence Mean Score Academic program development 3.2 2.4* Leadership training 3.8 2.3* Leadership theory 3.2 2.1* Effective communication 3.7 2.7* Conflict resolution 3.8 3* Management principles 3.7 2.7* Negotiation 3.7 2.8* Time management 4 2.8* Private or academic practice, managed care 3.6 2* Investment principles 3.5 2.2* Ethics 3.6 3.2 Billing, coding, and compliance 3.5 1.7* Program improvement 3 2* Writing proposals 3.3 2.2* Writing reports 3.4 2.4* Public speaking 3.7 2.7* Effective presentations 3.7 2.7* Risk management 3.5 2.1* Total 3.6 2.5* Skills Source: Reprinted with permission from Itani KMF, Liscum K, Brunicardi FC. Physician leadership is a new mandate in surgical training. Am J Surg. 2004;187:328-331. © Copyright Elsevier. * P<0.001 by Student t test between mean importance and mean competence scores. A number of leadership techniques, including time management techniques and applied conflict resolution techniques described earlier, were designed and implemented as part of this leadership training program. Within 6 months of implementation, residents’ self-perceived total commitment to the highest personal and professional standards, communication skills, visualization of clear missions of patient care, and leadership of others toward that mission increased significantly.45 Remarkably, the positive impact of this leadership curriculum was significant when measured using tools, such as the Multifactor Leadership Questionnaire (MLQ), social skills inventory, personality inventory, and internal strength scorecard.2,37,45-47 The MLQ is a well-validated instrument that objectively quantifies leadership beliefs and self-perceived outcomes across medical and nonmedical disciplines. Based on the MLQ, surgical residents more often use a passive-avoidant style of leadership that emphasizes taking corrective action only after a problem is “significant and obvious.”37 This tool can also be used to track progress toward more effective, collaborative styles of leadership. These studies demonstrated the ability to measure leadership behavior of surgical trainees in a standardized, quantifiable format.2,37,45-47 Taken together, these studies support the concept that leadership skills can and should Mentoring A formal leadership training program for surgical trainees should include mentoring. Mentoring is the active process by which an experienced, empathetic person guides another individual in the development and self-recognition of their own vision, learning, core competencies, and professional development. Halstead established the concept of a surgical mentor who directly provided the trainees with professional and technical guidance. Halstead’s concept went beyond a simple preceptorship by emphasizing clinical decision making based on scientific evidence. His goal was to develop surgeons who would go on to become outstanding leaders and innovators in the field. Although surgery has changed dramatically since Halstead’s era, mentorship remains crucial in surgical training. In addition to teaching technical skills, clinical judgment, and scientific inquiry, modern-day mentors must also model effective communication, empathy, humanism, and the prioritization of competing professional and personal activities. The mentor must also be an experienced and trusted advisor committed to the success of the mentee. A greater level of trust and commitment distinguishes the mentor from the teacher. More than a teacher, a mentor is a coach. The goal of a teacher is to pass on a defined level of knowledge for each stage of a student’s education. The underlying premise is a limited level of advancement for the student. The coach, on the other hand, has the sole purpose to make his or her student the best at their game with an unlimited level of advancement. Modern mentorship implies a partnership between the mentor and the mentee. Surgical residency program chairs and program directors must recruit and develop faculty “coaches” to mentor residents to optimize their potential. Emeritus Chair of University of California, Los Angeles Head and Neck Surgery, Dr. Paul Ward, said it best: “We strive to produce graduates of our residency program who are among those who change the way we think and practice . . . .” Having more than 25 former residents become chairs of academic head and neck surgical programs, Dr. Ward embodied the role as a surgeon’s coach. The responsibilities of an effective mentor are summarized by Barondess: “Mentoring, to be effective, requires of the mentor empathy, maturity, selfconfidence, resourcefulness, and willingness to commit time and energy to another. The mentor must be able to offer guidance for a new and evolving professional life, to stimulate and challenge, to encourage self-realization, to foster growth, and to make more comprehensible the landscape in which the protégé stands.”48 One of the major goals of a mentor is to assess the aptitudes and abilities of the mentee with regard to the appropriateness of their vision for their surgical career. Proper selection of the appropriate mentor can bring to the mentee much needed wisdom, guidance, and resources and can expand the scope of their vision. In addition, the mentor can refine the leadership 9 skills taught to their mentees in formal training programs. Highly successful surgeons most often have had excellent surgical mentors. It is impressive to note that more than 50% of United States Nobel laureates have served under other Nobel laureates in the capacity of student, postdoctoral fellow, or junior collaborator.49 In academic medicine, evidence-based studies have shown benefits to the mentees that include enhanced VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Although there are several definitions of leadership and a variety of leadership styles, all end with the common goal of improving patient care in the modern era. All forms of leadership require a vision and willingness—the willingness to assume the responsibility to lead, continue learning, practice effective communication styles, and resolve conflict. Effective leadership can change surgical departments and improve patient care through innovation. A growing body of evidence suggests the mastery of leadership requires practice through intentional curriculum and reinforcement through mentorship. Surgical leadership is bred through its training programs. Thus, innovation in surgical training programs is needed to enhance the development of leadership skills of surgical trainees, to prepare them for practice in modern healthcare systems, and to optimize patient care, as well as compliance with requirements set forth by regulatory institutions governing surgery and surgical education. A growing body of literature supports the value of effective leadership in improving patient care, productivity, and the work environment while it validates the ability to measure the impact of leadership training. Therefore, it is of paramount importance to teach modern leadership principles and skills to surgical trainees in order to create a new generation of surgeon leaders who will shape the modern era of surgery in the context of rapidly evolving science, technology, and systems of healthcare delivery. REFERENCES Entries highlighted in blue are key references. 1. Levinson W, Chaumeton N. Communication between surgeons and patients in routine office visits. Surgery. 1999;125:127-134. 2. Itani KM, Liscum K, Brunicardi FC. Physician leadership is a new mandate in surgical training. Am J Surg. 2004; 187:328-331. 3. Jensen AR, Wright A, Lance A, et al. The emotional intelligence of surgical residents: a descriptive study. Am J Surg. 2008;195:5-10. 4. Lee L, Brunicardi FC, Scott BG, et al. Impact of a novel education curriculum on surgical training within an academic training program. J Surg Res. 2008;145:308-312. 5. Larkin AC, Cahan MA, Whalen G, et al. Human Emotion and Response in Surgery (HEARS): a simulation-based curriculum for communication skills, systems-based practice, and professionalism in surgical residency training. J Am Coll Surg. 2010;211:285-292. 6. Lobas JG. Leadership in academic medicine: capabilities and conditions for organizational success. Am J Med. 2006;119: 617-621. 7. Chemers MM. An Integrative Theory of Leadership. Mahwah, NJ: Lawrence Erlbaum Associates; 1997:200. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 11 Fundamental Principles of Leadership Training in Surgery CONCLUSION 8. Slap S. Bury My Heart at Conference Room B: The Unbeatable Impact of Truly Committed Managers. New York, NY: Portfolio Penguin; 2010:234. 9. NobelPrize.org. Frederick G. Banting: Biography. Available at: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1923/banting-bio.html. Accessed June 23, 2013. 10. Brunicardi FC. Presidential Address. Academic program development. J Surg Res. 1999;83(1):1-6. 11. Brunicardi FC, Cotton R, Cole G, et al. The leadership principles of Dr. Martin Luther King, Jr. and their relevance to surgery. J Natl Med Assoc. 2007;99:7-14. 12. Isaacson W. Steve Jobs. New York, NY: Simon & Schuster; 2011. 13. Brunicardi FC, Gibbs R, Wheeler D, et al. Overview of the development of personalized genomic medicine and surgery. World J Surg. 2011;35:1693-1699. 14. American Board of Surgery CME Requirements for Recertification. Available at: http://www.absurgery.org/default.jsp? newscontinuingmedicaledrequirements. Accessed October 2, 2013. 15. Kohn LT, Corrigan J, Donaldson MS. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000. 16. Gawande AA, Zinner MJ, Studdert DM, et al. Analysis of errors reported by surgeons at three teaching hospitals. Surgery. 2003;133:614-621. 17. Sutcliffe KM, Lewton E, Rosenthal MM. Communication failures: an insidious contributor to medical mishaps. Acad Med. 2004;79:186-194. 18. Williams RG, Silverman R, Schwind C, et al. Surgeon information transfer and communication: factors affecting quality and efficiency of inpatient care. Ann Surg. 2007;245:159-169. 19. Ambady N, Laplante D, Nguyen T, et al. Surgeons’ tone of voice: a clue to malpractice history. Surgery. 2002;132:5-9. 20. Nolin CE. Malpractice claims, patient communication, and critical paths: a lawyer’s perspective. Qual Manag Health Care. 1995;3:65-70. 21. Stewart MA. Effective physician-patient communication and health outcomes: a review. CMAJ. 1995;152:1423-1433. 22. Leonard M. The human factor: the critical importance of effective teamwork and communication in providing safe care. Qual Safe Health Care. 2004;13(Suppl 1):i85-i90. 23. Dine CJ, Kahn JM, Abella BS, et al. Key elements of clinical physician leadership at an academic medical center. J Grad Med Educ. 2011;3:31-36. 24. Pronovost P, Berenholtz S, Dorman T, et al. Improving communication in the ICU using daily goals. J Crit Care. 2003;18:71-75. 25. Gurses AP, Kim G, Martinez E, et al. Identifying and categorising patient safety hazards in cardiovascular operating rooms using an interdisciplinary approach: a multisite study. BMJ Qual Saf. 2012;21:810-818. 26. Makary MA, Sexton JB, Freischlag JA, et al. Operating room teamwork among physicians and nurses: teamwork in the eye of the beholder. J Am Coll Surg. 2006;202:746-752. 27. Weeks D. The Eight Essential Steps to Conflict Resolution: Preserving Relationships at Work, at Home, and in the Community. New York, NY: J.P. Tarcher/Perigee; 1994:290. 28. Covey SR. The Seven Habits of Highly Effective People: Restoring the Character Ethic. New York, NY: Free Press; 2004. 29. Lee L, Berger DH, Awad SS, et al. Conflict resolution: practical principles for surgeons. World J Surg. 2008;32:2331-2335. 30. Antiel RM, Reed DA, Van Arendonk KJ, et al. Effects of duty hour restrictions on core competencies, education, quality of life, and burnout among general surgery interns. JAMA Surg. 2013;148:448-455. 31. Lyssa Ochoa M. Evaluation of resident training activities using a novel time-motion study prior to the implementation of the 80 hour work week. Chicago, IL: American College of Surgeons Annual Conference, 2006. CHAPTER 1 research productivity, higher likelihood of obtaining research grants, and greater success in obtaining desired positions in practice or at academic institutions.50 Mentoring provides benefits to the mentors themselves, including refinement of their own personal leadership skills and a strong sense of satisfaction and accomplishment. Mentorship is essential to accomplish the successful development of surgical trainees and to help cultivate their vision. Therefore, formal leadership training programs that have a goal of training the future leaders in surgery should include mentoring. 12 PART I BASIC CONSIDERATIONS 32. Brunicardi FC, Hobson FL. Time management: a review for physicians. J Natl Med Assoc. 1996;88:581-587. 33. Goleman D. Leadership that gets results. Harvard Business Review. 2000;78:78-93. 34. Xirasagar S, Samuels ME, Stoskopf CH. Physician leadership styles and effectiveness: an empirical study. Med Care Res Rev. 2005;62:720-740. 35. Baird DS, Soldanska M, Anderson B, et al. Current leadership training in dermatology residency programs: a survey. J Am Acad Dermatol. 2012;66:622-625. 36. Kiesau CD, Heim KA, Parekh SG. Leadership and business education in orthopaedic residency training programs. J Surg Orthop Adv. 2011;20:117-121. 37. Horwitz IB, Horwitz S, Daram P, et al. Transformational, transactional, and passive-avoidant leadership characteristics of a surgical resident cohort: analysis using the multifactor leadership questionnaire and implications for improving surgical education curriculums. J Surg Res. 2008;148:49-59. 38. Ackerly DC, Sangvai DG, Udayakumar K, et al. Training the next generation of physician-executives: an innovative residency pathway in management and leadership. Acad Med. 2011;86:575-579. 39. Stoller JK, Rose M, Lee R, et al. Teambuilding and leadership training in an internal medicine residency training program. J Gen Intern Med. 2004;19:692-697. 40. Hanna WC, Mulder D, Fried G, et al. Training future surgeons for management roles: the resident-surgeon-manager conference. Arch Surg. 2012;147:940-944. 41. Boulanger B, Buencamino A, Dovichi S. Training young pediatricians as leaders. Pediatrics. 2005;116:518. 42. Leslie LK, Miotto MB, Liu GC, et al. Training young pediatricians as leaders for the 21st century. Pediatrics. 2005;115: 765-773. 43. Accreditation Council for Graduate Medical Education. Leadership Skills for Chief Residents. Available at: http://www. acgme.org/acgmeweb/. Accessed January 1, 2014. 44. American College of Surgeons. Surgeons as leaders: from operating room to boardroom. Available at: http://www.facs.org/ education/surgeonsasleaders.html. Accessed January 1, 2014. 45. Awad SS, Hayley B, Fagan SP, et al. The impact of a novel resident leadership training curriculum. Am J Surg. 2004;188: 481-484. 46. Horwitz IB, Horwitz S, Brandt M, et al. Assessment of communication skills of surgical residents using the Social Skills Inventory. Am J Surg. 2007;194:401-405. 47. Horwitz IB, Horwitz S, Brunicardi F, et al. Improving comprehensive surgical resident training through use of the NEO Five-Factor Personality Inventory: results from a cohort-based trial. Am J Surg. 2011;201:828-834. 48. Barondess JA. On mentoring. J R Soc Med. 1997;90:347-349. 49. Zuckerman H. Scientific Elite: Nobel Laureates in the United States. New York, NY: Free Press; 1977:335. 50. Sambunjak D, Straus SE, Marusic A. Mentoring in academic medicine: a systematic review. JAMA. 2006;296:1103-1115. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 2 Systemic Response to Injury and Metabolic Support chapter Siobhan A. Corbett* Overview: Injury-Associated Systemic Inflammatory Response 13 The Detection of Cellular Injury 14 The Detection of Injury is Mediated by Members of the Damage-Associated Molecular Pattern Family / 14 DAMPs Are Ligands for Pattern Recognition Receptors / 16 Pattern Recognition Receptor Signaling: Toll-Like Receptors and the Inflammasome / 18 Central Nervous System Regulation of Inflammation in Response to Injury Transcriptional and Translational Regulation of the Injury Response 36 18 Neuroendocrine Response to Injury / 19 The Cellular Stress Responses 23 Reactive Oxygen Species and the Oxidative Stress Response / 23 The Heat Shock Response / 23 The Unfolded Protein Response / 23 Autophagy / 24 Apoptosis / 24 Necroptosis / 25 Mediators of Inflammation Transcriptional Events Following Blunt Trauma / 36 Transcriptional Regulation of Gene Expression / 36 Epigenetic Regulation of Transcription / 37 Translation Regulation of Inflammatory Gene Expression / 38 Cell-Mediated Inflammatory Response 26 Cytokines / 26 Eicosanoids / 31 Plasma Contact System / 33 Serotonin / 33 Histamine / 34 Cellular Response to Injury Cytokine Receptor Families and Their Signaling Pathways / 34 JAK-STAT Signaling / 34 Suppressors of Cytokine Signaling / 35 Chemokine Receptors Are Members of the G-Protein–Coupled Receptor Family / 35 Tumor Necrosis Factor Superfamily / 36 Transforming Growth Factor-β Family of Receptors / 36 Endothelium-Mediated Injury 34 38 Platelets / 38 Lymphocytes and T-Cell Immunity / 38 Dendritic Cells/ 39 Eosinophils / 39 Mast Cells / 39 Monocyte/Macrophages / 39 Neutrophils / 40 40 Vascular Endothelium / 40 Neutrophil-Endothelium Interaction / 40 OVERVIEW: INJURY-ASSOCIATED SYSTEMIC INFLAMMATORY RESPONSE The inflammatory response to injury or infection occurs as a consequence of the local or systemic release of “pathogenassociated” or “damage-associated” molecules, which use similar signaling pathways to mobilize the necessary resources required for the restoration of homeostasis. Minor host insults result in a localized inflammatory response that is transient and in most cases beneficial. Major host insults, however, may lead to amplified reactions, resulting in systemic inflammation, remote organ damage, and multiple organ failure in as many as 30% of those who are severely injured. Recent data support Chemokines / 40 Nitric Oxide / 41 Prostacyclin / 42 Endothelins / 42 Platelet-Activating Factor / 43 Natriuretic Peptides / 43 Surgical Metabolism 43 Metabolism during Fasting / 44 Metabolism after Injury / 46 Lipid Metabolism after Injury / 46 Ketogenesis / 47 Carbohydrate Metabolism / 48 Protein and Amino Acid Metabolism / 50 Nutrition in the Surgical Patient 50 Estimation of Energy Requirements / 51 Vitamins and Minerals / 51 Overfeeding / 52 Enteral Nutrition 52 Rationale for Enteral Nutrition / 52 Hypocaloric Enteral Nutrition / 53 Enteral Formulas / 53 Access for Enteral Nutritional Support / 55 Parenteral Nutrition 56 Rationale for Parenteral Nutrition / 56 Total Parenteral Nutrition / 57 Peripheral Parenteral Nutrition / 57 Initiation of Parenteral Nutrition / 58 Complications of Parenteral Nutrition / 58 this idea and suggest that severely injured patients who are destined to die from their injuries differ from survivors only in the degree and duration of their dysregulated acute inflammatory response.1,2 This topic is highly relevant because systemic inflammation is a central feature3 of both sepsis and severe trauma. Understanding the complex pathways that regulate local and systemic inflammation is necessary to develop therapies to intervene during overwhelming sepsis or after severe injury. Sepsis, defined by a systemic inflammatory response to infection, is a disease process with an incidence of over 900,000 cases per year. Further, trauma is the leading cause of mortality and morbidity for individuals under age 45. *This chapter is dedicated to its previous author, Dr. Stephen Lowry, my mentor and friend. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 Endogenous damage-associated molecular patterns (DAMPs) are produced following tissue and cellular injury. These molecules interact with immune and nonimmune cell receptors to initiate a “sterile” systemic inflammatory response following severe traumatic injury. In many cases, DAMP molecules are sensed by pattern recognition receptors (PRRs), which are the same receptors that cells use to sense invading pathogens. This explains, in part, the similar clinical picture of systemic inflammation observed in injured and/or septic patients. The central nervous system receives information with regard to injury-induced inflammation via soluble mediators as well as direct neural projections that transmit information to regulatory areas in the brain. The resulting neuroendocrine reflex plays an important modulatory role in the immune response. In this chapter, we will review what is known about the soluble and cellular effectors of the injury-induced inflammatory response; how the signals are sensed, transduced, and modulated; and how their dysregulation is associated with immune suppression. We will also discuss how these events are monitored and regulated by the central nervous system. Finally, we will review how injury reprograms cellular metabolism, in an attempt to mobilize energy and structural stores to meet the challenge of restoring homeostasis. 5 6 7 Inflammatory signals activate key cellular stress responses (the oxidative stress response, the heat shock protein response, the unfolded protein response, autophagy, and programmed cell death), which serve to mobilize cellular defenses and resources in an attempt to restore homeostasis. The cells, mediators, signaling mechanisms, and pathways that compose and regulate the systemic inflammatory response are closely networked and tightly regulated by transcriptional events as well as by epigenetic mechanisms, posttranslational modification, and microRNA synthesis. Nutritional assessments, whether clinical or laboratory guided, and intervention should be considered at an early juncture in all surgical and critically ill patients. Management of critically ill and injured patients is optimized with the use of evidence-based and algorithm-driven therapy. SIRS MOF Recovery MOF CARS THE DETECTION OF CELLULAR INJURY The Detection of Injury is Mediated by Members of the Damage-Associated Molecular Pattern Family 14 4 Traumatic injury activates the innate immune system to produce a systemic inflammatory response in an attempt to limit damage and to restore homeostasis. It includes two general responses: (a) an acute proinflammatory response resulting from innate immune system recognition of ligands, and (b) an antiinflammatory response that may serve to modulate the proinflammatory phase and direct a return to homeostasis (Fig. 2-1). This is accompanied by a suppression of adaptive immunity.4 Rather than occurring sequentially, recent data indicate that all three responses are simultaneously and rapidly induced 1 following severe traumatic injury.2 The degree of the systemic inflammatory response following trauma is proportional to injury severity and is an independent predictor of subsequent organ dysfunction and resultant mortality. Recent work has provided insight into the mechanisms by which immune activation in this setting is triggered. The clinical features of the injury-mediated systemic inflammatory response, characterized by increased body temperature, heart rate, respirations, and white blood cell count, are similar to those observed with infection (Table 2-1). While significant efforts have been devoted to establishing a microbial etiology for this response, it is now widely accepted that systemic inflammation following trauma is sterile. Although the mechanisms for the sterile response are Hours Days Figure 2-1. Schematic representation of the systemic inflammatory response syndrome (SIRS) after injury, followed by a period of convalescence mediated by the counterregulatory anti-inflammatory response syndrome (CARS). Severe inflammation may lead to acute multiple organ failure (MOF) and early death after injury (dark blue arrow). A lesser inflammatory response followed by excessive CARS may induce a prolonged immunosuppressed state that can also be deleterious to the host (light blue arrow). Normal recovery after injury requires a period of systemic inflammation followed by a return to homeostasis (red arrow). (Adapted with permission from Guirao X, Lowry SF. Biologic control of injury and inflammation: Much more than too little or too late. World J Surg. 1996;20:437. With kind permission from Springer Science + Business Media.) less well understood, it is likely to result from endogenous molecules that are produced as a consequence of tissue damage or cellular stress, as may occur with hemorrhagic shock and resuscitation.5 Termed alarmins or damage-associated molecular patterns (DAMPs), these effectors, along with the pathogen-associated molecular patterns (PAMPs), interact with specific cell receptors that are located both on the cell surface and intracellularly.6 The best described of these 2 receptors are members of the toll-like receptor family. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 2-1 Definition Infection Identifiable source of microbial insult SIRS Two or more of following criteria are met:  Temperature ≥38°C (100.4°F) or ≤36°C (96.8°F) Heart rate ≥90 beats per minute  Respiratory rate ≥20 breaths per minute or Paco2 ≤32 mmHg or mechanical ventilation White blood cell count ≥12,000/μL or ≤4000/μL or ≥10% band forms Sepsis Identifiable source of infection + SIRS Severe sepsis Sepsis + organ dysfunction Septic shock Sepsis + cardiovascular collapse (requiring vasopressor support) Paco2 = partial pressure of arterial carbon dioxide. Trauma DAMPs are structurally diverse endogenous molecules that are immunologically active. Table 2-2 includes a partial list of DAMPs that are released either passively from necrotic/damaged cells or actively from physiologically “stressed” cells by upregulation or overexpression. Once they are outside the cell, DAMPs promote the activation of innate immune cells, as well as the recruitment and activation of antigen-presenting cells, which are engaged in host defense.7 The best-characterized DAMP with significant preclinical evidence for its release after trauma and with a direct link to the systemic inflammatory response is high-mobility group protein B1 (HMGB1). Additional evidence for the role of DAMP molecules in postinjury inflammation, including mitochondrial proteins and DNA, as well as extracellular matrix molecules, is also presented. Table 2-2 Damage-associated molecular patterns (DAMPs) and their receptors DAMP Molecule Putative Receptor(s) HMGB1 TLRs (2,4,9), RAGE Heat shock proteins TLR2, TLR4, CD40, CD14 S100 protein RAGE Mitochondrial DNA TLR9 Hyaluronan TLR2, TLR4, CD44 Biglycan TLR2 and TLR4 Formyl peptides (mitochondrial) Formyl peptide receptor 1 IL-1α IL-1 receptor HMGB1 = high-mobility group protein B1; IL = interleukin; RAGE = receptor for advanced glycosylation end products; TLK = toll-like receptor. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Term 15 CHAPTER 2 Clinical spectrum of infection and systemic inflammatory response syndrome (SIRS) High-Mobility Group Protein B1. The best-characterized DAMP in the context of the injury-associated inflammatory response is HMGB1 protein, which is rapidly released into the circulation within 30 minutes following trauma. HMGB1 is highly evolutionarily conserved across species. It was first described as a constitutively expressed, nonhistone chromosomal protein that participated in a variety of nuclear events, including DNA repair and transcription. HMGB1 was also detected in the cytosol and extracellular fluids at low levels, although its function outside the cell was not clear. Subsequent studies have proven, however, that HMGB1 is actively secreted from immune-competent cells stimulated by PAMPs (e.g., endotoxin) or by inflammatory cytokines (e.g., tumor necrosis factor and interleukin-1). This process occurs outside the classic secretory pathway via a mechanism that is independent of endoplasmic reticulum and the Golgi complex. Moreover, recent data indicate that HMGB1 release can be regulated by the inflammasome.8 Stressed nonimmune cells such as endothelial cells and platelet also actively secrete HMGB1. Finally, passive release of HMGB1 can occur following cell death, whether it is programmed or uncontrolled (necrosis). Once outside the cell, HMGB1 interacts with its putative receptors either alone or in concert with pathogenic molecules to activate the immune response, and in this way, functions as a proinflammatory cytokine. HMGB1 has been shown to signal via the toll-like receptors (TLR2, TLR4, TLR9), the receptor for advanced glycosylation end products (RAGE), CD24, and others. The activation of TLRs mainly occurs in myeloid cells, whereas RAGE is thought to be the receptor target in endothelial and somatic cells. The diverse proinflammatory biologic responses that result from HMGB1 signaling include: (a) the release of cytokines and chemokines from macrophages/ monocytes and dendritic cells; (b) neutrophil activation and chemotaxis; (c) alterations in epithelial barrier function, including increased permeability; and (d) increased procoagulant activity on platelet surfaces, among others. 9 In particular, HMGB1 binding to TLR4 triggers the proinflammatory cytokine release that mediates “sickness behavior.” This effect is dependent on the highly conserved domain structure of HMGB1 that can be recapitulated by a synthetic 20-amino acid peptide containing a critical cysteine residue at position 106.10 Recent data have explored the role of this cysteine residue, as well as two others that are highly conserved, in the biologic function of HMGB1. They demonstrate that the redox state of the three residues regulates the receptor binding ability of HMGB1 to influence its activity, including cytokine production. For example, a thiol at C106 is required for HMGB1 to promote macrophage tumor necrosis factor (TNF) release. In addition, a disulfide bond between C23 and C45 is also required for cytokine release because reduction of the disulfide linkage or further oxidation will reduce the ability of HMGB1 to function as a cytokine. Therefore, if all three cysteine residues are in reduced form, HMGB1 lacks the ability to bind and signal through TLR4, but gains the capacity to bind to CXCL12 to activate CXCR4 and serve as a chemotactic mediator. Importantly, shifts between the redox states have been demonstrated and indicate that redox state dynamics are important regulators of HMGB1.11 Importantly, HMGB1 levels in human subjects following injury correlate with the Injury Severity Score, complement activation, and an increase in circulating inflammatory mediators such as TNF.12 Unchecked, excessive HMGB1 has the capacity 16 to promote a self-injurious innate immune response. In fact, exogenous administration of HMGB1 to normal animals produces fever, weight loss, epithelial barrier dysfunction, and even death. PART I A Role for Mitochondrial DAMPs in the Injury-Mediated Inflammatory Response. Mitochondrial proteins and/or BASIC CONSIDERATIONS DNA can act as DAMPs by triggering an inflammatory response to necrosis and cellular stress. Specifically, the release of mitochondrial DNA (mtDNA) and formyl peptides from damaged or dysfunctional mitochondria has been implicated in activation of the macrophage inflammasome, a cytosolic signaling complex that responds to cellular stress. In support of this idea, plasma mtDNA has been shown to be thousands of times higher in both trauma patients and patients undergoing femoral fracture repair when compared to normal volunteers. Further, direct injection of mitochondria lysates in an animal model caused remote organ damage, including liver and lung inflammation.13 These data suggest that with stress or tissue injury, mtDNA and peptides are released from damaged mitochondria where they can contribute to a sterile inflammatory response. From an evolutionary perspective, given that eukaryotic mitochondria derive from bacterial origin, it would make sense that they retain bacterial features capable of eliciting a strong response that is typically associated with a pathogen trigger. For example, mtDNA is circular and contains hypomethylated CpG motifs that resemble bacterial CpG DNA. It is thus capable of producing formylated peptides, which potently induce an inflammatory phenotype in neutrophils, by increasing chemotaxis, oxidative burst, and cytokine secretion. In addition, the mitochondrial transcription factor A (TFAM), a highly abundant mitochondrial protein, is functionally and structurally homologous to HMGB1. It has also been shown be released in high amounts from damaged cells where it acts in conjunction with mtDNA to activate TLR9 signaling.14 Extracellular Matrix Molecules Act as DAMPs. Recent work has explored the role of extracellular matrix (ECM) proteins in the TLR-mediated inflammatory response that follows tissue injury. These molecules, which are sequestered under normal conditions, can be released in a soluble form with proteolytic digestion of the ECM. Proteoglycans, glycosaminoglycans, and glycoproteins such as fibronectin have all been implicated as key players in the DAMP/TLR interaction. Proteoglycans, in particular, have also been shown to activate the intracellular inflammasomes that trigger sterile inflammation. These molecules, which consist of a protein core with one or more covalently attached glycosaminoglycan chains, can be membrane-bound, secreted, or proteolytically cleaved and shed from the cell surface. Biglycan is one of the first proteoglycans to be described as a TLR ligand.15 It consists of a protein core containing leucinerich repeat regions, with two glycosaminoglycan (GAG) side chains (chondroitin sulfate or dermatan sulfate). Although biglycan typically exists in a matrix-bound form, with tissue injury, it is released from the ECM in a soluble form where it interacts with TLR2 or TLR4 to generate an immediate inflammatory response. Various proinflammatory cytokines and chemokines, including TNF-α and interleukin (IL)-1β, are downstream effector molecules of biglycan/TLR2/4 signaling. Among these, the mechanism of biglycan-mediated autonomous synthesis and secretion of mature IL-1β is unique. Usually, release of mature IL-1β from the cell requires two signals, one which is needed to initiate synthesis (TLR2/4-mediated) and the other to process pro-IL-1β to its mature form (inflammasomemediated). How is it possible for biglycan to provide both signals? Current evidence indicates that when soluble biglycan binds to the TLR, it simultaneously serves as a ligand for a purinergic receptor, which facilitates the inflammasome activation required for IL-1β processing.16 These data support the idea that DAMP-mediated signals can initiate a robust inflammatory response. DAMPs Are Ligands for Pattern Recognition Receptors The inflammatory response that occurs following traumatic injury is similar to that observed with pathogen exposure. Not surprising, surface and cytoplasmic receptors that 2 mediate the innate immune response to microbial infection have been implicated in the activation of sterile inflammation. In support of this idea, genes have been identified that are dysregulated acutely both in response to a microbial ligand administered to human volunteers and in response to traumatic injury in a large patient population.17 The classes of receptors that are important for sensing damaged cells and cell debris are part of the larger group of germline encoded pattern recognition receptors (PRRs). The best-described ligands for these receptors are microbial components, the PAMPs. The PRRs of the innate immune system fall into at least four distinct classes: TLRs, calcium-dependent (C-type) lectin receptors (CLRs), retinoic acid–inducible gene (RIG)-I-like receptors (RLRs), and the nucleotide-binding domain, leucine-rich repeat–containing (NBD-LRR) proteins (NLRs; also nucleotide-binding and oligomerization domain [NOD]-like receptors). Following receptor ligation, intracellular signaling modulates transcriptional and posttranslational events necessary for host defense by coordinating the synthesis and release of cytokines and chemokines to either initiate or suppress the inflammatory response. The best described of these, the TLRs, NLRs, and CLRs, are discussed in the following sections. Toll-Like Receptors. The TLRs are evolutionarily conserved type 1 transmembrane proteins that are the best-characterized PRRs in mammalian cells. They were first identified in Drosophila, where a mutation in the Toll gene led to its identification as a key component in their immune defense against fungal infection. The first human TLR, TLR4, was identified shortly thereafter. Now, more than 10 human TLR family members have been identified, with distinct ligands that include lipid, carbohydrate, peptide, and nucleic acid components of various pathogens. TLRs are expressed on both immune and nonimmune cells. At first, the expression of TLR was thought to be isolated to professional antigen-presenting cells such as dendritic cells and macrophages. However, mRNA for TLR family members have been detected in most cells of myeloid lineage, as well as natural killer (NK) cells.18 In addition, activation of T cells increases their TLR expression and induces their survival and clonal expansion. Direct engagement of TLR in T-regulatory (Treg) cells promotes their expansion and reprograms them to differentiate into T helper cells, which in turn provides help to effector cells. In addition, B cells express a distinct subset of the TLR family that determines their ability to respond to DAMPs; however, the significance of restricted TLR expression in these cells is not yet clear. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ of intracellular PRRs that sense both endogenous (DAMPs) and exogenous (PAMPs) molecules to trigger innate immune activation. The best characterized of the NLRs is the NLR family pyrin domain-containing 3 (NLRP3), which is highly expressed in peripheral blood leukocytes. It forms the key “sensing” component of the larger, multiprotein inflammasome complex, which is composed of NLRP3; the adapter protein apoptosisassociated speck-like protein containing a CARD (ASC); and the effector protein, caspase 1.20 In the cytoplasm, the receptor resides in an inactive form due to an internal interaction between two adjacent and highly conserved domains. In conjunction with a priming event, such as mitochondrial stress, phagocytosed DAMPs can be sensed by NLRP3, resulting in the removal of the self-repression. The protein can then oligomerize and recruit other complex members. The net result is the autoactivation of pro-caspase 1 to caspase 1. The NLRP3 inflammasome plays a central role in immune regulation by initiating the caspase 1–dependent processing and secretion of the proinflammatory cytokines IL-1β and IL-18. In fact, NLRP3 is the key protein in the mechanism by which IL-1β production is regulated in macrophages. NLRP3 inflammasome activity is tightly regulated by cell-cell interactions, cellular ion flux, and oxidative stress in order to maintain a balanced immune response to danger signals. While the role of the NLRP3 inflammasome in the sterile inflammatory response following trauma has not been well described, recent evidence suggests that genetic variations in the NLRP3 gene might affect the magnitude of immune inflammatory responses following trauma. Single nucleotide polymorphisms within the NLRP3 gene were found to be associated with increased risk of sepsis and multiple organ dysfunction syndrome in patients with major trauma.21 In an animal model of burn injury, early C-Type Lectin Receptors. Macrophages and dendritic cells possess receptors that detect molecules released from damaged or dying cells in order to retrieve and process antigens from cell corpses for T-cell presentation. A key family of receptors that directs this process is the CLR family that includes the selectin and the mannose receptor families and that binds carbohydrates in a calcium-dependent fashion. Best described for their sensing of PAMPs, particularly fungal antigens, the CLRs can also act to promote the endocytosis and clearance of cell corpses. More recent work has demonstrated, however, that a subset of CLR receptors such as dendritic cell-NK lectin group receptor-1 (DNGR-1) and macrophage-inducible C-type lectin receptor (Mincle) recognize DAMPS of intracellular origin, such as F-actin and the ribonucleoprotein SAP-130.23 Ligation and activation of Mincle promotes its interaction with an Fcγ receptor, which contains immunoreceptor tyrosine-based activation motifs. This leads to proinflammatory cytokine, chemokine, and nitric oxide production, in addition to neutrophil recruitment. In this way, Mincle may contribute to local inflammation at sites of tissue injury. Soluble Pattern Recognition Molecules: The Pentraxins. Soluble pattern recognition molecules (PRMs) are a molecularly diverse group of molecules that share a conserved mode of action that is defined by complement activation, agglutination and neutralization, and opsonization. The best described of the PRMs are the pentraxins. PRMs can be synthesized at sites of injury and inflammation by macrophages and dendritic cells, while neutrophils can store PRMs and can release them rapidly following activation. In addition, epithelial tissues (the liver in particular) serve as a reservoir source for systemic mass release. The short pentraxin, C-reactive protein (CRP), was the first PRM to be identified. Serum amyloid protein (SAP), which has 51% sequence similarity to human CRP, also contains the pentraxin molecular signature. CRP and SAP plasma levels are low (≤3 mg/L) under normal circumstances. However, CRP is synthesized by the liver in response to IL-6, increasing serum levels more than a 1000-fold. Thus, CRP is considered part of the acute-phase protein response in humans. For this reason, CRP has been studied as a marker of the proinflammatory response in many clinical settings, including appendicitis, vasculitis, and ulcerative colitis. CRP and SAP are ancient immune molecules that share many functional properties with antibodies: they bind bacterial polysaccharides, ECM components, apoptotic cells, and nuclear materials, as well as all three classes of Fcγ receptors (FcγR). Both molecules also participate in the activation and regulation of complement pathways. In this way, short pentraxins can link immune cells to the complement system.24 Finally, significant data support a role for pentraxin 3 (PTX3), a long pentraxin family member, in the “sterile” VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 17 Systemic Response to Injury and Metabolic Support Nucleotide-Binding Oligomerization Domain-Like Receptor Family. The NLRs are a large family of proteins composed inflammasome activation has been detected in a variety of immune cells (NK cells, CD4/CD8 T cells, and B cells), as determined by the assessment of caspase 1 cleavage by flow cytometry.22 Further, inhibition of caspase 1 activity in vivo results in increased burn mortality, suggesting that inflammasome activation may play an unanticipated protective role in the host response to injury that may be linked to increased production of specific cytokines. In addition to the NLRP3 inflammasome, there are numerous other NLRP sensors that are capable of detecting a diverse range of molecular targets. Among them are those endogenous molecules that are released as a consequence of tissue injury and cellular stress (hypoxia/hypoperfusion). CHAPTER 2 All TLRs consist of an extracellular domain, characterized by multiple leucine-rich repeats (LRRs), and a carboxyterminal, intracellular toll/IL-1 receptor (TIR) domain. The LRR domains recognize bacterial and viral PAMPs in the extracellular environment (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11) or in the endolysosomes (TLR3, TLR7, TLR8, TLR9, and TLR10). Although the role of TLRs in sepsis has been well described, more recent data indicate that a subset of the TLRs, TLR4 in particular, also recognizes DAMPs released from injured cells and tissues.19 Signal transduction occurs with receptor dimerization and recruitment of cytoplasmic adaptor proteins. These adaptor molecules initiate and amplify downstream signals, resulting in the activation of transcription. The transcription factors, which include nuclear factor-κB (NF-κB), activator protein (AP)-1, and interferon regulatory factor (IRF), bind to regulatory elements in promoters and/or enhancers of target genes leading to the upregulation of a large cohort of genes that include interferon (IFN)-α and IFN-β, nitric oxide synthase 2 (NOS2A), and TNF, which play critical roles in initiating innate immune responses to cellular injury and stress. Given the importance of TLR triggering of the innate immune response to immune homeostasis, it is no surprise that the process is tightly regulated. TLR expression is significantly increased following blunt traumatic injury. Further, TLR signaling is controlled at multiple levels, both posttranscriptionally via ubiquitination, phosphorylation, and microRNA actions that affect mRNA stability, as well as by the localization of the TLRs and their signaling complexes within the cell. 18 PART I BASIC CONSIDERATIONS inflammatory response associated with cellular stress. While CRP is produced solely in the liver, PTX3 is produced by various cells in peripheral tissues, including immune cells. PTX3 plasma concentrations increase rapidly in various inflammatory conditions, including sepsis. Further, in a recent prospective study of polytraumatized patients, serum PTX3 concentrations were highly elevated, peaking at 24 hours. In addition, PTX3 concentrations at admission were associated with injury severity, whereas higher PTX3 serum concentrations 24 hours after admission correlated with lower probability for survival.25 Pattern Recognition Receptor Signaling: TollLike Receptors and the Inflammasome As noted earlier, members of the TLR family respond to endogenous molecules released from damaged or stressed cells. In animal models, activation of TLRs in the absence of bacterial pathogens correlates with the development of critical illness including “sterile inflammation.” What we know about TLR signaling events has largely been derived from the TLR-mediated response to bacterial pathogens. However, it is likely that the intracellular adaptors required for signal transmission by TLRs in response to exogenous ligands are conserved and used for “damage” sensing of endogenous (“self”) ligands as well. The intracellular domain structure of TLRs is highly conserved and is characterized by a cytoplasmic toll/IL-1R homology (TIR) domain. Binding of ligand to the receptor results in a receptor dimer, either a homodimer (e.g., TLR4/TLR4) or heterodimer (e.g., TLR2/TLR1), which recruits a number of adaptor proteins to the TIR domains, through TIR-TIR interaction.26 With one exception (TLR3), the universal adaptor protein central to the TLR signaling complex is myeloid differentiation factor 88 (MyD88), a member of the IL-1 receptor subfamily. MyD88 works through the recruitment of a second TIR-containing adaptor, MyD88 adaptor-like protein (Mal), in the context of TLR4 and TLR2 signaling, which serves as a bridge between MyD88 and activated TLRs to initiate signal transduction. It is interesting that Mal’s adaptor function requires cleavage of the carboxyterminal portion of the protein by caspase 1, a key effector of the inflammasome.27 This finding suggests an important synergy between TLRs and NLRs that may potentiate TLR-mediated signaling. There are three other TIR domain-containing adaptor proteins that are also important to TLR-signaling events; these are TIR-domain-containing adapter-inducing INF-β (TRIF), TRIF-related adaptor molecule (TRAM), and sterile α- (SAM) and HEAT/armadillo (ARM) motif-containing protein (SARM). Two of these, TRIF and TRAM, are involved in the MyD88independent signaling pathways, which are activated by TLR3 and TLR4. Signaling through the MyD88-dependent pathway results in the activation of numerous cytoplasmic protein kinases including IL-1 receptor–associated kinases (IRAK-1 and IRAK-4), resulting in an interaction with TNF receptor–associated factor 6 (TRAF6). TRAF6, an E3 ubiquitin ligase, forms a complex with two other proteins, which together activate the complex that subsequently phosphorylates IκB kinase (IKK)-β and the MAP kinases (MAPKs). Ultimately, the phosphorylation of IκB by the IKK complex and NEMO (NF-κB essential modulator) leads to its degradation, which frees NF-κB and allows its translocation to the nucleus and the transcription of NF-κB target genes. Simultaneously, MAPK activation is critical for activation of the activator protein-1 (AP-1) transcription factor, and thus production of inflammatory cytokines. The MyD88-independent pathway acts through TRIF to activate NF-κB, similar to the MyD88-dependent pathway. However, TRIF can also recruit other signaling molecules to phosphorylate interferon-regulatory factor 3 (IRF3), which induces expression of type I IFN genes.26 Signaling from the Inflammasome. As discussed earlier, activation and assembly of the inflammasome in response to DAMP sensing result in the cleavage of pro-caspase 1 into two products. This event is pivotal to all known inflammasome signaling pathways. The caspase 1 products assemble to form the IL-1 converting enzyme (ICE), which cleaves the IL-1 cytokines, IL-1β, IL-18, and IL-33. This final step is required for activation and secretion of the cytokines from the cell.20 IL-1β and IL-18 are potent proinflammatory cytokines that promote key immune responses that are essential to host defense. Thus, the synthesis, processing, and secretion of these cytokines are tightly regulated, as successful cytokine release requires a two-step process. The first signal, which is typically TLR-mediated, initiates the synthesis and storage of the inactive cytokine precursors in the cytoplasm. The second signal, which is inflammasome-mediated, initiates proteolytic cleavage of the procytokine, which is a requirement for its activation and secretion from the cell. Of further interest, evidence has demonstrated that both IL-1β and IL-18 lack a signal sequence, which is usually necessary for those proteins that are destined for cellular export. These signal peptides target proteins to the endoplasmic reticulum (ER) and to the Golgi complex, where they are packaged for secretion from the cell through the classical secretory pathway. More than 20 proteins in addition to IL-1β and IL-18 undergo unconventional protein secretion independent of the ER and Golgi complex.28 The list includes signaling molecules involved in inflammatory, cell survival, and repair responses, such as HMGB1, IL-1α, galectins 1 and 3, and FGF2. Currently, the mechanisms responsible for unconventional protein secretion are not understood; however, the process is also evident in yeast under conditions of cellular stress. It makes evolutionary sense that a mechanism for rapid secretion of stored proteins essential to the stress response is highly conserved. CENTRAL NERVOUS SYSTEM REGULATION OF INFLAMMATION IN RESPONSE TO INJURY The central nervous system (CNS) communicates with the body through ordered systems of sensory and motor neurons, which receive and integrate information to generate a coordinated response. Rather than being an immune-privileged organ, recent work indicates that the CNS receives information with regard to injury-induced inflammation both via soluble mediators as well as direct neural projections that transmit information to regulatory areas in the brain (Fig. 2-2). How does 3 the CNS sense inflammation? DAMPs and inflammatory molecules convey stimulatory signals to the CNS via multiples routes. For example, soluble inflammatory signaling molecules from the periphery can reach neurons and glial cells directly through the fenestrated endothelium of the circumventricular organs (CVO) or via a leaky blood brain barrier in pathologic settings such as may occur following a traumatic brain injury. 29 In addition, inflammatory stimuli can interact with receptors located on the brain endothelial cells to generate a variety of proinflammatory mediators (cytokines, chemokines, adhesion molecules, proteins of the complement system, and immune receptors) that directly impact the brain parenchyma. Not surprising, this VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Central nervous system CHAPTER 2 ACTH glucocorticoids Injury site Sensory vagus Sympathetic TNF IL-1 Parasympathetic (Motor vagus) EPI, NOREPI Inflammatory cascade Acetylcholine Figure 2-2. Neural circuit relaying messages of localized injury to the brain (nucleus tractus solitarius). The brain follows with a hormone release (adrenocorticotropic hormone [ACTH], glucocorticoids) into the systemic circulation and by sympathetic response. The vagal response rapidly induces acetylcholine release directed at the site of injury to curtail the inflammatory response elicited by the activated immunocytes. This vagal response occurs in real time and is site specific. EPI = epinephrine; IL-1 = interleukin-1; NOREPI = norepinephrine; TNF = tumor necrosis factor. (Adapted and re-created with permission from Macmillan Publishers Ltd. Tracey KJ. The inflammatory reflex. Nature. 2002;420:853. Copyright © 2002.) response is countered by potent anti-inflammatory signaling, a portion of which is provided by the hypothalamic-pituitaryadrenal (HPA) axis and the release of systemic glucocorticoids. Inflammatory stimuli in the CNS result in behavioral changes, such as increased sleep, lethargy, reduced appetite, and the most common feature of infection, fever. Information regarding peripheral inflammation and tissue damage can also be signaled to the brain via afferent neural fibers, particularly those of the vagus nerve.30 These afferent fibers can interconnect with neurons that project to the hypothalamus to modulate the HPA axis. In addition, afferent vagal nerve impulses modulate cells in the brain stem, at the dorsal motor nucleus of the vagus, from which efferent preganglionic parasympathetic impulses originate. Axons from these cells, which comprise the visceromotor component of the vagus nerve, form an “inflammatory reflex” that feeds back to the periphery to regulate inflammatory signaling events.31 Although the mechanisms by which cholinergic signals from the CNS regulate immune cells in the periphery are incompletely understood, recent evidence has provided some mechanistic insight. The first line of evidence to support this idea is the observation that vagal stimulation reduces proinflammatory cytokine production from the spleen in several experimental models systems.32 This effect is dependent on both the vagal efferent signals and, in part, splenic catecholaminergic nerve fibers that originate in the celiac plexus and that terminate in a T-cell–rich area of the spleen. Interestingly, these signals propagated by adrenergic nerves result in measurable increases in acetylcholine (ACh) levels in the spleen. In addition, the resident immune cells in the spleen require the expression of cholinergic receptors, specifically α7 nicotinic acetylcholine receptors (α7nAChR), for the suppression of cytokine synthesis.33 How is this effect mediated? The apparent source of ACh is choline-acetyltransferase–expressing T cells, which compose 2% to 3% of CD4+ T cells in the spleen and are capable of ACh production. Data also indicate that the vagus nerve may regulate inflammation in tissues that it directly innervates. Neuroendocrine Response to Injury Traumatic injury results in complex neuroendocrine signaling from the brain that serves to enhance immune defense and rapidly mobilize substrates necessary to meet essential energy and structural needs. The two principle neuroendocrine pathways that orchestrate the host response are the hypothalamicpituitary-adrenal (HPA) axis, which results in the release of glucocorticoid hormones, and the sympathetic nervous system, which results in release of the catecholamines, epinephrine, and norepinephrine. Virtually every hormone of the HPA axis influences the physiologic response to injury and stress (Table 2-3), but some with direct influence on the inflammatory response or immediate clinical impact are highlighted here, including growth hormone (GH), macrophage inhibitory factor (MIF), aldosterone, and insulin. The Hypothalamic-Pituitary-Adrenal Axis. One of the main mechanisms by which the brain responds to injury-associated stress is through activation of the HPA axis. Following injury, corticotrophin-releasing hormone (CRH) is secreted from the paraventricular nucleus (PVN) of the hypothalamus. This action is mediated in part by circulating cytokines produced as VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Injury inflammation 19 20 Table 2-3 Hormones regulated by the hypothalamus, pituitary, and autonomic system PART I Hypothalamic Regulation Corticotropin-releasing hormone Thyrotropin-releasing hormone Growth hormone–releasing hormone Luteinizing hormone–releasing hormone BASIC CONSIDERATIONS Anterior Pituitary Regulation Adrenocorticotropic hormone Cortisol Thyroid-stimulating hormone Thyroxine Triiodothyronine Growth hormone Gonadotrophins Sex hormones Insulin-like growth factor Somatostatin Prolactin Endorphins Posterior Pituitary Regulation Vasopressin Oxytocin Autonomic System Norepinephrine Epinephrine Aldosterone Renin-Angiotensin System Insulin Glucagon Enkephalins a result of the innate immune response to injury. These include TNF-α, IL-1β, IL-6, and the type I IFNs (IFN-α/β). Cytokines that are produced as a result of the adaptive immune response (IL-2 and IFN-γ) are also capable of increasing cortisol release. Direct neural input via afferent vagal fibers that interconnect with neurons projecting to the hypothalamus can also trigger CRH release. CRH acts on the anterior pituitary to stimulate the secretion of adrenocorticotropin hormone (ACTH) into the systemic circulation. Interestingly, the cytokines that act on the hypothalamus are also capable of stimulating ACTH release from the anterior pituitary so that marked elevations in ACTH and in cortisol can occur that are proportional in magnitude to the injury severity. Additionally, pain, anxiety, vasopressin, angiotensin II, cholecystokinin, vasoactive intestinal peptide, and catecholamines all contribute to ACTH release in the injured patient. ACTH acts on the zona fasciculata of the adrenal glands to synthesize and secrete glucocorticoids (Fig. 2-3). Cortisol is the major glucocorticoid in humans and is essential for survival during significant physiologic stress. The resulting increase in cortisol levels following trauma have several important antiinflammatory actions. Cortisol elicits its many actions through a cytosolic receptor, the glucocorticoid receptor (GR). Because it is lipid soluble, cortisol can diffuse through the plasma membrane to interact with its receptor, which is sequestered in the cytoplasm in a complex with heat shock proteins (Fig. 2-4). Upon ligand binding, the GR is activated and can employ a number of mechanisms to modulate proinflammatory gene transcription and signaling events, with a “net” anti-inflammatory effect.34 For example, the activated GR complex can interact with transcription factors to sequester them in the cytoplasm, promote their degradation, or inhibit them through other mechanisms. Affected target genes include proinflammatory cytokines, growth factors, adhesion molecules, and nitric oxide. In addition, glucocorticoids can negatively affect the access of the transcription factor, NF-κB, Cholesterol ACTH Pregnenolone Progesterone 17-α-OH-Pregnenolone Dehydroepiandrosterone 11-Deoxycorticosterone 17-α-OH-progesterone Corticosterone 11-Deoxycortisol Testosterone Aldosterone Cortisol Estradiol Mineralocorticoid Glucocorticoid Androstenedione Sex steroids VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 2-3. Steroid synthesis from cholesterol. Adrenocorticotropic hormone (ACTH) is a principal regulator of steroid synthesis. The end products are mineralocorticoids, glucocorticoids, and sex steroids. 21 S HSP HSP S S mRNA S R S R S Nucleus S Protein synthesis Cytoplasmic membrane to the promoter regions of its target genes via a mechanism that involves histone deacetylase 2. In this way, glucocorticoids can inhibit a major mechanism by which TLR ligation induces proinflammatory gene expression.35 The GR complex can also bind to specific nucleotide sequences (termed glucocorticoid response elements) to promote the transcription of genes that have antiinflammatory functions. These include IL-10 and IL-1 receptor antagonist. Further, GR complex activation can indirectly influence TLR activity via an interaction with signaling pathways such as the mitogen-activated protein kinase and transforming growth factor–activated kinase-1 (TAK1) pathways. Finally, a recent report demonstrated that the GR complex can target both suppressor of cytokine signaling 1 (SOCS1) and type 1 IFNs to regulate TLR-induced STAT1 activation.36 Adrenal insufficiency represents a clinical syndrome highlighted largely by inadequate amounts of circulating cortisol and aldosterone. Classically, adrenal insufficiency is described in patients with atrophic adrenal glands caused by exogenous steroid administration who undergo a stressor such as surgery. These patients subsequently manifest signs and symptoms such as tachycardia, hypotension, weakness, nausea, vomiting, and fever. Critical illness may be associated with a relative adrenal insufficiency such that the adrenal gland cannot mount an effective cortisol response to match the degree of injury. More recently, investigators have determined that critical illness-associated cortisol insufficiency in trauma patients occurs more frequently than previously thought.37 It has a bimodal presentation in which the patient is at increased risk both early following the injuryassociated inflammatory response and in a delayed fashion, with sepsis being the initiating event. Laboratory findings in adrenal insufficiency include hypoglycemia from decreased gluconeogenesis, hyponatremia from impaired renal tubular sodium resorption, and hyperkalemia from diminished kaliuresis. Rigorous testing to establish the diagnosis includes monitoring of basal and ACTH-stimulated cortisol levels, both of which are lower than normal during adrenal insufficiency. Treatment strategies remain controversial; however, they include low-dose steroid supplementation.38 Macrophage Inhibitory Factor Modulates Cortisol Function. Macrophage inhibitory factor (MIF) is a proinflammatory Figure 2-4. Simplified schematic of steroid transport into the nucleus. Steroid molecules (S) diffuse readily across cytoplasmic membranes. Intracellularly, the receptors (R) are rendered inactive by being coupled to heat shock protein (HSP). When S and R bind, HSP dissociates, and the S-R complex enters the nucleus, where the S-R complex induces DNA transcription, resulting in protein synthesis. mRNA = messenger RNA. cytokine expressed by a variety of cells and tissues, including the anterior pituitary, macrophages, and T lymphocytes. Several important functions of MIF in innate and adaptive immune responses and in inflammation have been described, supporting the idea that MIF may function to counteract the antiinflammatory activity of glucocorticoids.39 For example, MIF has been reported to play a central role in the exacerbation of inflammation associated with acute lung injury, where it has been detected in the affected lungs and in alveolar macrophages. MIF has also been reported to upregulate the expression of TLR4 in macrophages.40 Finally, an early increase in plasma MIF has been detected in severely injured patients and was found to correlate with NF-κB translocation and respiratory burst in polymorphonuclear lymphocytes (PMNs) derived from severely injured patients. Further, nonsurvivors were shown to have higher serum MIF concentrations early after injury than survivors.41 These data suggest that targeting MIF after injury may be beneficial in preventing early PMN activation and subsequent organ failure in severely injured patients. Growth Hormone, Insulin-Like Growth Factor, and Ghrelin. Growth hormone (GH) is a neurohormone expressed primarily by the pituitary gland that has both metabolic and immunomodulatory effects. GH promotes protein synthesis and insulin resistance and enhances the mobilization of fat stores. GH secretion is upregulated by hypothalamic GH-releasing hormone and downregulated by somatostatin. GH primarily exerts its downstream effects through direct interaction with GH receptors and through the enhanced hepatic synthesis of insulin-like growth factor (IGF)-1, an anabolic growth factor that is known to improve the metabolic rate, gut mucosal function, and protein loss after traumatic injury. Less than 5% of IGF-1 circulates free in the plasma, with the remainder bound principally to one of six IGF-binding proteins (IGFBPs), the majority to IGFBP-3. In the liver, IGF stimulates protein synthesis and glycogenesis; in adipose tissue, it increases glucose uptake and lipid utilization; and in skeletal muscles, it mediates glucose uptake and protein synthesis. In addition to its effects on cellular metabolism, GH enhances phagocytic activity of immunocytes through increased lysosomal superoxide production. It also increases the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support S R CHAPTER 2 DNA 22 PART I BASIC CONSIDERATIONS proliferation of T-cell populations.42 The catabolic state that follows severe injury has been linked to the suppression of the GHIGF-IGFBP axis, as critical illness is associated with decreased circulating IGF levels. Not surprising, the administration of exogenous recombinant human GH (rhGH) has been studied in a prospective, randomized trial of critically ill patients where it was associated with increased mortality, prolonged ventilator dependence, and increased susceptibility to infection.43 More recently, circulating GH levels were examined on admission in 103 consecutive critically ill adult patients. In this study, circulating GH levels were about seven-fold increased in the 24 nonsurvivors when compared with survivors, and GH level was an independent predictor of mortality, along with the APACHE II/SAPS II scores. In distinct contrast, the effect of rhGH administration in severely burned children, both acutely and following prolonged treatment, has been proven to be beneficial. Pediatric burn patients receiving rhGH demonstrated markedly improved growth and lean body mass, whereas hypermetabolism was significantly attenuated.44 This finding was associated with significant increases in serum GH, IGF-1, and IGFBP-3. Ghrelin, a natural ligand for the GH-secretagogue receptor 1a (GHS-R1a), is an appetite stimulant that is secreted by the stomach. GHS-R1a is expressed in a variety of tissues in different concentrations including the immune cells, B and T cells, and neutrophils. Ghrelin seems to play a role in promoting GH secretion and in glucose homeostasis, lipid metabolism, and immune function. In a rodent gut ischemia/reperfusion model, ghrelin administration inhibited proinflammatory cytokine release, reduced neutrophil infiltration, ameliorated intestinal barrier dysfunction, attenuated organ injury, and improved survival. It is interesting that this effect was dependent on an intact vagus nerve and that intracerebroventricular injection of ghrelin was also protective.45 These data suggest that the effect of ghrelin is mediated via the CNS, most likely through the “cholinergic antiinflammatory pathway.” More recently, high ghrelin levels were demonstrated in critically ill patients as compared to healthy controls, independent of the presence of inflammatory markers. Moreover, the high ghrelin levels were a positive predictor of intensive care unit survival in septic patients, matching previous results from animal models. The Role of Catecholamines in Postinjury Inflammation. Injury-induced activation of the sympathetic nervous system results in secretion of ACh from the preganglionic sympathetic fibers innervating the adrenal medulla. The adrenal medulla is a special case of autonomic innervation and is considered a modified postganglionic neuron. Thus, ACh signaling to the resident chromaffin cells ensures that a surge of epinephrine (EPI) and norepinephrine (NE) release into the circulation takes place in a ratio that is tightly regulated by both central and peripheral mechanisms. Circulating levels of EPI and NE are three- to four-fold elevated, an effect that persists for an extended time. The release of EPI can be modulated by transcriptional regulation of phenylethanolamine N-methyltransferase (PNMT), which catalyzes the last step of the catecholamine biosynthesis pathway methylating NE to form EPI. PNMT transcription, a key step in the regulation of EPI production, is activated in response to stress and tissue hypoxia by hypoxia-inducible factor 1α (HIF1A). Catecholamine release almost immediately prepares the body for the “fight or flight” response with well-described effects on the cardiovascular and pulmonary systems and on metabolism. These include increased heart rate, myocardial contractility, conduction velocity, and blood pressure; the redirection of blood flow to skeletal muscle; increased cellular metabolism throughout the body; and mobilization of glucose from the liver via glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. To compound the resulting hyperglycemia, insulin release is decreased mainly through the stimulation of α-adrenergic pancreatic receptors. Hyperglycemia, as will be discussed later, contributes to the proinflammatory response and to further mitochondrial dysfunction. The goal of this well-orchestrated catecholamine response is to re-establish and maintain the systems’ homeostasis, including the innate immune system. Circulating catecholamines can directly influence inflammatory cytokine production.46 Data indicate that basal EPI levels condition the activity and responsiveness of cytokine-secreting cells, which may explain large interindividual variability in innate cytokine profiles observed following injury. Epinephrine infusion at higher doses has been found to inhibit production of TNF-α in vivo and to enhance the production of the anti-inflammatory cytokine IL-10.47 Additionally, in vitro studies indicate that stress levels of glucocorticoids and EPI, acting in concert, can inhibit production of IL-12, a potent stimulator of Th1 responses. Further, they have been shown in vitro to decrease Th1 cytokine production and increase Th2 cytokine production to a significantly greater degree compared to either adrenal hormone alone. Thus, catecholamines secreted from the adrenal gland, specifically EPI, play a role in both innate proinflammatory cytokine regulation and adaptive Th responses, and may act in concert with cortisol during the injury response to modulate cytokine activity.48 How are these effects explained? It is well established that a variety of human immune cells (e.g., mononuclear cells, macrophages, granulocytes) express adrenergic receptors that are members of the family of G-protein–coupled receptors that act through the activation of intracellular second messengers such as cyclic adenosine monophosphate (cAMP) and calcium ion influx (discussed in more detail later). These second messengers can regulate a variety of immune cell functions, including the release of inflammatory cytokines and chemokines. The sympathetic nervous system also has direct immunemodulatory properties via its innervation of lymphoid tissues that contain resting and activated immune cells. With stimulation of these postganglionic nerves, NE is released where it can interact with β2-adrenergic receptors expressed by CD4+ T and B lymphocytes, many of which also express α2-adrenergic receptors. Additionally, endogenous catecholamine expression has been detected in these cells, as has the machinery for catecholamine synthesis. For example, human peripheral blood mononuclear cells contain inducible mRNA for the catecholamine-generating enzymes, tyrosine-hydroxylase and dopamine-β-hydroxylase, and data suggest that cells can regulate their own catecholamine synthesis in response to extracellular cues. Exposure of peripheral blood mononuclear cells to NE triggers a distinct genetic profile that indicates a modulation of Th cell function. What the net effect of dopamine, NE, and EPI synthesis by circulating and resident immune cells may be relative to that secreted by the adrenal medulla is not clear and is an area that would certainly benefit from ongoing research efforts to identify novel therapeutic targets. Aldosterone. Aldosterone is a mineralocorticoid released by the zona glomerulosa of the adrenal cortex. It binds to the mineralocorticoid receptor (MR) of principal cells in the collecting duct of the kidney where it can stimulate expression of genes involved in sodium reabsorption and potassium excretion VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ THE CELLULAR STRESS RESPONSES Reactive Oxygen Species and the Oxidative Stress Response Reactive oxygen and nitrogen species (ROS and RNS, respectively) are small molecules that are highly reactive due to the presence of unpaired outer orbit electrons. They can cause cellular injury to both host cells and invading pathogens through 4 the oxidation of cell membrane substrates. Oxygen radicals The Heat Shock Response Heat shock proteins (HSPs) are a group of intracellular proteins that are increasingly expressed during times of stress, such as burn injury, inflammation, oxidative stress, and infection. HSPs are expressed in the cytoplasm, nucleus, endoplasmic reticulum, and mitochondria, where they function as molecular chaperones that help monitor and maintain appropriate protein folding.56 HSPs accomplish this task through the promotion of protein refolding, the targeting of misfolded proteins for degradation, and the assistance of partially folded proteins to appropriate membrane compartments. HSPs bind also bind foreign proteins and thereby function as intracellular chaperones for ligands such as bacterial DNA and endotoxin. HSPs are presumed to protect cells from the effects of traumatic stress and, when released by damaged cells, alert the immune system of the tissue damage. However, depending on their location and the type of immune cell in which they are expressed, HSPs may exert proinflammatory immune activating signals or anti-inflammatory immune dampening signals (Table 2-4).57 The Unfolded Protein Response Secreted, membrane-bound, and organelle-specific proteins fold in the lumen of the endoplasmic reticulum (ER) where they also VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 23 Systemic Response to Injury and Metabolic Support Insulin. Hyperglycemia and insulin resistance are hallmarks of injury and critical illness due to the catabolic effects of circulating mediators, including catecholamines, cortisol, glucagon, and GH. The increase in these circulating proglycemic factors, particularly EPI, induces glycogenolysis, lipolysis, and increased lactate production independent of available oxygen in a process that is termed “aerobic glycolysis.” Although there is an increase in insulin production at the same time, severe stress is frequently associated with insulin resistance, leading to decreased glucose uptake in the liver and the periphery contributing to acute hyperglycemia. Insulin is a hormone secreted by the pancreas, which mediates an overall host anabolic state through hepatic glycogenesis and glycolysis, peripheral glucose uptake, lipogenesis, and protein synthesis.50 The insulin receptor (IR) is widely expressed and consists of two isoforms, which can form homo- or heterodimers with insulin binding. Dimerization leads to receptor autophosphorylation and activation of intrinsic tyrosine kinase activity. Downstream signaling events are dependent on the recruitment of the adaptor proteins, insulin receptor substrate (IRS-1), and Shc to the IR. Systemic insulin resistance likely results from proinflammatory signals, which modulate the phosphorylation of IRS-1 to affect its function. Hyperglycemia during critical illness is predictive of increased mortality in critically ill trauma patients.51 It can modulate the inflammatory response by altering leukocyte functions, and the resulting decreases in phagocytosis, chemotaxis, adhesion, and respiratory burst activities are associated with an increased risk for infection. In addition, glucose administration results in a rapid increase in NF-κB activation and proinflammatory cytokine production. Insulin therapy to manage hyperglycemia has grown in favor and has been shown to be associated with both decreased mortality and a reduction in infectious complications in select patient populations. However, the trend toward tight glycemic control in the intensive care unit failed to show benefit when examined in several reviews.52 Thus, the ideal blood glucose range within which to maintain critically ill patients and to avoid hypoglycemia has yet to be determined. are produced as a by-product of oxygen metabolism in the mitochondria as well as by processes mediated by cyclooxygenases, NADPH oxidase (NOX), and xanthine oxidase. The main areas of ROS production include mitochondrial respiratory chain, peroxisomal fatty acid metabolism, cytochrome P450 reactions, and the respiratory burst of phagocytic cells. In addition, protein folding in the endoplasmic reticulum can also result in the formation of ROS.53 Potent oxygen radicals include oxygen, superoxide, hydrogen peroxide, and hydroxyl radicals. RNS include NO and nitrite. The synthesis of ROS is regulated at several checkpoints and via several signaling mechanisms, including Ca2+ signaling, phosphorylation, and small G protein activation, which influence both the recruitment of the molecules required for NOX function and the synthesis of ROS in the mitochondria. NOX activation is triggered by a number of inflammatory mediators (e.g., TNF, chemokines, lysophospholipids, complement, and leukotrienes). Host cells are protected from the damaging effects of ROS through a number of mechanisms. The best described of these is via the upregulation and/or activation of endogenous antioxidant proteins. However, pyruvate kinase also provides negative feedback for ROS synthesis, as do molecules that react nonenzymatically with ROS. Under normal physiologic conditions, ROS production is balanced by these antioxidative strategies. In this context, ROS can act effectively as signaling molecules through their ability to modulate cysteine residues by oxidation and thus influence the functionality of target proteins.54 This has recently been described as a mechanism in the regulation of phosphatases. ROS can also contribute to transcription activity both indirectly, through its effects on transcription factor lifespan, and directly, through the oxidation of DNA. An important role for ROS has been well described in phagocytes, which use these small molecules for pathogen killing. Recent data, however, indicate that ROS may mediate inflammasome activation by diverse agonists.55 In addition, ROS appear to be involved in adaptive immunity. They have been described as a prime source of phosphatase activation in both B and T lymphocytes, which can regulate the function of key receptors and intracellular signaling molecules in these cells by affecting phosphorylation events. CHAPTER 2 to regulate extracellular volume and blood pressure. MRs have also been shown to have effects on cell metabolism and immunity. For example, recent studies show aldosterone interferes with insulin signaling pathways and reduces expression of the insulin-sensitizing factors, adiponectin and peroxisome proliferator activated receptor-γ (PPAR-γ), which contribute to insulin resistance. In the immune system, mononuclear cells, such as monocytes and lymphocytes, have been shown to possess an MR that binds aldosterone with high specificity, regulating sodium and potassium flux, as well as plasminogen activator inhibitor-1 and p22 phox expression, in these cells.49 Further, aldosterone inhibits cytokine-mediated NF-κB activation in neutrophils, which also possess a functional MR. 24 TABLE 2-4 The immunomodulatory functions of heat shock proteins (HSPs) PART I Cell Location Recognized as DAMP? Immunomodulatory Function BASIC CONSIDERATIONS HSP90 Cytoplasm, endoplasmic May act as DAMP reticulum chaperone to activate Can function both inside innate immune and outside the cell response Binds and optimizes RNA polymerase II action to regulate gene transcription Stabilizes glucocorticoid receptor in the cytoplasm Important for processing and membrane expression of TLR Chaperones include IKK Facilitates antigen presentation to dendritic cells HSP70 Can function both inside Exogenous HSP70 and outside the cell elicits cellular Endoplasmic reticulum calcium flux, NF-κB homolog is BiP activation, cytokine production Can have anti-inflammatory actions when expression is increased Inhibits TLR-mediated cytokine production via NF-κB Reduces dendritic cell capacity for T-cell stimulation BiP sequesters proteins important to the unfolded protein response HSP60 Mitochondria Plays a role in intracellular protein trafficking Modulates cytokine synthesis Exogenous HSP60 inhibits NF-κB activation BiP = binding immunoglobulin protein; DAMP = damage-associated molecular pattern; IKK = IκB kinase; NF-κB, nuclear factor-κB; TLR = toll-like receptor receive their posttranslational modifications. Millimolar calcium concentrations are required to maintain the normal cellular protein folding capacity. Cellular stress decreases calcium concentration in the ER, disrupting the machinery required for this process and leading to the accumulation of misfolded or unfolded proteins. These occurrences are sensed by a highly conserved array of signaling proteins in the ER, including inositol requiring enzyme 1 (IRE1), protein kinase RNA (PKR)– like ER kinase (PERK), and activating transcription factor 6 (ATF6). Together, this complex generates the unfolded protein response (UPR), a mechanism by which ER distress signals are sent to the nucleus to modulate transcription in an attempt to restore homeostasis. Prolongation of the UPR, indicative of irreversible cellular damage, can result in cell death. Genes activated in the UPR result not only in the inhibition of translation, but also other potentially immunomodulatory events including induction of the acute-phase response, activation of NF-κB, and the generation of antibody-producing B cells.58 Burn injury leads to the marked reduction in ER calcium levels and activation of UPR sensing proteins. Moreover, recent data in a series of burn patients strongly link the UPR to insulin resistance and hyperglycemia in these patients.59 Thus, a better understanding of the UPR, which is triggered by severe inflammation, may allow the identification of novel therapeutic targets for injury-associated insulin resistance. Autophagy Under normal circumstances, cells need to have a way of disposing of damaged organelles and debris aggregates that are too large to be managed by proteasomal degradation. In order to accomplish this housekeeping task, cells use a process referred to as “macroautophagy” (autophagy), which is thought to have originated as a stress response.60 The steps of autophagy include the engulfment of cytoplasm/organelle by an “isolation membrane,” which is also called a phagophore. The edges of the phagophore then fuse to form the autophagosome, a doublemembraned vesicle that sequesters the cytoplasmic material and that is a characteristic feature of autophagy. The autophagosome then fuses with a lysosome to form an autolysosome where the contents, together with the inner membrane, are degraded. This process is controlled by numerous autophagy-specific genes and by the specific kinase, mammalian target of rapamycin (mTOR). As noted earlier, autophagy is a normal cellular process that occurs in quiescent cells for cellular maintenance. However, under conditions of hypoxia and low cellular energy, autophagy is induced in an attempt to provide additional nutrients for energy production. The induction of autophagy promotes a shift from aerobic respiration to glycolysis and allows cellular components of the autophagosome to be hydrolyzed to energy substrates. Increased levels of autophagy are typical in activated immune cells and are a mechanism for the disposal of ROS and phagocytosed debris. Recent data support the idea that autophagy may also play an important role in the immune response.61 Autophagy is stimulated by Th1 cytokines and with activation of TLR in macrophages, but is inhibited by Th2 cytokines. It is also recognized as an important regulator of cytokine secretion, particularly those cytokines of the IL-1 family that are dependent on inflammasome processing for activation. For example, autophagosomes can sequester and degrade pro-IL-1β and inflammasome components. In animal models of sepsis, inhibition of autophagy results in increased proinflammatory cytokine levels that correlate with increased mortality.62 These data suggest that autophagy is a protective mechanism whereby the cell can regulate the levels of cytokine production. Apoptosis Apoptosis (regulated cell death) is an energy-dependent, organized mechanism for clearing senescent or dysfunctional cells, including macrophages, neutrophils, and lymphocytes, without promoting an inflammatory response. This contrasts with cellular necrosis that results in disorganized intracellular molecule release with subsequent immune activation and inflammatory response. Systemic inflammation modulates apoptotic signaling in active immunocytes, which subsequently influences the inflammatory response through the loss of effector cells. Apoptosis proceeds primarily through two pathways: the extrinsic pathway and the intrinsic pathway. The extrinsic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ TNFR-1 (p55) D D D D D D D T T R D D D R TRAF2 D D A A D IAP D D D D D FADD D D 25 TNFR-2 (p75) CHAPTER 2 CD95 D E D D E D D E D D FADD D D E D TRAF2 IAP RAIDD D E D Caspase 8 TRAF1 Recruited RIP Caspase 2 Caspase Cascade NIK MEKK1 I-κB/NF-κB Apoptosis NF-κB JNK c-Jun Figure 2-5. Signaling pathway for tumor necrosis factor receptor 1 (TNFR-1) (55 kDa) and TNFR-2 (75 kDa) occurs by the recruitment of several adapter proteins to the intracellular receptor complex. Optimal signaling activity requires receptor trimerization. TNFR-1 initially recruits TNFR-associated death domain (TRADD) and induces apoptosis through the actions of proteolytic enzymes known as caspases, a pathway shared by another receptor known as CD95 (Fas). CD95 and TNFR-1 possess similar intracellular sequences known as death domains (DDs), and both recruit the same adapter proteins known as Fas-associated death domains (FADDs) before activating caspase 8. TNFR-1 also induces apoptosis by activating caspase 2 through the recruitment of receptor-interacting protein (RIP). RIP also has a functional component that can initiate nuclear factor-κB (NF-κB) and c-Jun activation, both favoring cell survival and proinflammatory functions. TNFR-2 lacks a DD component but recruits adapter proteins known as TNFR-associated factors 1 and 2 (TRAF1, TRAF2) that interact with RIP to mediate NF-κB and c-Jun activation. TRAF2 also recruits additional proteins that are antiapoptotic, known as inhibitor of apoptosis proteins (IAPs). DED = death effector domain; I-κB = inhibitor of κB; I-κB/NF-κB = inactive complex of NF-κB that becomes activated when the I-κB portion is cleaved; JNK = c-Jun N-terminal kinase; MEKK1 = mitogen-activated protein/extracellular regulatory protein kinase kinase kinase-1; NIK = NF-κB–inducing kinase; RAIDD = RIP-associated interleukin-1b-converting enzyme and ced-homologue-1–like protein with death domain, which activates proapoptotic caspases. (Adapted with permission from Lin E, Calvano SE, Lowry SF. Tumor necrosis factor receptors in systemic inflammation. In: Vincent J-L (series ed), Marshall JC, Cohen J, eds. Update in Intensive Care and Emergency Medicine: Vol. 31: Immune Response in Critical Illness. Berlin: Springer-Verlag; 2002:365. With kind permission from Springer Science + Business Media.) pathway is activated through the binding of death receptors (e.g., Fas, TNFR), which leads to the recruitment of Fas-associated death domain protein and subsequent activation of caspase 3 (Fig. 2-5). On activation, caspases are the effectors of apoptotic signaling because they mediate the organized breakdown of nuclear DNA. The intrinsic pathway proceeds through protein mediators (e.g., Bcl-2, Bcl-2–associated death promoter, Bcl-2– associated X protein, Bim) that influence mitochondrial membrane permeability. Increased membrane permeability leads to the release of mitochondrial cytochrome C, which ultimately activates caspase 3 and thus induces apoptosis. These pathways do not function in a completely autonomous manner, because there is significant interaction and crosstalk between mediators of both extrinsic and intrinsic pathways. Apoptosis is modulated by several regulatory factors, including inhibitor of apoptosis proteins and regulatory caspases (e.g., caspases 1, 8, 10). Apoptosis during sepsis may influence the ultimate competency of the acquired immune response. In a murine model of peritoneal sepsis, increased lymphocyte apoptosis was associated with mortality, which may be due to a resultant decrease in IFN-γ release. In postmortem analysis of patients who expired from overwhelming sepsis, there was an increase in lymphocyte apoptosis, whereas macrophage apoptosis did not appear to be affected. Clinical trials have observed an association between the degree of lymphopenia and disease severity in sepsis. In addition, after the phagocytosis of apoptotic cells by macrophages, anti-inflammatory mediators such as IL-10 are released that may exacerbate immune suppression during sepsis. Neutrophil apoptosis is inhibited by inflammatory products, including TNF, IL-1, IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IFN-γ. This retardation in regulated cell death may prolong and exacerbate secondary injury through neutrophil free radical release as the clearance of senescent cells is delayed.63 Necroptosis Cellular necrosis refers to the premature uncontrolled death of cells in living tissue typically caused by accidental exposure VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support D FADD D 26 PART I BASIC CONSIDERATIONS to external factors, such as ischemia, inflammation, or trauma, which result in extreme cellular stress. Necrosis is characterized by the loss of plasma membrane integrity and cellular collapse with extrusion of cytoplasmic contents, but the cell nuclei typically remain intact. Recent data have defined a process by which necrosis occurs through a series of well-described steps that are dependent on a signaling pathway that involves the receptor-interacting protein kinase (RIPK) complex. Termed “necroptosis,” it occurs in response to specific stimuli, such as TNF- and TLR-mediated signals.64 For example, ligation of the TNF receptor 1 (TNFR1) under conditions in which caspase 8 is inactivated (e.g., by pharmacologic agents) results in the overgeneration of ROS and a metabolic collapse. The net result is programmed necrosis (necroptosis). The effect of cell death by necroptosis on the immune response is not yet known. However, it is likely that the “DAMP” signature that occurs in response to necroptotic cell death is an important contributor to the systemic inflammatory response. Evidence to support this concept was provided by investigators who examined the role of necroptosis in murine models of sepsis. They demonstrated that Ripk3−/− mice were capable of recovering body temperature better, exhibited lower circulating DAMP levels, and survived at higher rates than their wild-type littermates.65 These data suggest that the cellular damage that occurs with programmed necrosis exacerbates the sepsis-associated systemic inflammatory response. MEDIATORS OF INFLAMMATION Cytokines Cytokines are a class of protein signaling compounds that are essential for both innate and adaptive immune responses. Cytokines mediate a broad sequence of cellular responses, 5 including cell migration, DNA replication, cell turnover, and immunocyte proliferation (Table 2-5). When functioning locally at the site of injury and infection, cytokines mediate the eradication of invading microorganisms and also promote wound healing. However, an exaggerated proinflammatory cytokine response to inflammatory stimuli may result in hemodynamic instability (i.e., septic shock) and metabolic derangements (i.e., muscle wasting). Anti-inflammatory cytokines also are released, at least in part, as an opposing influence to the proinflammatory cascade. These anti-inflammatory mediators may also result in immunocyte dysfunction and host immunosuppression. Cytokine signaling after an inflammatory stimulus can best be represented as a finely tuned balance of opposing influences and should not be oversimplified as a “black and white” proinflammatory/anti-inflammatory response. A brief discussion of the important cytokine molecules is included. Tumor Necrosis Factor-α. TNF-α is a cytokine that is rapidly mobilized in response to stressors such as injury and infection and is a potent mediator of the subsequent inflammatory response. TNF is primarily synthesized by immune cells, such as macrophages, dendritic cells, and T lymphocytes, but nonimmune cells have also been reported to secrete low amounts of the cytokine. TNF is generated in a precursor form called transmembrane TNF that is expressed as a trimer on the surface of activated cells. After being processed by the metalloproteinase TNF-α–converting enzyme (TACE; also known as ADAM-17), a smaller, soluble form of TNF is released, which mediates its biologic activities through type 1 and 2 TNF receptors (TNFR1; TNFR2).66 Transmembrane TNF-α also binds to TNFR1 and TNFR2, but its biologic activities are likely mediated through TNFR2. While the two receptors share homology in their ligand binding regions, there are distinct differences that regulate their biologic function. For example, TNFR1 is expressed by a wide variety of cells but is typically sequestered in the Golgi complex. Following appropriate cell signaling, TNFR1 is mobilized to the cell surface, where it sensitizes cells to TNF, or it can be cleaved from the surface in the form of a soluble receptor that can neutralize TNF.67 In contrast, TNFR2 expression is confined principally to immune cells where it resides in the plasma membrane. Both TNF receptors are capable of binding intracellular adaptor proteins that lead to activation of complex signaling processes and mediate the effects of TNF. Although the circulating half-life of soluble TNF is brief, it acts upon almost every differentiated cell type, eliciting a wide range of important cellular responses. In particular, TNF elicits many metabolic and immunomodulatory activities. It stimulates muscle breakdown and cachexia through increased catabolism, insulin resistance, and redistribution of amino acids to hepatic circulation as fuel substrates. TNF also mediates coagulation activation, cell migration, and macrophage phagocytosis, and enhances the expression of adhesion molecules, prostaglandin E2, platelet-activating factor, glucocorticoids, and eicosanoids. Recent studies indicate that a significant early TNF response after trauma may be associated with improved survival in these patients.68 Interleukin-1. IL-1α and IL-1β, which are encoded by two distinct IL-1 genes, were the first described members of the IL-1 cytokine family. Currently, the family has expanded to 11 members, with the three major forms being IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1Rα). IL-1α and IL-1β share similar biologic functions, but have limited sequence homology. They use the same cell surface receptor, termed IL-1 receptor type 1 (IL-1R1), which is present on nearly all cells. Although IL-1Rα is synthesized and released in response to the same stimuli that lead to IL-1 production, it lacks the necessary domain to form a bioactive complex with the IL-1 receptor when bound. Thus, IL-1Rα serves as a competitive antagonist for the receptor. IL-1R activation initiates signaling events, which result in the synthesis and release of a variety of inflammatory mediators. The IL-1α precursor is constitutively expressed and stored in a variety of healthy cells, including epithelium, endothelium, and platelets. Both the precursor and mature forms of IL-1α are active. With appropriate signals, IL-1α moves to the cell membrane where it can act on adjacent cells bearing the IL-1 receptor. It can also be released directly from injured cells. In this way, IL-1α is believed to function as a DAMP, which promotes the synthesis of inflammatory mediators, such as chemokines and eicosanoids. These mediators attract neutrophils to the injured site, facilitate their exit from the vasculature, and promote their activation. Once they have reached their target, neutrophil lifespan is extended by the presence of IL-1α.69 IL-1β, a multifunctional proinflammatory cytokine, is not detectable in healthy cells. Rather, its expression and synthesis occur in a more limited number of cells, such as monocytes, tissue macrophages, and dendritic cells, following their activation. IL-1β expression is tightly regulated at multiple levels (e.g., transcription, translation, and secretion), although the rate-limiting step is its transcription. IL-1β is synthesized and released in response to inflammatory stimuli, including cytokines VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 27 Table 2-5 Cytokines and their sources Cytokine Source Comment TNF Macrophages/monocytes Kupffer cells Neutrophils NK cells Astrocytes Endothelial cells T lymphocytes Adrenal cortical cells Adipocytes Keratinocytes Osteoblasts Mast cells Dendritic cells Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and catabolism CHAPTER 2 IL-1 Macrophages/monocytes B and T lymphocytes NK cells Endothelial cells Epithelial cells Keratinocytes Fibroblasts Osteoblasts Dendritic cells Astrocytes Adrenal cortical cells Megakaryocytes Platelets Neutrophils Neuronal cells Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min Systemic Response to Injury and Metabolic Support IL-2 T lymphocytes Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis IL-3 T lymphocytes Macrophages Eosinophils Mast cells IL-4 T lymphocytes Mast cells Basophils Macrophages B lymphocytes Eosinophils Stromal cells Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF, IL-1, IL-6, IL-8 IL-5 T lymphocytes Eosinophils Mast cells Basophils Promotes eosinophil proliferation and airway inflammation IL-6 Macrophages B lymphocytes Neutrophils Basophils Mast cells Fibroblasts Endothelial cells Astrocytes Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs activated neutrophil survival (Continued) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 28 Table 2-5 Cytokines and their sources (continued) Cytokine Source Comment PART I BASIC CONSIDERATIONS Synovial cells Adipocytes Osteoblasts Megakaryocytes Chromaffin cells Keratinocytes IL-8 Macrophages/monocytes T lymphocytes Basophils Mast cells Epithelial cells Platelets Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes IL-10 T lymphocytes B lymphocytes Macrophages Basophils Mast cells Keratinocytes Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models IL-12 Macrophages/monocytes Neutrophils Keratinocytes Dendritic cells B lymphocytes Promotes Th1 differentiation; synergistic activity with IL-2 IL-13 T lymphocytes Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation IL-15 Macrophages/monocytes Epithelial cells Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections IL-18 Macrophages Kupffer cells Keratinocytes Adrenal cortical cells Osteoblasts Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac deaths IFN-γ T lymphocytes NK cells Macrophages Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS GM-CSF T lymphocytes Fibroblasts Endothelial cells Stromal cells Promotes wound healing and inflammation through activation of leukocytes IL-21 T lymphocytes Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes; influences adaptive immunity HMGB1 Monocytes/lymphocytes High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation (ARDS, gut barrier disruption); induces “sickness behavior” ARDS = acute respiratory distress syndrome; GM-CSF = granulocyte-macrophage colony-stimulating factor; IFN = interferon; Ig = immunoglobulin; IL = interleukin; NK = natural killer; Th1 = helper T cell subtype 1; Th2 = helper T cell subtype 2; TNF = tumor necrosis factor. (TNF, IL-18) and foreign pathogens. IL-1α or IL-1β itself can also induce IL-1β transcription. In contrast to IL-1α, IL-1β is synthesized as an inactive precursor molecule. The formation of mature IL-1β requires the assembly of the inflammasome complex by the cell and the activation of caspase 1, which is required for the processing of stored pro-IL-1β. Mature IL-1β is then released from the cell via an unconventional secretory pathway. IL-1β has a spectrum of proinflammatory effects that are largely similar to those induced by TNF, and injection of IL-1β alone is sufficient to induce inflammation. High doses of either IL-1β or TNF are associated with profound hemodynamic compromise. Interestingly, low doses of both IL-1β and TNF VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ primarily by CD4+ T cells after antigen activation, which plays a pivotal role in the immune response. Other cellular sources for IL-2 include CD8+ and NK T cells, mast cells, and activated dendritic cells. Discovered as a T-cell growth factor, IL-2 also promotes CD8+ T-cell and NK cell cytolytic activity and modulates T-cell differentiation programs in response to antigen. Thus, IL-2 promotes naïve CD4+ T-cell differentiation into T helper 1 (Th1) and T helper 2 (Th2) cells while inhibiting T helper 17 (Th17) and T follicular helper (Tfh) cell differentiation. Moreover, IL-2 is essential for the development and maintenance of T regulatory (Treg) cells and for activation-induced cell death, thereby mediating tolerance and limiting inappropriate immune reactions. The upregulation of IL-2 requires calcium as well as protein kinase C signaling, which leads to the activation of transcription factors such as nuclear factor of activated T cells (NFAT) and NF-κB. MicroRNAs also play a role in the regulation of IL-2 expression.71 IL-2 binds to IL-2 receptors (IL-2R), which are expressed on leukocytes. IL-2Rs are formed from various combinations of three receptor subunits: IL-2Rα, IL-2Rβ, and IL-2Rγ; these form low-, medium-, and high-affinity forms of the receptor depending on the subunit combination. IL-2Rγ has been renamed the common cytokine receptor γ chain (γc), which is now known to be shared by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Constitutive IL-2 receptor expression is low and is inducible by T-cell receptor ligation and cytokine stimulation. Importantly, the transcription of each receptor subunit is individually regulated via a complex process to effect tight control of surface expression. Once the receptor is ligated, the major IL-2 signaling pathways that are engaged include Janus kinase (JAK) signal transducer and activator of transcription (STAT), Shc-Ras-MAPK, and phosphoinositol-3-kinase (PI3K)-AKT. Partly due to its short half-life of <10 minutes, IL-2 is not readily detectable after acute injury. IL-2 receptor blockade induces immunosuppressive effects and can be pharmacologically used for organ transplantation. Attenuated IL-2 expression observed during major injury or blood transfusion may contribute to the relatively immunosuppressed state of the surgical patient.72 Interleukin-6. Following burn or traumatic injury, DAMPs from damaged or dying cells stimulate TLRs to produce IL-6, a pleiotropic cytokine that plays a central role in host defense. IL-6 levels in the circulation are detectable by 60 minutes, peak Interleukin-10. We have talked almost exclusively about the factors that initiate the inflammatory response following cellular stress or injury. The re-establishment of immune homeostasis following these events requires the resolution of inflammation and the initiation of tissue repair processes. IL-10 plays a central role in this anti-inflammatory response by regulating the duration and magnitude of inflammation in the host. The IL-10 family currently has six members including IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26. IL-10 is produced by a variety of immune cells of both myeloid and lymphoid origin. Its synthesis is upregulated during times of stress and systemic inflammation; however, each cell type that produces IL-10 does so in response to different stimuli, allowing for tight control of its expression. IL-10 exerts effects by binding to the IL-10 receptor (IL-10R), which is a tetramer formed from two distinct subunits, IL-10R1 and IL-10R2. Specifically, IL-10 binds first to the IL-10R1 subunit, which then recruits IL-10R2, allowing the receptor complex to form. Whereas IL-10R2 is widely expressed, IL-10R1 expression is confined to leukocytes so that this differential expression of the receptor confines the effects of IL-10 to the immune system. Once receptor ligation occurs, signaling proceeds by the activation of JAK1 and STAT3. In particular, STAT3 in conjunction with IL-10 is absolutely required for the transcription of genes responsible for the anti-inflammatory response. IL-10 inhibits the secretion of proinflammatory cytokines, including TNF and IL-1, partly through the downregulation of NF-κB, and thereby functions as a negative feedback regulator of the inflammatory cascade.76 In macrophages, IL-10 suppresses the transcription of 20% of all lipopolysaccharide (LPS)-induced genes. Further, experimental VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 29 Systemic Response to Injury and Metabolic Support Interleukin-2. IL-2 is a multifunctional cytokine produced between 4 and 6 hours, and can persist for as long as 10 days. Further, plasma levels of IL-6 are proportional to the degree of injury. In the liver, IL-6 strongly induces a broad spectrum of acute-phase proteins such as CRP and fibrinogen, among others, whereas it reduces expression of albumin, cytochrome P450, and transferrin. In lymphocytes, IL-6 induces B-cell maturation into immunoglobulin-producing cells and regulates Th17/ Treg balance. IL-6 modulates T-cell behavior by inducing the development of Th17 cells and inhibiting Treg cell differentiation in conjunction with transforming growth factor-β. IL-6 also promotes angiogenesis and increased vascular permeability, which are associated with local inflammatory responses. To date, 10 IL-6 family cytokines have been identified, including IL-6, oncostatin M, neuropoietin, IL-11, IL-27, and IL-31, all of which use trans signaling.73 The IL-6 receptor (IL-6R, gp80) is expressed on hepatocytes, monocytes, B cells, and neutrophils in humans. However, many other cells respond to IL-6 through a process known as trans signaling.74 In this case, soluble IL-6Rs (sIL-6R) exist in the serum and bind to IL-6, forming an IL-6/sIL-6R complex. The soluble receptor is produced by proteolytic cleavage from the surface of neutrophils in a process that is stimulated by CRP, complement factors, and leukotrienes. The IL-6/sIL-6R complex can then bind to the gp130 receptor, which is expressed ubiquitously on cells. Upon IL-6 stimulation, gp130 transduces two major signaling pathways: the JAK-STAT3 pathway and the SHP2-Gab-Ras-Erk-MAPK pathway, which is regulated by cytoplasmic suppressor of cytokine signaling (SOCS3). These signaling events can lead to increased expression of adhesion molecules as well as proinflammatory chemokines and cytokines. High plasma IL-6 levels have been associated with mortality during intra-abdominal sepsis.75 CHAPTER 2 combined elicit hemodynamic events similar to those elicited by high doses of either mediator, which suggests a synergistic effect. There are two primary receptor types for IL-1: IL-1R1 and IL-1R2. IL-1R1 is widely expressed and mediates inflammatory signaling on ligand binding. IL-1R2 is proteolytically cleaved from the membrane surface to soluble form on activation and thus serves as another mechanism for competition and regulation of IL-1 activity. IL-1α or IL-1β binds first to IL-1R1. This is followed by recruitment of a transmembrane coreceptor, termed the IL-1R accessory protein (IL-1RAcP). A complex is formed of IL-1R1 plus IL-1 plus the coreceptor. The signal is initiated with recruitment of the adaptor protein MyD88 to the toll–IL-1 receptor (TIR) domains of the receptor complex and signal transduction then occurs via intermediates, which are homologous to the signal cascade initiated by TLRs. These events culminate in the activation of NF-κB and its nuclear translocation.70 30 PART I BASIC CONSIDERATIONS models of inflammation have shown that neutralization of IL-10 increases TNF production and mortality, whereas restitution of circulating IL-10 reduces TNF levels and subsequent deleterious effects. Increased plasma levels of IL-10 also have been associated with mortality and disease severity after traumatic injury. IL-10 may significantly contribute to the underlying immunosuppressed state during sepsis through the inhibition and subsequent anergy of immunocytes. For example, IL-10 produced by Th2 cells directly suppresses Th1 cells and can feedback to suppress Th2 cell activity.77 Interleukin-12. IL-12 is unique among the cytokines in being the only heterodimeric cytokine. This family, which includes IL-12, IL-23, IL-27, and IL-35, consists of an α-chain that is structurally similar to the IL-6 cytokine and a β-chain that is similar to the class I receptor for cytokines. The individual IL-12 family members are formed from various combinations of the α and β subunits. Despite the sharing of individual subunits and the similarities of their receptors, the IL-12 cytokines have different biologic functions. IL-12 and IL-23 are considered proinflammatory, stimulatory cytokines with key roles in the development of Th1 and Th17 subsets of helper T cells. In contrast, both IL-27 and IL-35 appear to have immunoregulatory functions that are associated with cytokine inhibition in specific Treg cell populations, particularly the Th17 cells.78 The effects of these cytokines require specific receptor chains that are also shared among the cytokines. The complexity of signaling is evidenced by the fact that these receptor chains can function both as dimers and as monomers. Ligation of the IL-12 receptors initiates signaling events mediated by the JAK-STAT pathway. IL-12 synthesis and release are increased during endotoxemia and sepsis.79 IL-12 stimulates lymphocytes to increase secretion of IFN-γ with the costimulus of IL-18 and also stimulates NK cell cytotoxicity and helper T-cell differentiation in this setting. IL-12 release is inhibited by IL-10. IL-12 deficiency inhibits phagocytosis in neutrophils. In experimental models of inflammatory stress, IL-12 neutralization conferred a mortality benefit in mice during endotoxemia. However, in a cecal ligation and puncture model of intraperitoneal sepsis, IL-12 blockade was associated with increased mortality. Furthermore, later studies of intraperitoneal sepsis observed no difference in mortality with IL-12 administration; however, IL-12 knockout mice exhibited increased bacterial counts and inflammatory cytokine release, which suggests that IL-12 may contribute to an antibacterial response. IL-12 administration in chimpanzees is capable of stimulating the release of proinflammatory mediators such as IFN-γ and also anti-inflammatory mediators, including IL-10, soluble TNFR, and IL-1 receptor antagonists. In addition, IL-12 enhances coagulation as well as fibrinolysis. Interleukin-18. IL-18 is a member of the IL-1 superfamily of cytokines. First noted as an IFN-γ–inducing factor produced by LPS-stimulated macrophages, IL-18 expression is found both in immune cells and nonimmune cells at low to intermediate levels. However, activated macrophages and Kupffer cells produce large amounts of mature IL-18. Similar to IL-1β, IL-18 is synthesized and stored as an inactive precursor form (pro-IL-18), and activation requires processing by caspase 1 in response to the appropriate signaling. It then exits the cell through a nontraditional secretory pathway. The IL-18 receptor (IL-18R) is composed of two subunits, IL-18Rα and IL-18Rβ, and is a member of the IL-1R superfamily, which is structurally similar in its cytoplasmic domains to the TLR. One unique biologic property of IL-18 is the potential, in conjunction with IL-12, to promote the Th1 response to bacterial infection. At the same time, exogenous IL-18 can also enhance the Th2 response and Ig-mediated humoral immunity, as well as augment neutrophil function. Recent studies suggest that IL-18 therapy may hold promise as effective therapy in promoting immune recovery after severe surgical stress.80 Interferons. Interferons were first recognized as soluble mediators that inhibited viral replication through the activation of specific antiviral genes in infected cells. Interferons are categorized into three types based on receptor specificity and sequence homology. The two major types, type I and type II, are discussed here. Type I interferons, of which there are 20, include IFN-α, IFN-β, and IFN-ω, which are structurally related and bind to a common receptor, IFN-α receptor. They are likely produced by most cell types and tissues in response to appropriate pathogens or DAMP signaling. Type I interferons are expressed in response to many stimuli, including viral antigens, double-stranded DNA, bacteria, tumor cells, and LPS. Type I interferons influence adaptive immune responses by inducing the maturation of dendritic cells and by stimulating class I major histocompatibility complex (MHC) expression. IFN-α and IFN-β also enhance immune responses by increasing the cytotoxicity of NK cells both in culture and in vivo. Further, they have been implicated in the enhancement of chemokine synthesis, particularly those that recruit myeloid cells and lymphoid cells. Thus, IFN/ STAT signaling has important effects on the mobilization, tissue recruitment, and activation of immune cells that compose the inflammatory infiltrate. In contrast, IFN-I appears to inhibit inflammasome activity, possibly via IL-10.81 Many of the physiologic effects observed with increased levels of IL-12 and IL-18 are mediated through IFN-γ. IFN-γ is a type II interferon that is secreted by various T cells, NK cells, and antigen-presenting cells in response to bacterial antigens, IL-2, IL-12, and IL-18. IFN-γ stimulates the release of IL-12 and IL-18. Negative regulators of IFN-γ include IL-4, IL-10, and glucocorticoids. IFN-γ binding with a cognate receptor activates the JAK-STAT pathway, leading to subsequent induction of biologic responses. Macrophages stimulated by IFN-γ demonstrate enhanced phagocytosis and microbial killing and increased release of oxygen radicals, partly through an NADPdependent phagocyte oxidase. IFN-γ mediates macrophage stimulation and thus may contribute to acute lung injury after major surgery or trauma. Diminished IFN-γ level, as seen in knockout mice, is associated with increased susceptibility to both viral and bacterial pathogens. In addition, IFN-γ promotes differentiation of T cells to the helper T-cell subtype 1 and also enhances B-cell isotype switching to immunoglobulin G.82 Receptors of all IFN subtypes belong to the class II of cytokine receptors and use the JAK-STAT signaling pathway for nuclear signaling, although different STAT activation (e.g., STAT1 and STAT2) is favored by individual receptors. Granulocyte-Macrophage Colony-Stimulating Factor/ Interleukin-3/Interleukin-5. GM-CSF, IL-3, and IL-5 compose a small family of cytokines that regulate the growth and activation of immune cells. They are largely the products of activated T cells, which when released stimulate the behavior of myeloid cells by inducing cytokine expression and antigen presentation. In this way, GM-CSF, IL-3, and IL-5 are able to link the innate and acquired immune responses. With the exception VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Eicosanoids Omega-6 Polyunsaturated Fat Metabolites: Arachidonic Acid. Eicosanoids are derived primarily by oxidation of the membrane phospholipid, arachidonic acid [all-cis-5,8,11,14eicosatetraenoic acid; 20:4(ω-6) eicosatetraenoic acid], which Phospholipid Phospholipase A2 Corticosteroids Arachidonic acid Cyclooxygenase Lipoxygenase Cyclic endoperoxides (PGG2 ,PGH2 ) Hydroperoxyeicosatetraenoic acid (HPETE) Thromboxane TXA2 Prostaglandins PGD2 Hydroxyeicosatetraenoic acid Leukotrienes (HETE) LTA4 PGE2 LTB4 PGF2α LTC4 PGI2 LTD4 LTE4 A Free eicosapentaenoic acid Cyclooxygenase B Lipoxygenase 3-series prostaglandins 5-series leukotrienes PGG3 5-HPEPE PGH3 LTA5 E-series resolvins Anti-inflammatory and inflammation resolving LTC5 LTB5 Figure 2-6. Schematic diagram of (A) arachidonic acid and (B) eicosapentaenoic acid metabolism. LT = leukotriene; PG = prostaglandin; TXA2 = thromboxane A2; HPEPE = hydroperoxyeicosapentaenoic acid. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 31 Systemic Response to Injury and Metabolic Support is relatively abundant in the membrane lipids of inflammatory cells. They are composed of three families, which include prostaglandins, thromboxanes, and leukotrienes. Arachidonic acid is not stored free in the cell but in an esterified form in phospholipids and neutral lipids. When a cell senses the proper stimulus, arachidonic acid is released from phospholipids or diacylglycerols by the enzymatic activation of phospholipase A2 (Fig. 2-6A). Prostanoids, which include all of the prostaglandins and the thromboxanes, result from the sequential action of the cyclooxygenase (COX) enzyme and terminal synthetases on arachidonic acid. In contrast, arachidonic acid may be oxidized along the lipoxygenase pathway via the central enzyme 5-lipoxygenase, to produce several classes of leukotrienes and lipoxins. In general, the effects of eicosanoids are mediated via specific receptors, which are members of a superfamily of G-protein–coupled receptors. Eicosanoids are not stored within cells but are instead generated rapidly in response to many stimuli, including hypoxic injury, direct tissue injury, endotoxin (lipopolysaccharide), NE, vasopressin, angiotensin II, bradykinin, serotonin, ACh, cytokines, and histamine. Eicosanoid pathway activation also leads to the formation of the anti-inflammatory compound lipoxin, which inhibits chemotaxis and NF-κB activation. Glucocorticoids, nonsteroidal anti-inflammatory drugs, and leukotriene CHAPTER 2 of eosinophils, GM-CSF, IL-3, and IL-5 are not essential for constitutive hematopoietic cell function. Rather, they play an important role when the host is stressed, by serving to increase the numbers of activated and sensitized cells required to bolster host defense.83 Currently, GM-CSF is in clinical trials for administration to children with an Injury Severity Score >10 following blunt or penetrating trauma. The goal of the study is to provide evidence of the effectiveness of GM-CSF as an agent that can ameliorate posttraumatic immune suppression. Receptors for the GM-CSF/IL-3/IL-5 family of cytokines are expressed at very low levels on hematopoietic cells. Similar to the other cytokine receptors discussed, they are heterodimers composed of a cytokine-specific α subunit and a common β subunit (βc), which is shared by all three receptors and is required for high-affinity signal transduction. The binding of cytokine to its receptor activates JAK2-STAT–, MAPK-, and PI3K-mediated signaling events to regulate a variety of important cell behaviors including effector function in mature cells. 32 PART I BASIC CONSIDERATIONS inhibitors block the end products of eicosanoid pathways. Eicosanoids have a broad range of physiologic roles, including neurotransmission and vasomotor regulation. They are also involved in immune cell regulation (Table 2-6) by modulating the intensity and duration of inflammatory responses. The production of eicosanoids is cell- and stimulus-specific. Therefore, the signaling events that are initiated will depend on the concentrations and types of eicosanoids generated, as well as the unique complement of receptors expressed by their target cells. For example, prostaglandin E2 (PGE2) suppresses the effector function of macrophages (i.e., phagocytosis and intracellular pathogen killing) via a mechanism that is dependent on increased cAMP levels. PGE 2 also modulates chemokine TABLE 2-6 Systemic stimulatory and inhibitory actions of eicosanoids Organ/Function Pancreas  Glucose-stimulated insulin secretion Glucagon secretion Stimulator Inhibitor 12-HPETE PGE2 PGD2, PGE2 Liver  Glucagon-stimulated glucose production PGE2 Fat  Hormone-stimulated lipolysis PGE2 Bone Resorption Pituitary Prolactin Luteinizing hormone  Thyroid-stimulating hormone Growth hormone PGE2, PGE-m, 6-KPGE1, PGF1α, PGI2 Omega-3 Polyunsaturated Fat Metabolites: All-cis5,8,11,14,17-Eicosapentaenoic Acid [20:5(ω-3) Eicosapentaenoic Acid]. As noted earlier, polyunsaturated fatty acid PGE1 PGE1, PGE2, 5-HETE PGA1, PGB1, PGE1, PGE1 PGE1 Parathyroid Parathyroid hormone PGE2 PGF2 Lung Bronchoconstriction PGE2 Kidney  Stimulation of renin secretion PGF2α TXA2, LTC4, LTD4, LTE4 PGE2, PGI2 Gastrointestinal system Cytoprotective effect PGE2 Immune response  Suppression of lymphocyte activity Hematologic system Platelet aggregation PGE2 TXA2 production and enhances local accumulation of regulatory T cells and myeloid-derived suppressor cells. Prostacyclin (PGI2) has an inhibitory effect on Th1- and Th2-mediated immune responses, while enhancing Th17 differentiation and cytokine production. Leukotrienes are potent mediators of capillary leakage as well as leukocyte adherence, neutrophil activation, bronchoconstriction, and vasoconstriction. Leukotriene B4 is synthesized from arachidonic acid in response to acute Ca2+ signaling induced by inflammatory mediators.84 High-affinity leukotriene receptors (BLT1) are expressed primarily in leukocytes, including granulocytes, eosinophils, macrophages, and differentiated T cells, whereas the low-affinity receptor is expressed in many cell types. Activation of BLT1 results in inhibition of adenylate cyclase and reduced production of cAMP. Not surprisingly, a role for leukotriene B4 signaling in abrogating the effects of prostaglandins on macrophage effector function has recently been shown.85 Recent evidence supports a role for lipid droplets (LDs) as an important intracellular source of arachidonic acid. LDs are neutral lipid storage organelles ubiquitous to eukaryotic cells that are a rich source of esterified arachidonic acid especially in leukocytes. Accumulation of LDs in response to TLR signaling has been reported with an associated increase in the generation of eicosanoid metabolites.86 While experimental models of sepsis have shown a benefit to inhibiting eicosanoid production, human sepsis trials have failed to show a mortality benefit.87 Eicosanoids also have several recognized metabolic effects. COX pathway products inhibit pancreatic β-cell release of insulin, whereas lipoxygenase pathway products stimulate β-cell activity. Prostaglandins such as PGE2 can inhibit gluconeogenesis through the binding of hepatic receptors and also can inhibit hormone-stimulated lipolysis.88 PGI2 5-HETE = 5-hydroxyeicosatetraenoic acid; 12-HPETE = 12-hydroxyperoxyeicosatetraenoic acid; 6-K-PGE1 = 6-keto-prostaglandin E1; LT = leukotriene; PG = prostaglandin; PGE-m = 13,14-dihydro-15-keto-PGE2 (major urine metabolite of PGE2); TXA2 = thromboxane A2. (PUFA) metabolites of endogenous arachidonic acid function as inflammatory mediators and have significant roles in the inflammatory response. The major direct dietary source of arachidonic acid is from meat. However, a much larger quantity of ω-6 PUFAs is ingested as linoleic acid, which is found in many vegetable oils, including corn, sunflower, and soybean oils, and in products made from such oils, such as margarines. Linolenic acid is not synthesized in mammals; however, it can be converted to arachidonic acid through lengthening of the carbon chain and the addition of double bonds. The second major family of PUFAs is the ω-3 fatty acid. They can also be derived from shorter chain ω-3 fatty acids of plant origin such as α-linolenic acid, which can be converted after ingestion to eicosapentaenoic acid (EPA) and to docosahexaenoic acid (DHA). ω-3 fatty acids are found in cold water fish, especially tuna, salmon, mackerel, herring, and sardine, which can provide between 1.5 and 3.5 g of these long-chain ω-3 PUFAs per serving. EPA and DHA are also substrates for the COX and lipoxygenase (LOX) enzymes that produce eicosanoids, but the mediators produced have a different structure from the arachidonic acid–derived mediators, and this influences their potency (Fig. 2-6B). In addition, ω-3 fatty acids are reported to have specific anti-inflammatory effects, including inhibition of NF-κB activity, TNF release from hepatic Kupffer cells, and leukocyte adhesion and migration. These are achieved via two purported mechanisms: (a) by decreasing the production of arachidonic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Complement. Following traumatic injury, there is almost immediate activation of the complement system, which is a major effector mechanism of the innate immune system. The complement system was thought to act initially as the required “first line of defense” for the host against pathogens, by binding and clearing them from the circulation. Recent data indicate that complement also participates in the elimination of immune complexes as well as damaged and dead cells. In addition, complement is recognized as contributing to mobilization of hematopoietic stem/progenitor cells and lipid metabolism.91 Although complement activation is typically depicted as a linear process in which parallel pathways are activated, it actually functions more like a central node that is tightly networked with other systems. Then, depending on the activating signal, several initiation and regulatory events act in concert to heighten immune surveillance. Complement activation proceeds via three different pathways. Initiation of these pathways occurs by the binding and activation of the recognition unit of each pathway to its designated ligand. The classical pathway, which is often referred to as “antibody dependent,” is initiated by direct binding of C1q to its common ligands, which include immunoglobulin (Ig) M/IgG aggregates. Alternately C1q can activate complement signaling by binding to soluble pattern recognition molecules such as pentraxins (e.g., CRP). In a series of subsequent activation and amplification steps, the pathway ultimately leads to the assembly of the C3 convertase, which cleaves C3 into C3a and C3b. As C3b then complexes with C3 convertase, the C5 convertase is activated, cleaving C5 into C5a and C5b. C3a and C5a are potent anaphylatoxins. C3b acts as an opsonin, whereas C5b initiates the formation of the membrane attack complex. When C5b Kallikrein-Kinin System. The kallikrein-kinin system is a group of proteins that contribute to inflammation, blood pressure control, coagulation, and pain responses. Prekallikrein is synthesized in the liver and circulates in the plasma bound to high molecular weight kininogen (HK). A variety of stimuli lead to the binding of prekallikrein-HK complex to Hageman factor, (factor XII) followed by its activation, to produce the serine protease kallikrein, which plays a role in the coagulation cascade. HK, produced by the liver, is cleaved by kallikrein to form bradykinin (BK). The kinins (e.g., BK) mediate several physiologic processes, including vasodilation, increased capillary permeability, tissue edema, pain pathway activation, inhibition of gluconeogenesis, and increased bronchoconstriction. They also increase renal vasodilation and consequently reduce renal perfusion pressure. Kinin receptors are members of the rhodopsin family of G-protein–coupled receptors and are located on vascular endothelium and smooth muscle cells. Kinin receptors are rapidly upregulated following TLR4 signaling and in response to cytokines and appear to have important effects on both immune cell behavior and on immune mediators.93 For example, B1 activation results in increased neutrophil chemotaxis, while increased B2 receptor expression causes activation of arachidonic-prostaglandin pathways. Bradykinin and kallikrein levels are increased during gram-negative bacteremia, hypotension, hemorrhage, endotoxemia, and tissue injury. The degree of elevation in the levels of these mediators has been associated with the magnitude of injury and mortality. Clinical trials using bradykinin antagonists have shown some benefit in patients with gram-negative sepsis.94 Serotonin Serotonin is a monoamine neurotransmitter (5-hydroxytryptamine [5-HT]) derived from tryptophan. Serotonin is synthesized by neurons in the CNS as well as by intestinal enterochromaffin cells, which are the major source of plasma 5-HT. Once in the plasma, 5-HT is taken up rapidly into platelets via the serotonin transporter (SERT) where it is either stored in the dense granules in millimolar concentrations or targeted for degradation. It is VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 33 Systemic Response to Injury and Metabolic Support Plasma Contact System associates with C6 and C7, the complex becomes inserted into cell membrane and interacts with C8, inducing the binding of several units of C9 to form a lytic pore. The lectin pathway of complement activation is initiated by mannose-binding lectins or ficolins, which act as the soluble PRM by binding specific carbohydrate structures that are often present on pathogens. The alternative pathway also includes a PRM-based initiation mechanism that resembles those found in the lectin pathway but involves properdin. The latter recognizes several PAMPs and DAMPs on foreign and apoptotic cells. Once bound, it initiates and propagates the complement response by attracting fluid-phase C3b to recognized surfaces and by stabilizing C3 convertase complexes. Despite its name, the alternative pathway may account for up to 80% to 90% of total complement activation.92 The major source of the circulating complement components is the liver. Complement proteins can also be produced locally where they have been implicated in the regulation of adaptive immune processes. Complement protein synthesis has been demonstrated in immune cells, including T cells, which when surface bound, interact with C3 and C4 receptors. Also, complement synergistically enhances TLR-induced production of proinflammatory cytokines through convergence of their signaling pathways. CHAPTER 2 acid (ω-6)–derived proinflammatory mediators (by competition for the same enzymes) and (b) by generation of proresolving bioactive lipid mediators. In fact, key derivatives of ω-3 PUFAs, termed resolvins, have been identified and synthesized. Resolvins are now categorized as either E-series (from EPA) or D-series (from DHA). In a variety of model systems, resolvins have been shown to attenuate the inflammatory phenotypes of a number of immune cells.89 The ratio of dietary ω-6 to ω-3 PUFAs is reflected in the membrane composition of various cells, including cells of the immune system, which has potential implications for the inflammatory response. For example, a diet that is rich in ω-6 PUFAs will result in cells whose membranes are “ω-6 PUFA rich.” When ω-6 PUFAs are the main plasma membrane lipid available for phospholipase activity, more proinflammatory PUFAs (i.e., two-series prostaglandins) are generated. Many lipid preparations are soy-based and thus primarily composed of ω-6 fatty acids. These are thought to be “inflammation enhancing.” Nutritional supplementation with ω-3 fatty acid has the potential to dampen inflammation by shifting the cell membrane composition in favor of ω-3 PUFAs. In experimental models of sepsis, ω-3 fatty acids inhibit inflammation, ameliorate weight loss, increase small-bowel perfusion, and may increase gut barrier protection. In human studies, ω-3 supplementation is associated with decreased production of TNF, IL-1β, and IL-6 by endotoxin-stimulated monocytes. In a study of surgical patients, preoperative supplementation with ω-3 fatty acid was associated with reduced need for mechanical ventilation, decreased hospital length of stay, and decreased mortality with a good safety profile.90 34 PART I BASIC CONSIDERATIONS interesting that the surface expression of SERT on platelets is sensitive to plasma 5-HT levels, which in turn modulates platelet 5-HT content. Receptors for serotonin are widely distributed in the periphery and are found in the gastrointestinal tract, cardiovascular system, and some immune cells.95 Serotonin is a potent vasoconstrictor and also modulates cardiac inotropy and chronotropy through nonadrenergic cAMP pathways. Serotonin is released at sites of injury, primarily by platelets. Recent work has demonstrated an important role for platelet 5-HT in the local inflammatory response to injury. Using mice that lack the nonneuronal isoform of tryptophan hydroxylase (Tph1), the ratelimiting step for 5-HT synthesis in the periphery, investigators demonstrated fewer neutrophils rolling on mesenteric venules.96 Tph1–/– mice, in response to an inflammatory stimulus, also showed decreased neutrophil extravasation. Finally, survival of lipopolysaccharide-induced endotoxic shock was reduced in Tph1–/– mice. Together, these data indicate an important role for nonneuronal 5-HT in neutrophil recruitment to sites inflammation and injury. Histamine Histamine is a short-acting endogenous amine that is widely distributed throughout the body. It is synthesized by histidine decarboxylase (HDC), which decarboxylates the amino acid histidine. Histamine is either rapidly released or stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets, and plasma levels are increased with hemorrhagic shock, trauma, thermal injury, and sepsis.97 Not surprisingly, circulating cytokines can increase immune cell expression of HDC to further contribute to histamine synthesis. There are four histamine receptor (HR) subtypes with varying physiologic roles, but they are all members of the rhodopsin family of G-protein–coupled receptors. H1R binding mediates vasodilation, bronchoconstriction, intestinal motility, and myocardial contractility. H1R knockout mice demonstrate significant immunologic defects, including impaired B- and T-cell responses. H2R binding is best described for its stimulation of gastric parietal cell acid secretion. However, H2R can also modulate a range of immune system activities, such as mast cell degranulation, antibody synthesis, Th1 cytokine production, and T-cell proliferation. H3R was initially classified as a presynaptic autoreceptor in the peripheral nervous system and CNS. However, data using H3R knockout mice demonstrate that it also participates in inflammation in the CNS. H3R knockout mice display increased severity of neuroinflammatory diseases, which correlates with dysregulation of blood-brain barrier permeability and increased expression of macrophage inflammatory protein 2, IFN-inducible protein 10, and CXCR3 by peripheral T cells. H4R is expressed primarily in bone marrow but has also been detected in leukocytes, including neutrophils, eosinophils, mast cells, dendritic cells, T cells, and basophils. H4R is emerging as an important modulator of chemoattraction and cytokine production in these cells. Thus, it is clear that cells of both the innate and adaptive immune response can be regulated by histamine, which is upregulated following injury.98 CELLULAR RESPONSE TO INJURY Cytokine Receptor Families and Their Signaling Pathways Cytokines act on their target cells by binding to specific membrane receptors. These receptor families have been organized by structural motifs and include: type I cytokine receptors, type II cytokine receptors, chemokine receptors, TNF receptors (TNFRs), and transforming growth factor receptors (TGFRs). In addition, there are cytokine receptors that belong to the immunoglobulin receptor superfamilies. Several of these receptors have characteristic signaling pathways that are associated with them. These will be reviewed in the following sections. JAK-STAT Signaling A major subgroup of cytokines, comprising roughly 60 factors, bind to receptors termed type I/II cytokine receptors. Cytokines that bind these receptors include type I IFNs, IFN-γ, many ILs (e.g., IL-6, IL-10, IL-12, and IL-13), and hematopoietic growth factors. These cytokines play essential roles in the initiation, maintenance, and modulation of innate and adaptive immunity for host defense. All type I/II cytokine receptors selectively associate with the Janus kinases (JAKs), which represent a family of tyrosine kinases that mediate the signal transduction for these receptors. JAKs are constitutively bound to the cytokine receptors, and on ligand binding and receptor dimerization, activated JAKs phosphorylate the receptor to recruit signal transducer and activator of transcription (STAT) molecules (Fig. 2-7). Activated STAT proteins further dimerize and translocate into Receptor dimerization JAK JAK JAK JAK P P STAT STAT P ST AT P SOCS Nucleus STAT P STAT P P P STAT Nuclear translocation STAT Figure 2-7. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway also requires dimerization of monomeric units. STAT molecules possess “docking” sites that allow for STAT dimerization. The STAT complexes translocate into the nucleus and serve as gene transcription factors. JAK/STAT activation occurs in response to cytokines (e.g., interleukin-6) and cell stressors, and has been found to induce cell proliferation and inflammatory function. Intracellular molecules that inhibit STAT function, known as suppressors of cytokine signaling (SOCSs), have been identified. P = phosphate. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Suppressor of cytokine signaling (SOCS) molecules are a family of proteins that function as a negative feedback loop for type I and II cytokine receptors by terminating JAK-STAT signaling. There are currently eight family members; SOCS1-3 are typically associated with cytokine receptor signaling, whereas SOCS4-8 are associated with growth factor receptor signaling. PRRs, including both TLR and C-type lectin receptors, have also been shown to activate SOCS. Interestingly, induction of SOCS proteins is also achieved through activators of JAK-STAT signaling, creating an inhibitory feedback loop through which cytokines can effectively self-regulate by extinguishing their own signal. SOCS molecules can positively and negatively influence the activation of macrophages and dendritic cells and are crucial for T-cell development and differentiation. All SOCS proteins are able to regulate receptor signaling through the recruitment of proteasomal degradation components to their target proteins, Chemokine Receptors Are Members of the G-Protein–Coupled Receptor Family All chemokine receptors are members of the G-protein–coupled seven-transmembrane family of receptors (GPCR), which is one of the largest and most diverse of the membrane protein families. GPCRs function by detecting a wide spectrum of extracellular signals, including photons, ions, small organic molecules, and entire proteins. After ligand binding, GPCRs undergo conformational changes, causing the recruitment of heterotrimeric G proteins to the cytoplasmic surface (Fig. 2-8). Heterotrimeric G proteins are composed of three subunits, Gα, Gβ, and Gγ, each of which has numerous members, adding to the complexity of the signaling. When signaling however, G proteins perform functionally as dimers because the signal is communicated either by the Gα subunit or the Gβγ complex. The GPCR family includes the receptors for catecholamines, bradykinins, and leukotrienes, in addition to a variety of other ligands important to the inflammatory response.101 In general, GPCRs can G-protein receptors (vasoactive polypeptides, mitogens, phospholipids, neurotransmitters, prostaglandins) Ligand Ligand Cell membrane R G E R G Cytoplasm E Second messengers (cAMP, IP3 ) Protein kinase C activation ER CA2+ release Figure 2-8. G-protein–coupled receptors are transmembrane proteins. The G-protein receptors respond to ligands such as adrenaline and serotonin. On ligand binding to the receptor (R), the G protein (G) undergoes a conformational change through guanosine triphosphate–guanosine diphosphate conversion and in turn activates the effector (E) component. The E component subsequently activates second messengers. The role of inositol triphosphate (IP3) is to induce release of calcium from the endoplasmic reticulum (ER). cAMP = cyclic adenosine triphosphate. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 35 Systemic Response to Injury and Metabolic Support Suppressors of Cytokine Signaling whether the target is a specific receptor or an associated adaptor molecule. Once associated with the SOCS complex, target proteins are readily ubiquinated and targeted to the proteasome for degradation. SOCS1 and SOCS3 can also exert an inhibitory effect on JAK-STAT signaling via their N-terminal kinase inhibitory region (KIR) domain, which acts as a pseudosubstrate for JAK. The KIR domain binds with high affinity to the JAK kinase domain to inhibit its activity. SOCS3 has been shown to be a positive regulator of TLR4 responses in macrophages via inhibition of IL-6 receptor–mediated STAT3 activation.100 A deficiency of SOCS activity may render a cell hypersensitive to certain stimuli, such as inflammatory cytokines and GHs. Interestingly, in a murine model, SOCS knockout resulted in a lethal phenotype in part because of unregulated interferon signaling. CHAPTER 2 the nucleus where they modulate the transcription of target genes. Rather than being a strictly linear pathway, it is likely that individual cytokines activate more than one STAT. The molecular implications for this in terms of cytokine signaling are still being unraveled. Interestingly, STAT-DNA binding can be observed within minutes of cytokine binding. STATs have also been shown to modulate gene transcription via epigenetic mechanisms. Thus, JAKs and STATs are central players in the regulation of key immune cell function, by providing a signaling platform for proinflammatory cytokines (IL-6 via JAK1 and STAT3) and anti-inflammatory cytokines (IL-10 via STAT3) and integrating signals required for helper and regulatory T-cell development and differentiation. The JAK/STAT pathway is inhibited by the action of phosphatase, the export of STATs from the nucleus, and the interaction of antagonistic proteins.99 36 PART I BASIC CONSIDERATIONS be classified according to their pharmacologic properties into four main families: class A rhodopsin-like, class B secretinlike, class C metabotropic glutamate/pheromone, and class D frizzled receptors. As noted earlier, GPCR activation by ligand binding results in an extracellular domain shift, which is then transmitted to cytoplasmic portion of the receptor to facilitate coupling to its principle effector molecules, the heterotrimeric G proteins. Although there are more than 20 known Gα subunits, they have been divided into four families based on sequence similarity, which has served to define both receptor and effector coupling. These include Gαs and Gαi, which signal through the activation (Gαs) or inhibition (Gαi) of adenylate cyclase to increase or decrease cAMP levels, respectively. Increased intracellular cAMP can activate gene transcription through the activity of intracellular signal transducers such as protein kinase A. The Ga subunits also include the Gq pathway, which stimulates phospholipase C-β to produce the intracellular messengers inositol trisphosphate and diacylglycerol. Inositol triphosphate triggers the release of calcium from intracellular stores, whereas diacylglycerol recruits protein kinase C to the plasma membrane for activation. Finally, Gα12/13 appears to act through Rho- and Ras-mediated signaling. Tumor Necrosis Factor Superfamily The signaling pathway for TNFR1 (55 kDa) and TNFR2 (75 kDa) occurs by the recruitment of several adapter proteins to the intracellular receptor complex. Optimal signaling activity requires receptor trimerization. TNFR1 initially recruits TNFRassociated death domain (TRADD) and induces apoptosis through the actions of proteolytic enzymes known as caspases, a pathway shared by another receptor known as CD95 (Fas). CD95 and TNFR1 possess similar intracellular sequences known as death domains (DDs), and both recruit the same adapter proteins known as Fas-associated death domains (FADDs) before activating caspase 8. TNFR1 also induces apoptosis by activating caspase 2 through the recruitment of receptor-interacting protein (RIP). RIP also has a functional component that can initiate NF-κB and c-Jun activation, both favoring cell survival and proinflammatory functions. TNFR2 lacks a DD component but recruits adapter proteins known as TNFR-associated factors 1 and 2 (TRAF1, TRAF2) that interact with RIP to mediate NF-κB and c-Jun activation. TRAF2 also recruits additional proteins that are antiapoptotic, known as inhibitor of apoptosis proteins (IAPs). Transforming Growth Factor-β Family of Receptors Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine expressed by immune cells that has potent immunoregulatory activities. Specifically, recent data indicate that TGF-β is essential for T-cell homeostasis, as mice deficient in TGF-β1 develop a multiorgan autoimmune inflammatory disease and die a few weeks after birth, an effect that is dependent on the presence of mature T cells. The receptors for TGF-β ligands are the TGF-β superfamily of receptors, which are type I transmembrane proteins that contain intrinsic serine/threonine kinase activity. These receptors comprise two subfamilies, the type I and the type II receptors, which are distinguished by the presence of a glycine/serine-rich membrane domain found in the type I receptors. Each TGF-β ligand binds a characteristic combination of type I and type II receptors, both of which are required for signaling. Whether the type I or the type II receptor binds first is ligand-dependent, and the second type I or type II receptor is then recruited to form a heteromeric signaling complex. When TGF-β binds to the TGF-β receptor, heterodimerization activates the receptor, which then directly recruits and activates a receptor-associated Smad (Smad2 or Smad3) through phosphorylation. An additional “common” Smad is then recruited. The activated Smad complex translocates into the nucleus and, with other nuclear cofactors, regulates the transcription of target genes. TGF-β can also induce the rapid activation of the Ras-extracellular signal-regulated kinase (ERK) signaling pathway in addition to other MAPK pathways (JNK, p38MAPK). How does TGF-β inhibit immune responses? One of the most important effects is the suppression of IL-2 production by T cells. It also inhibits T-cell proliferation.102 More recently, it was noted that TGF-β can regulate the maturation of differentiated dendritic cells and dendritic cell–mediated T-cell responses. Importantly, TGF-β can induce “alternative activation” macrophages, designated M2 macrophages, which express a wide array of anti-inflammatory molecules, including IL-10 and arginase-1. 5 TRANSCRIPTIONAL AND TRANSLATIONAL REGULATION OF THE INJURY RESPONSE Transcriptional Events Following Blunt Trauma Recent data have examined the transcriptional response in circulating leukocytes in a large series of patients who suffered severe blunt trauma. This work identified an overwhelming shift in the leukocyte transcriptome, with more than 80% of the cellular functions and pathways demonstrating some alteration in gene expression. In particular, changes in gene expression for pathways involved in the systemic inflammatory, innate immune, compensatory anti-inflammatory, and adaptive immune responses were simultaneous and marked. Moreover, they occurred rapidly (within 4 to 12 hours) and were prolonged for days and weeks. When different injuries (i.e., blunt trauma, burn injury, human model of endotoxemia) were compared, the patterns of gene expression were surprisingly similar, suggesting that the stress response to both injury and inflammation is highly conserved and may follow a universal pathway that includes common denominators. Finally, delayed clinical recovery and organ injury were not associated with a distinct pattern of transcriptional response elements.2 These data describe a new paradigm based on the observation of a rapid and coordinated transcriptional response to severe traumatic injury that involves both the innate and adaptive immune systems. Further, the data support the idea that individuals who are destined to die from their injuries are characterized primarily by the degree and duration of their dysregulated inflammatory response rather than a “unique signature” indicative of a “second hit.” Transcriptional Regulation of Gene Expression Many genes are regulated at the point of DNA transcription and thus influence whether messenger RNA (mRNA) and its subsequent product are expressed (Fig. 2-9). Gene expression relies on the coordinated action of transcription factors and coactivators (i.e., regulatory proteins), which are complexes that bind to highly specific DNA sequences upstream of the target gene known as the promoter region. Enhancer sequences of DNA mediate gene expression, whereas repressor sequences are noncoding regions that bind proteins to inhibit gene expression. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Nucleus ane Protein Transcription mRNA mRNA Inactive mRNA Inactive protein Figure 2-9. Gene expression and protein synthesis can occur within a 24-hour period. The process can be regulated at various stages: transcription, messenger RNA (mRNA) processing, or protein packaging. At each stage, it is possible to inactivate the mRNA or protein, rendering these molecules nonfunctional. For example, NF-κB is one of the best-described transcription factors, which has a central role in regulating the gene products expressed after inflammatory stimuli (Fig. 2-10). NF-κB is composed of two smaller polypeptides, p50 and p65. NF-κB resides in the cytosol in the resting state primarily through the inhibitory binding of inhibitor of κB (I-κB). In response to an inflammatory stimulus such as TNF, IL-1, or endotoxin, a sequence of intracellular mediator phosphorylation reactions leads to the degradation of I-κB and subsequent release of NF-κB. On release, NF-κB travels to the nucleus and promotes gene expression. NF-κB also stimulates the gene expression for I-κB, which results in negative feedback regulation. In clinical Epigenetic Regulation of Transcription The DNA access of protein machineries involved in transcription processes is tightly regulated by histones, which are a family of basic proteins that associate with DNA in the nucleus. Histone proteins help to condense the DNA into tightly packed nucleosomes that limit transcription. Emerging evidence indicates that transcriptional activation of many proinflammatory genes requires nucleosome remodeling that is modulated by the posttranslational modification of histone proteins through the recruitment of histone-modifying enzymes.103 There are at least seven identified chromatin modifications including acetylation, methylation, phosphorylation, ubiquitinylation, sumoylation, ADP ribosylation, deimination, and proline isomerization. Recently, the development of chromatin immunoprecipitation (ChIP) coupled to massively parallel DNA sequencing technology (ChIPSeq) has enabled the mapping of histone modifications in living cells in response to TLR signaling. In this way, it has allowed the identification of the large number of posttranslational histone modifications that are “written” and “erased” by histone-modifying enzymes. The role of histone modifications in the regulation of gene expression is referred to as “epigenetic” control. Addition of an acetyl group to lysine residues on histones is an epigenetic mark associated with gene activation. These acetyl groups are reversibly maintained by histone acetyltransferases (HATs) and histone deacetylases. Ultimately, histone acetylation is monitored by bromodomain-containing proteins such as the bromodomain and extraterminal domain (BET) family of proteins, which can regulate a number of important epigenetically controlled processes. Upon TLR4 activation, HATs are recruited to proinflammatory gene promoters where acetylation of specific histone NF-κB activation Ligand (e.g.: TNF, IL-1) p65 I-κB I-κB kinase p50 P I-κB p50 P p65 Ubiquitinization p65 Nuclear translocation p50 Degradation of I-κB p65 p50 I-κB Nucleus Figure 2-10. Inhibitor of κB (I-κB) binding to the p50-p65 subunits of nuclear factor κB (NF-κB) inactivates the molecule. Ligand binding to the receptor activates a series of downstream signaling molecules, of which I-κB kinase is one. The phosphorylated NF-κB complex further undergoes ubiquitinization and proteosome degradation of I-κB, activating NF-κB, which translocates into the nucleus. Rapid resynthesis of I-κB is one method of inactivating the p50-p65 complex. IL-1 = interleukin-1; P = phosphate; TNF = tumor necrosis factor. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 37 Systemic Response to Injury and Metabolic Support DNA appendicitis, for example, increased NF-κB activity was associated with initial disease severity, and levels returned to baseline within 18 hours after appendectomy in concert with resolution of the inflammatory response.30 CHAPTER 2 embr Cell m Cytoplasm 38 PART I BASIC CONSIDERATIONS residues serves as an organizing node for a complex of proteins that ultimately phosphorylate the large subunit of RNA polymerase II, promoting the elongation of inflammatory gene transcripts.104 Recently, investigators used a novel pharmacologic approach that targeted inflammatory gene expression by interfering with the recognition of acetylated histones by BET proteins. A synthetic compound (I-BET) that “mimicked” acetylated histones functioned as a BET antagonist.105 In this way, pretreatment decreased overall histone acetylation to reduce the expression of select inflammatory genes in LPS-activated macrophages. Additionally, I-BET conferred protection against bacteria-induced sepsis. Recent studies have also demonstrated a role for histone methyltransferases in proinflammatory gene programs. Translation Regulation of Inflammatory Gene Expression Once mRNA transcripts are generated, they can also be regulated by a variety of mechanisms, including (a) splicing, which can cleave mRNA and remove noncoding regions; (b) capping, which modifies the 5′ ends of the mRNA sequence to inhibit breakdown by exonucleases; and (c) the addition of a polyadenylated tail, which adds a noncoding sequence to the mRNA, to regulate the half-life of the transcript. Recent data have identified microRNAs (miRNAs) as important translational regulators of gene expression via their binding to partially complementary sequences in the 3′-untranslated region (3′UTR) of target mRNA transcripts.106 Binding of miRNA to the mRNA usually results in gene silencing. MicroRNAs are endogenous, single-stranded RNAs of approximately 22 nucleotides in length that are highly conserved in eukaryotes. miRNAs are encoded either singly or can be transcribed in “polycistronic” clusters and produced by an elaborate expression and processing mechanism. After a primary miRNA transcript is generated by RNA polymerase II or III, it is processed in the nucleus to produce a short hairpin precursor miRNA transcript. The precursor is then transported into the cytoplasm where the final mature miRNA is generated by a protein termed Dicer. The mature double-stranded miRNA is then incorporated into the RNA-induced silencing complex (RISC) in the cytoplasm. Once programmed with a small RNA, RISC can silence targeted genes by one of several distinct mechanisms, working at (a) the level of protein synthesis through translation inhibition, (b) the transcript level through mRNA degradation, or (c) the level of the genome itself through the formation of heterochromatin or by DNA elimination. Recent data indicate that miRNAs are involved in TLR signaling in the innate immune system by targeting multiple molecules in the TLR signaling pathways.107 For example, evidence has shown that miR-146a can inhibit the expression of IRAK1 and TRAF6, impair NF-κB activity, and suppress the expression of NF-κB target genes such as IL-6, IL-8, IL-1β, and TNF-α. CELL-MEDIATED INFLAMMATORY RESPONSE Platelets Platelets are small (2 μm), circulating fragments of a larger cell precursor, the megakaryocyte, that is located chiefly within the bone marrow. Although platelets lack a nucleus, they contain both mRNA and a large number of cytoplasmic and surface proteins that equip them for diverse functionality. While their role in hemostasis is well described, more recent work suggests that platelets play a role in both local and systemic inflammatory responses, particularly following ischemia reperfusion. Platelets express functional scavenger and TLRs that are important detectors of both pathogens and “damage”-associated molecules.108 At the site of tissue injury, complex interactions between platelets, endothelial cells, and circulating leukocytes facilitate cellular activation by the numerous local alarmins and immune mediators. For example, platelet-specific TLR4 activation can cause thrombocytes to bind to and activate neutrophils to extrude their DNA to form neutrophil extracellular traps (NETs), an action that facilitates the capacity of the innate immune system to trap bacteria, but also leads to local endothelial cell damage.109 Once activated, platelets adopt an initial proinflammatory phenotype by expressing and releasing a variety of adhesion molecules, cytokines, and other immune modulators, including HMGB1, IL-1β, and CD40 ligand (CD40L; CD154). However, activated platelets also express large amounts of the immunosuppressive factor TGF-β, which has been implicated in Treg cell homeostasis. Recently, in a large animal model of hemorrhage, TGF-β levels were shown to be significantly increased 2 hours after injury, suggesting a possible mechanism for injuryrelated immune dysfunction.110 And although soluble CD154 was not increased following hemorrhage and traumatic brain injury in that study, in a murine model of mesenteric ischemiareperfusion injury platelet expression of CD40 and CD154 was linked to remote organ damage. Lymphocytes and T-Cell Immunity The expression of genes associated with the adaptive immune response is rapidly altered following severe blunt trauma.2 In fact, significant injury is associated with adaptive immune suppression that is characterized by altered cell-mediated immunity, specifically the balance between the major populations of Th cells. In fact, Th lymphocytes are functionally divided into subsets, which principally include Th1 and Th2 cells, as well as Th17 and inducible Treg cells. Derived from precursor CD4+ Th cells, each of these groups produces specific effector cytokines that are under unique transcriptional control. CD4 T cells play central roles in the function of the immune system through their effects on B-cell antibody production and their enhancement of specific Treg cell functions and macrophage activation. The specific functions of these cells include the recognition and killing of intracellular pathogens (cellular immunity; Th1 cells), regulation of antibody production (humoral immunity; Th2 cells), and maintenance of mucosal immunity and barrier integrity (Th17 cells). These activities have been characterized as proinflammatory (Th1) and anti-inflammatory (Th2), respectively, as determined by their distinct cytokine signatures (Fig. 2-11). Activation of Th1 cytokine-producing cells following injury has been linked to signaling events triggered by endogenous ligands, often composed of intracellular proteins (e.g., mitochondrial and nuclear-binding proteins) or ECM fragments released with cellular damage. As discussed earlier, these DAMPs are recognized by members of the TLR superfamily, including TLR2, TLR4, and TLR9, and can activate innate immune pathways. A healthy immune response depends on a balanced Th1/ Th2 response. Following injury, however, there is a reduction in Th1 cell differentiation and cytokine production in favor of an increased population of Th2 lymphocytes and their signaling products. As a consequence, both macrophage activation and proinflammatory cytokine synthesis are inhibited. This imbalance, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ TH1 Dendritic Cells IL-12, IL-18, IFN- , TNF, IL-1, IL-21, TGF-β IL-4, IL-5, IL-6, IL-10, (Glucocorticoids) Figure 2-11. Specific immunity mediated by helper T lymphocytes subtype 1 (TH1) and subtype 2 (TH2) after injury. A TH1 response is favored in lesser injuries, with intact cell-mediated and opsonizing antibody immunity against microbial infections. This cell-mediated immunity includes activation of monocytes, B lymphocytes, and cytotoxic T lymphocytes. A shift toward the TH2 response from naïve helper T cells is associated with injuries of greater magnitude and is not as effective against microbial infections. A TH2 response includes the activation of eosinophils, mast cells, and B-lymphocyte immunoglobulin 4 and immunoglobulin E production. (Primary stimulants and principal cytokine products of such responses are in bold characters.) Interleukin-4 (IL-4) and IL-10 are known inhibitors of the TH1 response. Interferon-γ (IFN-γ) is a known inhibitor of the TH2 response. Although not cytokines, glucocorticoids are potent stimulants of a TH2 response, which may partly contribute to the immunosuppressive effects of cortisol. GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; TGF = transforming growth factor; TNF = tumor necrosis factor. (Adapted with permission from Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. Surgery. 2000;127:117. Copyright Elsevier.) which may be associated with decreased IL-12 production by activated monocytes/macrophages, has been associated with increased risk of infectious complications following surgery and trauma. What are the systemic mechanisms responsible for this shift? Several events have been implicated, including the direct effect of glucocorticoids on monocyte IL-12 production and T-cell IL-12 receptor expression. In addition, sympathoadrenal catecholamine production has also been demonstrated to reduce IL-12 production and proinflammatory cytokine synthesis.111 Finally, more recent work has implicated circulating immature myeloid cells, termed myeloid-derived suppressor cells, that have immune suppressive activity particularly through their increased expression of arginase.112 These cells have the potential to deplete the microenvironment of arginine, leading to further T-cell dysfunction. Recent evidence suggests that Th17 cells and their effector cytokines, IL-17, IL-21, and IL-22, regulate mucosal immunity and barrier function. While their specific role in the inflammatory response following trauma is not well understood, both murine and human studies indicate that normal Th17 effector functions are disordered following burn injury, due to the inhibition of normal Th17 cell development by IL-10.113 These changes may contribute to remote organ damage and further susceptibility to infection in this setting. Eosinophils Eosinophils are immunocytes whose primary functions are antihelminthic. Eosinophils are found mostly in tissues such as the lung and gastrointestinal tract, which may suggest a role in immune surveillance. Eosinophils can be activated by IL-3, IL-5, GM-CSF, chemoattractants, and platelet-activating factor. Eosinophil activation can lead to subsequent release of toxic mediators, including ROSs, histamine, and peroxidase.115 Mast Cells Mast cells are important in the primary response to injury because they are located in tissues. TNF release from mast cells has been found to be crucial for neutrophil recruitment and pathogen clearance. Mast cells are also known to play an important role in the anaphylactic response to allergens. On activation from stimuli including allergen binding, infection, and trauma, mast cells produce histamine, cytokines, eicosanoids, proteases, and chemokines, which leads to vasodilatation, capillary leakage, and immunocyte recruitment. Mast cells are thought to be important cosignaling effector cells of the immune system via the release of IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, and IL-14, as well as macrophage migration–inhibiting factor.116 Monocyte/Macrophages Monocytes are mononuclear phagocytes that circulate in the bloodstream and can differentiate into macrophages, osteoclasts, and DCs on migrating into tissues. Macrophages are the main effector cells of the immune response to infection and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Cell-mediated Immunity IL-3 IL-4 IL-5 IL-6 Injury Severity: IL-9 IL-10 IL-13 TNF-α less severe more severe GM-CSF Antibody-mediated Immunity CHAPTER 2 IL-2 IL-3 IL-6 IL-12 IFNTNF-α GM-CSF TNF-β T H2 Recent studies have focused on the cellular components of the immune system in the context of polytrauma. While the activation of granulocytes and monocyte/macrophages following trauma has been well described, more recent work has also demonstrated that dendritic cells (DCs) are also activated in response to damage signals, to stimulate both the innate and the adaptive immune responses. For example, primary “danger signals” that are recognized and activated by DCs include debris from damaged or dying cells (e.g., HMGB1, nucleic acids including single nucleotides, and degradation products of the ECM). DCs are specialized antigen-presenting cells (APCs) that have three major functions. They are frequently referred to as “professional APCs” since their principal function is to capture, process, and present both endogenous and exogenous antigens, which, along with their costimulatory molecules, are capable of inducing a primary immune response in resting naïve T lymphocytes. In addition, they have the capacity to further regulate the immune response, both positively and negatively, through the upregulation and release of immunomodulatory molecules such as the chemokine CCL5 and the CXC chemokine CXCL5. Finally, they have been implicated both in the induction and maintenance of immune tolerance as well as in the acquisition of immune memory.114 There are distinct classes and subsets of DC, which are functionally heterogeneous. Further, subsets of DC at distinct locations have been shown to express different levels damage-sensing receptors (e.g., TLR) that dictate a preferential response to DAMP at that site. While relatively small in number relative to the total leukocyte population, the diverse distribution of DC in virtually all body tissues underlines their potential for a collaborative role in the initiation of the trauma-induced sterile systemic inflammatory response. 39 40 PART I BASIC CONSIDERATIONS injury, primarily through mechanisms that include phagocytosis of microbial pathogens, release of inflammatory mediators, and clearance of apoptotic cells. Moreover, these cells fulfill homeostatic roles beyond host defense by performing important functions in the remodeling of tissues, both during development and in the adult animal. In tissues, mononuclear phagocytes are quiescent. However, they respond to external cues (e.g., PAMPs, DAMPs, activated lymphocytes) by changing their phenotype. In response to various signals, macrophages may undergo classical M1 activation (stimulated by TLR ligands and IFN-γ) or alternative M2 activation (stimulated by type II cytokines IL-4/IL-13); these states mirror the Th1-Th2 polarization of T cells. The M1 phenotype is characterized by the expression of high levels of proinflammatory cytokines, like TNF-α, IL-1, and IL-6, in addition to the synthesis of ROS and RNS. M1 macrophages promote a strong Th1 response. In contrast, M2 macrophages are considered to be involved in the promotion of wound repair and the restoration of immune homeostasis through their expression of arginase-1 and IL-10, in addition to a variety of PRRs (e.g., scavenging molecules).117 In humans, downregulation of monocyte TNFR expression has been demonstrated experimentally and clinically during systemic inflammation. In clinical sepsis, nonsurviving patients with severe sepsis have an immediate reduction in monocyte surface TNFR expression with failure to recover, whereas surviving patients have normal or near-normal receptor levels from the onset of clinically defined sepsis. In patients with congestive heart failure, there is also a significant decrease in the amount of monocyte surface TNFR expression compared with control patients. In experimental models, endotoxin has been shown to differentially regulate over 1000 genes in murine macrophages with approximately 25% of these corresponding to cytokines and chemokines. During sepsis, macrophages undergo phenotypic reprogramming highlighted by decreased surface human leukocyte antigen DR (a critical receptor in antigen presentation), which also may contribute to host immunocompromise during sepsis.118 Neutrophils Neutrophils are among the first responders to sites of infection and injury and, as such, are potent mediators of acute inflammation. Chemotactic mediators from a site of injury induce neutrophil adherence to the vascular endothelium and promote eventual cell migration into the injured tissue. Neutrophils are circulating immunocytes with short half-lives (4 to 10 hours). However, inflammatory signals may promote the longevity of neutrophils in target tissues, which can contribute to their potential detrimental effects and bystander injury. Once primed and activated by inflammatory stimuli, including TNF, IL-1, and microbial pathogens, neutrophils are able to enlist a variety of killing mechanisms to manage invading pathogens. Phagocytosed bacteria are killed using NADPH oxygenase-dependent generation of ROS or by releasing lytic enzymes and antibacterial proteins into the phagosome. Neutrophils can also dump their granule contents into the extracellular space, and many of these proteins also have important effects on the innate and adaptive immune responses. When highly activated, neutrophils can also extrude a meshwork of chromatin fibers, composed of DNA and histones that are decorated with granule contents. Termed neutrophil extracellular traps (NETs), this is an effective mechanism whereby neutrophils can immobilize bacteria to facilitate their killing.119 NETs may also serve to prime T cells, making their threshold for activation lower. Neutrophils do facilitate the recruitment of monocytes into inflamed tissues. These recruited cells are capable of phagocytosing apoptotic neutrophils to contribute to resolution of the inflammatory response.120 ENDOTHELIUM-MEDIATED INJURY Vascular Endothelium Under physiologic conditions, vascular endothelium has overall anticoagulant properties mediated via the production and cell surface expression of heparin sulfate, dermatan sulfate, tissue factor pathway inhibitor, protein S, thrombomodulin, plasminogen, and tissue plasminogen activator. Endothelial cells also perform a critical function as barriers that regulate tissue migration of circulating cells. During sepsis, endothelial cells are differentially modulated, which results in an overall procoagulant shift via decreased production of anticoagulant factors, which may lead to microthrombosis and organ injury. Neutrophil-Endothelium Interaction The regulated inflammatory response to infection facilitates neutrophil and other immunocyte migration to compromised regions through the actions of increased vascular permeability, chemoattractants, and increased endothelial adhesion factors referred to as selectins that are elaborated on cell surfaces (Table 2-7). In response to inflammatory stimuli released from sentinel leukocytes in the tissues, including chemokines, thrombin, leukotrienes, histamine, and TNF, vascular endothelium are activated and their surface protein expression is altered. Within 10 to 20 minutes, prestored reservoirs of the adhesion molecule P-selectin are mobilized to the cell surface where it can mediate neutrophil recruitment (Fig. 2-12). After 2 hours, endothelial cell transcriptional processes provide additional surface expression of E-selectin. E-selectin and P-selectin bind P-selectin glycoprotein ligand-1 (PSGL-1) on the neutrophils to orchestrate the capture and rolling of these leukocytes and allow targeted immunocyte extravasation. Immobilized chemokines on the endothelial surface create a chemotactic gradient to further enhance immune cell recruitment.121 Also important are secondary leukocyte-leukocyte interactions in which PGSL-1 and L-selectin binding facilitates further leukocyte tethering. Although there are distinguishable properties among individual selectins in leukocyte rolling, effective rolling most likely involves a significant degree of functional overlap.122 Chemokines Chemokines are a family of small proteins (8 to 13 kDa) that were first identified through their chemotactic and activating effects on inflammatory cells. They are produced at high levels following nearly all forms of injury in all tissues, where they are key attractants for immune cell extravasation. There are more than 50 different chemokines and 20 chemokine receptors that have been identified. Chemokines are released from endothelial cells, mast cells, platelets, macrophages, and lymphocytes. They are soluble proteins, which when secreted, bind to glycosaminoglycans on the cell surface or in the ECM. In this way, the chemokines can form a fixed chemical gradient that promotes immune cell exit to target areas. Chemokines are distinguished (in general) from cytokines by virtue of their receptors, which are members of the G-protein–coupled receptor superfamily. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 41 Table 2-7 Molecules that mediate leukocyte-endothelial adhesion, categorized by family Origin Inducers of Expression Target Cells L-selectin Fast rolling Leukocytes Native P-selectin Slow rolling Thrombin, histamine E-selectin Very slow rolling Platelets and endothelium Endothelium Selectins Cytokines Endothelium, platelets, eosinophils Neutrophils, monocytes Neutrophils, monocytes, lymphocytes Immunoglobulins ICAM-1 Firm adhesion/ transmigration ICAM-2 VCAM-1 Firm adhesion Firm adhesion/ transmigration Adhesion/ transmigration PECAM-1 Endothelium, Cytokines leukocytes, fibroblasts, epithelium Endothelium, platelets Native Endothelium Cytokines Leukocytes Endothelium, platelets, leukocytes Native Endothelium, platelets, leukocytes Firm adhesion/ transmigration Firm adhesion/ transmigration Adhesion Leukocytes Leukocyte activation Endothelium Neutrophils, monocytes, Leukocyte activation natural killer cells Neutrophils, monocytes, Leukocyte activation natural killer cells Endothelium Firm adhesion/ transmigration Lymphocytes, monocytes Monocytes, endothelium, epithelium Leukocytes Monocytes, lymphocytes β2-(CD18) Integrins CD18/11a CD18/11b (Mac-1) CD18/11c Endothelium β1-(CD29) Integrins VLA-4 Leukocyte activation ICAM-1 = intercellular adhesion molecule-1; ICAM-2 = intercellular adhesion molecule-2; Mac-1 = macrophage antigen 1; PECAM-1 = plateletendothelial cell adhesion molecule-1; VCAM-1 = vascular cell adhesion molecule-1; VLA-4 = very late antigen-4. Most chemokine receptors recognize more than one chemokine ligand, leading to redundancy in chemokine signaling. The chemokines are subdivided into families based on their amino acid sequences at their N-terminus. For example, CC chemokines contain two N-terminus cysteine residues that are immediately adjacent (hence the “C-C” designation), whereas the N-terminal cysteines in CXC chemokines are separated by a single amino acid. The CXC chemokines are particularly important for neutrophil (PMN) proinflammatory function. Members of the CXC chemokine family, which include IL-8, induce neutrophil migration and secretion of cytotoxic granular contents and metabolites. Additional chemokine families include the C and CX3C chemokines.121 Nitric Oxide Nitric oxide (NO) was initially known as endothelium-derived relaxing factor due to its effect on vascular smooth muscle. Normal vascular smooth muscle cell relaxation is maintained by a constant output of NO that is regulated in the endothelium by both flow- and receptor-mediated events. NO can also reduce microthrombosis by reducing platelet adhesion and aggregation (Fig. 2-13) and interfering with leukocyte adhesion to the endothelium. NO easily traverses cell membranes, has a short half-life of a few seconds, and is oxidized into nitrate and nitrite. Endogenous NO formation is derived largely from the action of NO synthase (NOS), which is constitutively expressed in endothelial cells (NOS3). NOS generates NO by catalyzing the degradation of L-arginine to L-citrulline and NO, in the presence of oxygen and NADPH. There are two additional isoforms of NOS: neuronal NOS (NOS1) and inducible NOS (iNOS/ NOS2). The vasodilatory effects of NO are mediated by guanylyl cyclase, an enzyme that is found in vascular smooth muscle cells and most other cells of the body. When NO is formed by endothelium, it rapidly diffuses into adjacent cells where it binds to and activates guanylyl cyclase. This enzyme catalyzes the dephosphorylation of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which serves as a second messenger for many important cellular functions, particularly for signaling smooth muscle relaxation. NO synthesis is increased in response to proinflammatory mediators such as TNF-α and IL-1β, as well as microbial products, due to the upregulation of iNOS expression.123 In fact, studies in both animal models and humans have shown that severe systemic injury and associated hemorrhage produce an early upregulation of iNOS in the liver, lung, spleen, and vascular system. In these circumstances, NO is reported to function as an immunoregulator, which is capable of modulating cytokine production and immune cell development. In particular, recent data support a role for iNOS in the regulation of T-cell VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Action CHAPTER 2 Adhesion Molecule 42 Capture Fast rolling Slow rolling PART I associated with an increase in mortality compared with placebo.125 More recent data using an ovine model of peritonitis demonstrated that selective iNOS inhibition reduced pulmonary artery hypertension and gas exchange impairment and promoted higher visceral organ blood flow, coinciding with lower plasma cytokine concentrations.126 These data suggest that specific targeting of iNOS in the setting of sepsis may remain a viable therapeutic option. Arrest Leukocyte Endothelium Prostacyclin 50–150 µm/sec 20–50 µm/sec 10–20 µm/sec 0–10 µm/sec 150 Velocity (µm/second) BASIC CONSIDERATIONS Velocity: 100 50 0 0 1 2 3 4 Seconds Figure 2-12. Simplified sequence of selectin-mediated neutrophilendothelium interaction after an inflammatory stimulus. CAPTURE (tethering), predominantly mediated by cell L-selectin with contribution from endothelial P-selectin, describes the initial recognition between leukocyte and endothelium, in which circulating leukocytes marginate toward the endothelial surface. FAST ROLLING (20 to 50 μm/s) is a consequence of rapid L-selectin shedding from cell surfaces and formation of new downstream L-selectin to endothelium bonds, which occur in tandem. SLOW ROLLING (10 to 20 μm/s) is predominantly mediated by P-selectins. The slowest rolling (3 to 10 μm/s) before arrest is predominantly mediated by E-selectins, with contribution from P-selectins. ARREST (firm adhesion) leading to transmigration is mediated by β-integrins and the immunoglobulin family of adhesion molecules. In addition to interacting with the endothelium, activated leukocytes also recruit other leukocytes to the inflammatory site by direct interactions, which are mediated in part by selectins. (Adapted with permission from Lin E, Calvano SE, Lowry SF. Selectin neutralization: does it make biological sense? Crit Care Med. 1999;27:2050.) dysfunction in the setting of trauma as evidenced by suppressed proliferative and Th1 cytokine release.124 Increased NO is also detectable in septic shock, where it is associated with low peripheral vascular resistance and hypotension. Increased production of NO in this setting correlates with changes in vascular permeability and inhibition of noradrenergic nerve transmission. While the increased NO in sepsis is largely attributed to greater iNOS activity and expression, cytokines are reported to modulate NO release by increasing arginine availability through the expression of the cationic amino acid transporter (CAT) or by increasing tetrahydrobiopterin levels, a key cofactor in NO synthesis. Additional effects associated with excess NO include protein and membrane phospholipid alterations by nitrosylation and the inhibition of mitochondrial respiration. Inhibition of NO production seemed initially to be a promising strategy in patients with severe sepsis. However, a randomized clinical trial in patients with septic shock determined that treatment with a nonselective NOS inhibitor was The immune effects of prostacyclin (PGI2) were discussed earlier. The best described effects of PGI2 are in the cardiovascular system, however, where it is produced by vascular endothelial cells. Prostacyclin is a potent vasodilator that also inhibits platelet aggregation. In the pulmonary system, PGI2 reduces pulmonary blood pressure and bronchial hyperresponsiveness. In the kidneys, PGI2 modulates renal blood flow and glomerular filtration rate. Prostacyclin acts through its receptor (a G-protein–coupled receptor of the rhodopsin family) to stimulate the enzyme adenylate cyclase, allowing the synthesis of cAMP from adenosine triphosphate (ATP). This leads to a cAMP-mediated decrease in intracellular calcium and subsequent smooth muscle relaxation. During systemic inflammation, endothelial prostacyclin expression is impaired, and thus the endothelium favors a more procoagulant profile. Exogenous prostacyclin analogues, both intravenous and inhaled, have been used to improve oxygenation in patients with acute lung injury. Early clinical studies with prostacyclin have delivered some encouraging results, showing that infusion of prostacyclin improved cardiac index, splanchnic blood flow as measured by intestinal tonometry, and oxygen delivery in patients with sepsis. Importantly, there was no significant decrease in mean arterial pressure.127 Endothelins Endothelins (ETs) are potent mediators of vasoconstriction and are composed of three members: ET-1, ET-2, and ET-3. ETs are 21-amino-acid peptides derived from a 38-amino-acid precursor molecule. ET-1, synthesized primarily by endothelial cells, is the most potent endogenous vasoconstrictor and is estimated to be 10 times more potent than angiotensin II. ET release is upregulated in response to hypotension, LPS, injury, thrombin, TGFβ, IL-1, angiotensin II, vasopressin, catecholamines, and anoxia. ETs are primarily released to the abluminal side of endothelial cells, and very little is stored in cells; thus a plasma increase in ET is associated with a marked increase in production. The half-life of plasma ET is between 4 and 7 minutes, which suggests that ET release is primarily regulated at the transcriptional level. Three ET receptors, referred to as ETA, ETB, and ETC, have been identified and function via the G-protein–coupled receptor mechanism. ET B receptors are associated with increased NO and prostacyclin production, which may serve as a feedback mechanism. Atrial ETA receptor activation has been associated with increased inotropy and chronotropy. ET-1 infusion is associated with increased pulmonary vascular resistance and pulmonary edema and may contribute to pulmonary abnormalities during sepsis. At low levels, in conjunction with NO, ETs regulate vascular tone. However, at increased concentrations, ETs can disrupt the normal blood flow and distribution and may compromise oxygen delivery to the tissue. Recent data link ET expression in pulmonary vasculature with persistent inflammation associated with the development of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 43 Platelet cAMP CHAPTER 2 cGMP PGI2 NO AA Big ET L-arginine PGI2 ET NO Endothelium cGMP cAMP Smooth muscle Relaxation pulmonary hypertension.128 ET expression is linked to posttranslational and transcriptional initiation of the unfolded protein response in the affected cells, which results in the production of inflammatory cytokines. Finally, ET-1 levels correlate with levels of brain natriuretic peptide and CRP, as well as the Sequential Organ Failure Assessment score in septic patients.129 Platelet-Activating Factor Phosphatidylcholine is a major lipid constituent of the plasma membrane. Its enzymatic processing by cytosolic phospholipase A2 (cPLA2) or calcium-independent phospholipase A2 (iPLA2) generates powerful small lipid molecules, which function as intracellular second messengers. One of these is arachidonic acid, the precursor molecule for eicosanoids. Another is platelet-activating factor (PAF). During acute inflammation, PAF is released by immune cells following the activation of PLA2. The receptor for PAF (PAFR), which is constitutively expressed by platelets, leukocytes, and endothelial cells, is a G-protein–coupled receptor of the rhodopsin family. Ligand binding to the PAFR promotes the activation and aggregation of platelets and leukocytes, leukocyte adherence, motility, chemotaxis, and invasion, as well as ROS generation.130 Additionally, PAF activation of human PMNs induces extrusion of NETs, while platelet activation induces IL-1 via a novel posttranscriptional mechanism. Finally, PAFR ligation results not only in the upregulation of numerous proinflammatory genes including COX-2, iNOS, and IL-6, but also in the generation of lipid intermediates such as arachidonic acid and lysophospholipids through the activation of PLA2. Antagonists to PAF receptors have been experimentally shown to mitigate the effects of ischemia and reperfusion injury. Of note, human sepsis is associated with a reduction in the levels of PAF-acetylhydrolase, which inactivates PAF by removing an acetyl group. Indeed, Figure 2-13. Endothelial interaction with smooth muscle cells and with intraluminal platelets. Prostacyclin (prostaglandin I2, or PGI2) is derived from arachidonic acid (AA), and nitric oxide (NO) is derived from L-arginine. The increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) results in smooth muscle relaxation and inhibition of platelet thrombus formation. Endothelins (ETs) are derived from “big ET,” and they counter the effects of prostacyclin and NO. PAF-acetylhydrolase administration in patients with severe sepsis has yielded some reduction in multiple organ dysfunction and mortality131; however, larger phase III clinical trials failed to show benefit. Natriuretic Peptides The natriuretic peptides, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), are a family of peptides that are released primarily by atrial tissue but are also synthesized by the gut, kidney, brain, adrenal glands, and endothelium. The functionally active forms of the peptides are C-terminal fragments of a larger prohormone, and both N- and C-terminal fragments are detectable in the blood (referred to a N-terminal pro-BNP and pro-ANF, respectively). ANF and BNP share most biologic properties including diuretic, natriuretic, vasorelaxant, and cardiac remodeling properties that are effected by signaling through a common receptor: the guanylyl cyclase-A (GC-A) receptor. They are both increased in the setting of cardiac disorders; however, recent evidence indicates some distinctions in the setting of inflammation. For example, endotoxemia in healthy volunteers increased plasma N-terminal pro-BNP without changing heart rate and blood pressure. Also, elevated pro-BNP has been detected in septic patients in the absence of myocardial dysfunction and appears to have prognostic significance.132 SURGICAL METABOLISM The initial hours after surgical or traumatic injury are metabolically associated with a reduced total body energy expenditure and urinary nitrogen wasting. On adequate resuscitation and stabilization of the injured patient, a reprioritization of substrate use ensues to preserve vital organ function and to support repair of injured tissue. This phase of recovery also is characterized VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support ET 44 Fuel utilization in short-term fasting man (70 kg) Brain PART I Muscle protein 75g BASIC CONSIDERATIONS Fat stores triglycerides 160g 144g Amino acids Glycerol 16g Fatty 40g acid 160g LIVER Glycogen 75g Glucose 180g 36g Gluconeogenesis RBC WBC Nerve Kidney Muscle 36g Oxidation Lactate + Pyruvate Ketone 60g Heart Kidney Muscle Fatty acid 120g by functions that participate in the restoration of homeostasis, such as augmented metabolic rates and oxygen consumption, enzymatic preference for readily oxidizable substrates such as glucose, and stimulation of the immune system. Understanding of the collective alterations in amino acid (protein), carbohydrate, and lipid metabolism characteristic of the surgical patient lays the foundation upon which metabolic and nutritional support can be implemented. Metabolism during Fasting Fuel metabolism during unstressed fasting states has historically served as the standard to which metabolic alterations after acute injury and critical illness are compared (Fig. 2-14). To maintain basal metabolic needs (i.e., at rest and fasting), a normal healthy adult requires approximately 22 to 25 kcal/kg per day drawn from carbohydrate, lipid, and protein sources. This requirement can be as high as 40 kcal/kg per day in severe stress states, such as those seen in patients with burn injuries. Figure 2-14. Fuel utilization in a 70-kg man during short-term fasting with an approximate basal energy expenditure of 1800 kcal. During starvation, muscle proteins and fat stores provide fuel for the host, with the latter being most abundant. RBC = red blood cell; WBC = white blood cell. (Adapted from Cahill GF: Starvation in man. N Engl J Med. 1970;282:668.) In the healthy adult, principal sources of fuel during shortterm fasting (<5 days) are derived from muscle protein and body fat, with fat being the most abundant source of energy (Table 2-8). The normal adult body contains 300 to 400 g of carbohydrates in the form of glycogen, of which 75 to 100 g are stored in the liver. Approximately 200 to 250 g of glycogen are stored within skeletal, cardiac, and smooth muscle cells. The greater glycogen stores within the muscle are not readily available for systemic use due to a deficiency in glucose-6-phosphatase but are available for the energy needs of muscle cells. Therefore, in the fasting state, hepatic glycogen stores are rapidly and preferentially depleted, which results in a fall of serum glucose concentration within hours (<16 hours). During fasting, a healthy 70-kg adult will use 180 g of glucose per day to support the metabolism of obligate glycolytic cells such as neurons, leukocytes, erythrocytes, and the renal medullae. Other tissues that use glucose for fuel are skeletal muscle, intestinal mucosa, fetal tissues, and solid tumors. Table 2-8 A. Body fuel reserves in a 70-kg man and B. Energy equivalent of substrate oxidation A. Component Mass (kg) Energy (kcal) Days Available Water and minerals 49 0 0 Protein 6.0 24,000 13.0 Glycogen 0.2 800 0.4 Fat 15.0 140,000 78.0 Total 70.2 164,800 91.4 B. Substrate O2 Consumed (L/g) CO2 Produced (L/g) Respiratory Quotient kcal/g Recommended Daily Requirement Glucose 0.75 0.75 1.0 4.0 7.2 g/kg per day Dextrose — — — 3.4 — Lipid 2.0 1.4 0.7 9.0 1.0 g/kg per day Protein 1.0 0.8 0.8 4.0 0.8 g/kg per day VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 45 Muscle LIVER Protein pyruvate Glucose Gluconeogenesis Glucose Alanine Lactate + Pyruvate Ketone Fatty acid Glucose-alanine cycle Cori cycle Glucagon, NE, vasopressin, and angiotensin II can promote the utilization of glycogen stores (glycogenolysis) during fasting. Although glucagon, EPI, and cortisol directly promote gluconeogenesis, EPI and cortisol also promote pyruvate shuttling to the liver for gluconeogenesis. Precursors for hepatic gluconeogenesis include lactate, glycerol, and amino acids such as alanine and glutamine. Lactate is released by glycolysis within skeletal muscles, as well as by erythrocytes and leukocytes. The recycling of lactate and pyruvate for gluconeogenesis is commonly referred to as the Cori cycle, which can provide up to 40% of plasma glucose during starvation (Fig. 2-15). Lactate production from skeletal muscle is insufficient to maintain systemic glucose needs during short-term fasting (simple starvation). Therefore, significant amounts of protein must be degraded daily (75 g/d for a 70-kg adult) to provide the amino acid substrate for hepatic gluconeogenesis. Proteolysis during starvation, which results primarily from decreased insulin and increased cortisol release, is associated with elevated urinary nitrogen excretion from the normal 7 to 10 g per day up to 30 g or more per day.133 Although proteolysis during starvation occurs mainly within skeletal muscles, protein degradation in solid organs also occurs. In prolonged starvation, systemic proteolysis is reduced to approximately 20 g/d, and urinary nitrogen excretion stabilizes at 2 to 5 g/d (Fig. 2-16). This reduction in proteolysis reflects the adaptation by vital organs (e.g., myocardium, brain, renal cortex, and skeletal muscle) to using ketone bodies as their principal fuel source. In extended fasting, ketone bodies become an important fuel source for the brain after 2 days and gradually become the principal fuel source by 24 days. Enhanced deamination of amino acids for gluconeogenesis during starvation consequently increases renal excretion of Fuel utilization in long-term fasting man (70 kg) KIDNEY 15g Muscle Protein 20g Fat stores Triglycerides 180g Amino acids 5g Glycerol 18g Fatty acid 180g Gluconeogenesis LIVER Glycogen 40g 40g 36g Glucose 80g 58g Gluconeogenesis 45g Oxidation 44g Ketone 68g Fatty acid 135g RBC WBC Nerve Kidney Muscle Brain 36g Lactate + Pyruvate 44g 10g (100 mEq) in urine Heart Kidney Muscle Figure 2-16. Fuel utilization in extended starvation. Liver glycogen stores are depleted, and there is adaptive reduction in proteolysis as a source of fuel. The brain uses ketones for fuel. The kidneys become important participants in gluconeogenesis. RBC = red blood cell; WBC = white blood cell. (Adapted from Cahill GF: Starvation in man. N Engl J Med. 1970;282:668.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Ketone Figure 2-15. The recycling of peripheral lactate and pyruvate for hepatic gluconeogenesis is accomplished by the Cori cycle. Alanine within skeletal muscles can also be used as a precursor for hepatic gluconeogenesis. During starvation, such fatty acid provides fuel sources for basal hepatic enzymatic function. RBC = red blood cell; WBC = white blood cell. CHAPTER 2 RBC WBC Nerve Kidney Muscle 46 Fuel utilization following trauma KIDNEY Amino acids Gluconeogenesis Gluconeogenesis BASIC CONSIDERATIONS Glycerol 17g Fat stores Triglycerides 170g Fatty 40g acid 170g Glucose 360g 180g RBC WBC Nerve Kidney Muscle LIVER Oxidation Ketone 60g Heart Kidney Muscle Fatty acid 130g ammonium ions. The kidneys also participate in gluconeogenesis by the use of glutamine and glutamate, and can become the primary source of gluconeogenesis during prolonged starvation, accounting for up to one half of systemic glucose production. Lipid stores within adipose tissue provide 40% or more of caloric expenditure during starvation. Energy requirements for basal enzymatic and muscular functions (e.g., gluconeogenesis, neural transmission, and cardiac contraction) are met by the mobilization of triglycerides from adipose tissue. In a resting, fasting, 70-kg person, approximately 160 g of free fatty acids and glycerol can be mobilized from adipose tissue per day. Free fatty acid release is stimulated in part by a reduction in serum insulin levels and in part by the increase in circulating glucagon and catecholamine. Such free fatty acids, like ketone bodies, are used as fuel by tissues such as the heart, kidney (renal cortex), muscle, and liver. The mobilization of lipid stores for energy importantly decreases the rate of glycolysis, gluconeogenesis, and proteolysis, as well as the overall glucose requirement to sustain the host. Furthermore, ketone bodies spare glucose utilization by inhibiting the enzyme pyruvate dehydrogenase. the predominant energy source (50% to 80%) during critical illness and after injury. Fat mobilization (lipolysis) occurs mainly in response to catecholamine stimulus of the hormone-sensitive triglyceride lipase. Other hormonal influences that potentiate lipolysis include adrenocorticotropic hormone (ACTH), catecholamines, thyroid hormone, cortisol, glucagon, GH release, and reduction in insulin levels.135 Lipid Absorption. Although the process is poorly understood, adipose tissue provides fuel for the host in the form of free fatty acids and glycerol during critical illness and injury. Oxidation of 1 g of fat yields approximately 9 kcal of energy. Although the liver is capable of synthesizing triglycerides from carbohydrates and 225 Injuries or infections induce unique neuroendocrine and immunologic responses that differentiate injury metabolism from that of unstressed fasting (Fig. 2-17). The magnitude of metabolic expenditure appears to be directly proportional to the severity of insult, with thermal injuries and severe infections having the highest energy demands (Fig. 2-18). The increase in energy expenditure is mediated in part by sympathetic activation and catecholamine release, which has been replicated by the administration of catecholamines to healthy human subjects. Lipid metabolism after injury is intentionally discussed first, because this macronutrient becomes the primary source of energy during stressed states.134 Lipids are not merely nonprotein, noncarbohydrate fuel sources that minimize protein catabolism in the injured patient. Lipid metabolism potentially influences the structural integrity of cell membranes as well as the immune response during systemic inflammation. Adipose stores within the body (triglycerides) are Major burns 200 Sepsis/peritonitis Skeletal trauma 175 Metabolism after Injury Lipid Metabolism after Injury Figure 2-17. Acute injury is associated with significant alterations in substrate utilization. There is enhanced nitrogen loss, indicative of catabolism. Fat remains the primary fuel source under these circumstances. RBC = red blood cell; WBC = white blood cell. Lactate + Pyruvate Elective surgery 150 % REE PART I Muscle Protein 250g WOUND 180g 125 Normal range 100 75 Starvation 50 25 0 10 20 30 40 50 Days after injury Figure 2-18. Influence of injury severity on resting metabolism (resting energy expenditure, or REE). The shaded area indicates normal REE. (From Long CL, Schaffel N, Geiger J, et al. Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr. 1979;3(6):452. Copyright © 1979 by A.S.P.E.N. Reprinted by permission of Sage Publications.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Monoglycerides 47 Fatty acids Dietary triglycerides CHAPTER 2 Pancreatic lipase Monoglyceride + 2 Fatty acyI-CoA Gut enterocyte + Protein Intestinal lumen Chylomicron Lymphatic duct amino acids, dietary and exogenous sources provide the major source of triglycerides. Dietary lipids are not readily absorbable in the gut but require pancreatic lipase and phospholipase within the duodenum to hydrolyze the triglycerides into free fatty acids and monoglycerides. The free fatty acids and monoglycerides are then readily absorbed by gut enterocytes, which resynthesize triglycerides by esterification of the monoglycerides with fatty acyl coenzyme A (acyl-CoA) (Fig. 2-19). Longchain triglycerides (LCTs), defined as those with 12 carbons or more, generally undergo this process of esterification and enter the circulation through the lymphatic system as chylomicrons. Shorter fatty acid chains directly enter the portal circulation and are transported to the liver by albumin carriers. Hepatocytes use free fatty acids as a fuel source during stress states but also can synthesize phospholipids or triglycerides (i.e., very-low-density lipoproteins) during fed states. Systemic tissue (e.g., muscle and the heart) can use chylomicrons and triglycerides as fuel by hydrolysis with lipoprotein lipase at the luminal surface of capillary endothelium.136 Trauma or sepsis suppresses lipoprotein lipase activity in both adipose tissue and muscle, presumably mediated by TNF. Lipolysis and Fatty Acid Oxidation. Periods of energy demand are accompanied by free fatty acid mobilization from adipose stores. This is mediated by hormonal influences (e.g., catecholamines, ACTH, thyroid hormones, GH, and glucagon) on triglyceride lipase through a cAMP pathway (Fig. 2-20). In adipose tissues, triglyceride lipase hydrolyzes triglycerides into free fatty acids and glycerol. Free fatty acids enter the capillary circulation and are transported by albumin to tissues requiring this fuel source (e.g., heart and skeletal muscle). Insulin inhibits lipolysis and favors triglyceride synthesis by augmenting lipoprotein lipase activity as well as intracellular levels of glycerol-3-phosphate. The use of glycerol for fuel depends on the availability of tissue glycerokinase, which is abundant in the liver and kidneys. Figure 2-19. Pancreatic lipase within the small intestinal brush borders hydrolyzes triglycerides into monoglycerides and fatty acids. These components readily diffuse into the gut enterocytes, where they are re-esterified into triglycerides. The resynthesized triglycerides bind carrier proteins to form chylomicrons, which are transported by the lymphatic system. Shorter triglycerides (those with <10 carbon atoms) can bypass this process and directly enter the portal circulation for transport to the liver. CoA = coenzyme A. Free fatty acids absorbed by cells conjugate with acylCoA within the cytoplasm. The transport of fatty acyl-CoA from the outer mitochondrial membrane across the inner mitochondrial membrane occurs via the carnitine shuttle (Fig. 2-21). Medium-chain triglycerides (MCTs), defined as those 6 to 12 carbons in length, bypass the carnitine shuttle and readily cross the mitochondrial membranes. This accounts in part for the fact that MCTs are more efficiently oxidized than LCTs. Ideally, the rapid oxidation of MCTs makes them less prone to fat deposition, particularly within immune cells and the reticuloendothelial system—a common finding with lipid infusion in parenteral nutrition.137 However, exclusive use of MCTs as fuel in animal studies has been associated with higher metabolic demands and toxicity, as well as essential fatty acid deficiency. Within the mitochondria, fatty acyl-CoA undergoes beta oxidation, which produces acetyl-CoA with each pass through the cycle. Each acetyl-CoA molecule subsequently enters the tricarboxylic acid (TCA) cycle for further oxidation to yield 12 ATP molecules, carbon dioxide, and water. Excess acetylCoA molecules serve as precursors for ketogenesis. Unlike glucose metabolism, oxidation of fatty acids requires proportionally less oxygen and produces less carbon dioxide. This is frequently quantified as the ratio of carbon dioxide produced to oxygen consumed for the reaction and is known as the respiratory quotient (RQ). An RQ of 0.7 would imply greater fatty acid oxidation for fuel, whereas an RQ of 1 indicates greater carbohydrate oxidation (overfeeding). An RQ of 0.85 suggests the oxidation of equal amounts of fatty acids and glucose. Ketogenesis Carbohydrate depletion slows the entry of acetyl-CoA into the TCA cycle secondary to depleted TCA intermediates and enzyme activity. Increased lipolysis and reduced systemic carbohydrate availability during starvation diverts excess acetylCoA toward hepatic ketogenesis. A number of extrahepatic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Triglycerides 48 PART I Hormone-receptor activation cAMP BASIC CONSIDERATIONS Protein kinase Triglyceride lipase Triglyceride Diglyceride Monoglyceride Glycerol Adipose cell FFA Capillary FFA FFA FFA Figure 2-20. Fat mobilization in adipose tissue. Triglyceride lipase activation by hormonal stimulation of adipose cells occurs through the cyclic adenosine monophosphate (cAMP) pathway. Triglycerides are serially hydrolyzed with resultant free fatty acid (FFA) release at every step. The FFAs diffuse readily into the capillary bed for transport. Tissues with glycerokinase can use glycerol for fuel by forming glycerol-3-phosphate. Glycerol-3-phosphate can esterify with FFAs to form triglycerides or can be used as a precursor for renal and hepatic gluconeogenesis. Skeletal muscle and adipose cells have little glycerokinase and thus do not use glycerol for fuel. tissues, but not the liver itself, are capable of using ketones for fuel. Ketosis represents a state in which hepatic ketone production exceeds extrahepatic ketone utilization. The rate of ketogenesis appears to be inversely related to the severity of injury. Major trauma, severe shock, and sepsis attenuate ketogenesis by increasing insulin levels and by causing rapid tissue oxidation of free fatty acids. Minor injuries and infections are associated with modest elevations in plasma free fatty acid concentrations and ketogenesis. However, in minor stress states ketogenesis does not exceed that in nonstressed starvation. Carbohydrate Metabolism Ingested and enteral carbohydrates are primarily digested in the small intestine, where pancreatic and intestinal enzymes reduce the complex carbohydrates to dimeric units. Disaccharidases (e.g., sucrase, lactase, and maltase) within intestinal brush borders dismantle the complex carbohydrates into simple hexose units, which are transported into the intestinal mucosa. Glucose and galactose are primarily absorbed by energy-dependent active transport coupled to the sodium pump. Fructose absorption, however, occurs by concentration-dependent facilitated diffusion. Neither fructose or galactose within the circulation nor exogenous mannitol (for neurologic injury) evokes an insulin response. Intravenous administration of low-dose fructose in fasting humans has been associated with nitrogen conservation, but the clinical utility of fructose administration in human injury remains to be demonstrated. Discussion of carbohydrate metabolism primarily refers to the utilization of glucose. The oxidation of 1 g of carbohydrate yields 4 kcal, but sugar solutions such as those found in intravenous fluids or parenteral nutrition provide only 3.4 kcal/g of dextrose. In starvation, glucose production occurs at the expense of protein stores (i.e., skeletal muscle). Hence, the primary goal for maintenance glucose administration in surgical patients is to minimize muscle wasting. The exogenous administration of small amounts of glucose (approximately 50 g/d) facilitates fat entry into the TCA cycle and reduces ketosis. Unlike in starvation in healthy subjects, in septic and trauma patients, provision of exogenous glucose never has been shown to fully suppress amino acid degradation for gluconeogenesis. This suggests that during periods of stress, other hormonal and proinflammatory mediators have a profound influence on the rate of protein degradation and that some degree of muscle wasting is inevitable. The administration of insulin, however, has been shown to reverse protein catabolism during severe stress by stimulating protein synthesis in skeletal muscles and by inhibiting hepatocyte protein degradation. Insulin also stimulates the incorporation of elemental precursors into nucleic acids in association with RNA synthesis in muscle cells. In cells, glucose is phosphorylated to form glucose-6phosphate. Glucose-6-phosphate can be polymerized during glycogenesis or catabolized in glycogenolysis. Glucose catabolism occurs by cleavage to pyruvate or lactate (pyruvic acid pathway) or by decarboxylation to pentoses (pentose shunt) (Fig. 2-22). Excess glucose from overfeeding, as reflected by RQs >1.0, can result in conditions such as glucosuria, thermogenesis, and conversion to fat (lipogenesis). Excessive glucose administration results in elevated carbon dioxide production, which may VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Carnitine acyltransferase I O R C R C CoA Carnitine Carnitine CoA Cytosol O Mitochondria R CoA C Carnitine O R C Carnitine CoA Beta Oxidation Carnitine acyltransferase II FFA Acetyl-CoA Figure 2-21. Free fatty acids (FFAs) in the cells form fatty acylcoenzyme A (CoA) with CoA. Fatty acyl-CoA cannot enter the inner mitochondrial membrane and requires carnitine as a carrier protein (carnitine shuttle). Once inside the mitochondria, carnitine dissociates and fatty acyl-CoA is re-formed. The carnitine molecule is transported back into the cytosol for reuse. The fatty acyl-CoA undergoes beta oxidation to form acetyl-CoA for entry into the tricarboxylic acid cycle. “R” represents a part of the acyl group of acyl-CoA. Glucose Glycogen Glucose-6-Phosphate 6-Phosphogluconate Pentose monophosphate shunt Pyruvic acid Lactic acid Tricarboxylic acid VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 2-22. Simplified schema of glucose catabolism through the pentose monophosphate pathway or by breakdown into pyruvate. Glucose6-phosphate becomes an important “crossroad” for glucose metabolism. Systemic Response to Injury and Metabolic Support Transport protein Mitochondrial membrane 49 CHAPTER 2 O be deleterious in patients with suboptimal pulmonary function, as well as hyperglycemia, which may contribute to infectious risk and immune suppression. Injury and severe infections acutely induce a state of peripheral glucose intolerance, despite ample insulin production at levels several fold above baseline. This may occur in part due to reduced skeletal muscle pyruvate dehydrogenase activity after injury, which diminishes the conversion of pyruvate to acetylCoA and subsequent entry into the TCA cycle. The three-carbon structures (e.g., pyruvate and lactate) that consequently accumulate are shunted to the liver as substrate for gluconeogenesis. Furthermore, regional tissue catheterization and isotope dilution studies have shown an increase in net splanchnic glucose production by 50% to 60% in septic patients and a 50% to 100% increase in burn patients.137 The increase in plasma glucose levels is proportional to the severity of injury, and this net hepatic gluconeogenic response is believed to be under the influence of glucagon. Unlike in the nonstressed subject, in the hypermetabolic, critically ill patient, the hepatic gluconeogenic response to injury or sepsis cannot be suppressed by exogenous or excess glucose administration but rather persists. Hepatic gluconeogenesis, arising primarily from alanine and glutamine catabolism, provides a ready fuel source for tissues such as those of the nervous system, wounds, and erythrocytes, which do not require insulin for glucose transport. The elevated glucose concentrations also provide a necessary energy source for leukocytes in inflamed tissues and in sites of microbial invasions. The shunting of glucose away from nonessential organs such as skeletal muscle and adipose tissues is mediated by catecholamines. Experiments with infusing catecholamines and glucagon in animals have demonstrated elevated plasma glucose levels as a result of increased hepatic gluconeogenesis and 50 PART I BASIC CONSIDERATIONS peripheral insulin resistance. Interestingly, although glucocorticoid infusion alone does not increase glucose levels, it does prolong and augment the hyperglycemic effects of catecholamines and glucagon when glucocorticoid is administered concurrently with the latter. Glycogen stores within skeletal muscles can be mobilized by EPI activation of β-adrenergic receptors, GTP-binding proteins (G proteins), which subsequently activates the second messenger, cAMP. The cAMP activates phosphorylase kinase, which in turn leads to conversion of glycogen to glucose-1phosphate. Phosphorylase kinase also can be activated by the second messenger, calcium, through the breakdown of phosphatidylinositol phosphate, which is the case in vasopressinmediated hepatic glycogenolysis.138 Glucose Transport and Signaling. Hydrophobic cell membranes are relatively impermeable to hydrophilic glucose molecules. There are two distinct classes of membrane glucose transporters in human systems. These are the facilitated diffusion glucose transporters (GLUTs) that permit the transport of glucose down a concentration gradient (Table 2-9) and the Na+/glucose secondary active transport system (SGLT), which transports glucose molecules against concentration gradients by active transport. Numerous functional human GLUTs have been cloned since 1985. GLUT1 is expressed at its highest level in human erythrocytes, where it may function to increase the glucose carrying capacity of the blood. It is expressed on several other tissues, but little is found in the liver and skeletal muscle. GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform that is constitutively expressed by the endothelium in the blood-brain barrier. GLUT2 is the major glucose transporter of hepatocytes. It is also expressed by intestinal absorptive cells, pancreatic β-cells, renal tubule cells, and insulin-secreting β-cells of the pancreas. GLUT2 is important for glucose uptake and release in the fed and fasted states. GLUT3 is highly expressed in neuronal tissue of the brain and appears to be important to neuronal glucose uptake. GLUT4 is significant to human metabolism because it is the primary glucose transporter of insulin-sensitive tissues, adipose tissue, and skeletal and cardiac muscle. Under basal conditions, these transporters are usually packaged as intracellular vesicles, but when insulin levels rise, rapid translocation of these vesicles to the cell surface occurs, increasing glucose uptake and metabolism in these tissues and preventing chronic elevations in blood glucose levels. Table 2-9 Human facilitated diffusion glucose transporter (GLUT) family Type Amino Acids Major Expression Sites GLUT1 492 Placenta, brain, kidney, colon GLUT2 524 Liver, pancreatic β-cells, kidney, small intestine GLUT3 496 Brain, testis GLUT4 509 Skeletal muscle, heart muscle, brown and white fat GLUT5 501 Small intestine, sperm A defect in this insulin-mediated translocation of GLUT4 to the plasma membrane causes peripheral insulin resistance. GLUT4 therefore plays a critical role in the regulation of whole-body glucose homeostasis. GLUT5 has been identified in several tissues but is primarily expressed in the jejunum. Although it possesses some capacity for glucose transport, it is predominantly a fructose transporter.139 SGLTs are distinct glucose transport systems found in the intestinal epithelium and in the proximal renal tubules. These systems transport both sodium and glucose intracellularly, and glucose affinity for this transporter increases when sodium ions are attached. SGLT1 is prevalent on brush borders of small intestine enterocytes and primarily mediates the active uptake of luminal glucose. In addition, SGLT1 within the intestinal lumen also enhances gut retention of water through osmotic absorption. SGLT1 and SGLT2 are both associated with glucose reabsorption at proximal renal tubules. Protein and Amino Acid Metabolism The average protein intake in healthy young adults ranges from 80 to 120 g/d, and every 6 g of protein yields approximately 1 g of nitrogen. The degradation of 1 g of protein yields approximately 4 kcal of energy, similar to the yield in carbohydrate metabolism. After injury, the initial systemic proteolysis, mediated primarily by glucocorticoids, increases urinary nitrogen excretion to levels in excess of 30 g/d, which roughly corresponds to a loss in lean body mass of 1.5% per day. An injured individual who does not receive nutrition for 10 days can theoretically lose 15% lean body mass. Therefore, amino acids cannot be considered a long-term fuel reserve, and indeed excessive protein depletion (i.e., 25% to 30% of lean body weight) is not compatible with sustaining life.140 Protein catabolism after injury provides substrates for gluconeogenesis and for the synthesis of acute-phase proteins. Radiolabeled amino acid incorporation studies and protein analyses confirm that skeletal muscles are preferentially depleted acutely after injury, whereas visceral tissues (e.g., the liver and kidney) remain relatively preserved. The accelerated urea excretion after injury also is associated with the excretion of intracellular elements such as sulfur, phosphorus, potassium, magnesium, and creatinine. Conversely, the rapid utilization of elements such as potassium and magnesium during recovery from major injury may indicate a period of tissue healing. The net changes in protein catabolism and synthesis correspond to the severity and duration of injury (Fig. 2-23). Elective operations and minor injuries result in lower protein synthesis and moderate protein breakdown. Severe trauma, burns, and sepsis are associated with increased protein catabolism. The rise in urinary nitrogen and negative nitrogen balance can be detected early after injury and peak by 7 days. This state of protein catabolism may persist for as long as 3 to 7 weeks. The patient’s prior physical status and age appear to influence the degree of proteolysis after injury or sepsis. Activation of the ubiquitinproteasome system in muscle cells is one of the major pathways for protein degradation during acute injury. This response is accentuated by tissue hypoxia, acidosis, insulin resistance, and elevated glucocorticoid levels. NUTRITION IN THE SURGICAL PATIENT The goal of nutritional support in the surgical patient is to prevent or reverse the catabolic effects of disease or injury. Although several important biologic parameters have been used VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 51 32 28 Major burns CHAPTER 2 Skeletal trauma 20 Severe sepsis 16 Infection 12 Elective surgery 8 4 Partial starvation Total starvation 0 0 10 20 30 40 Days to measure the efficacy of nutritional regimens, the ultimate validation for nutritional support in surgical patients should be improvement in clinical outcome and restoration of function. Estimation of Energy Requirements Overall nutritional assessment is undertaken to determine the severity of nutrient deficiencies or excess and to aid in predicting nutritional requirements. Pertinent information is obtained by determining the presence of weight loss, chronic illnesses, or dietary habits that influence the quantity and quality of food intake. Social habits predisposing to malnutrition and the use of medications that may influence food intake or urination should also be investigated. Physical examination seeks to assess loss of muscle and adipose tissues, organ dysfunction, and subtle changes in skin, hair, or neuromuscular function reflecting frank or impending nutritional deficiency. Anthropometric data (i.e., weight change, skinfold thickness, and arm circumference muscle area) and biochemical determinations (i.e., creatinine excretion, albumin level, prealbumin level, total lymphocyte count, and transferrin level) may be used to substantiate the patient’s history and physical findings. However, it is imprecise to rely on any single or fixed combination of the findings to accurately assess nutritional status or morbidity. Appreciation for the stresses and natural history of the disease process, in combination with nutritional assessment, remains the basis for identifying patients in acute or anticipated need of nutritional support. A fundamental goal of nutritional support is to meet the energy requirements for essential metabolic processes and tissue repair. Failure to provide adequate nonprotein energy sources will lead to consumption of lean tissue stores. The requirement for energy may be measured by indirect calorimetry and trends in serum markers (e.g., prealbumin level) and estimated from urinary nitrogen excretion, which is proportional to resting energy expenditure.138 However, the use of indirect calorimetry, particularly in the critically ill patient, is labor intensive and often leads to overestimation of caloric requirements. Figure 2-23. The effect of injury severity on nitrogen wasting. (From Long CL, Schaffel N, Geiger J, et al. Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr. 1979;3(6):452. Copyright © 1979 by A.S.P.E.N. Reprinted by permission of Sage Publications.) Basal energy expenditure (BEE) may also be estimated using the Harris-Benedict equations: BEE (men) = 66.47 + 13.75 (W) + 5.0 (H) – 6.76 (A) kcal/d BEE (women) = 655.1 + 9.56 (W) + 1.85 (H) – 4.68 (A) kcal/d where W = weight in kilograms; H = height in centimeters; and A = age in years. These equations, adjusted for the type of surgical stress, are suitable for estimating energy requirements in the majority of hospitalized patients. It has been demonstrated that the provision of 30 kcal/kg per day will adequately meet energy requirements in most postsurgical patients, with a low risk of overfeeding. After trauma or sepsis, energy substrate demands are increased, necessitating greater nonprotein calories beyond calculated energy expenditure (Table 2-10). These additional nonprotein calories provided after injury are usually 1.2 to 2.0 times greater than calculated resting energy expenditure, depending on the type of injury. It is seldom appropriate to exceed this level of nonprotein energy intake during the height of the catabolic phase. The second objective of nutritional support is to meet the substrate requirements for protein synthesis. An appropriate nonprotein-calorie:nitrogen ratio of 150:1 (e.g., 1 g N = 6.25 g protein) should be maintained, which is the basal calorie requirement provided to limit the use of protein as an energy source. There is now greater evidence suggesting that increased protein intake and a lower calorie:nitrogen ratio of 80:1 to 100:1 may benefit healing in selected hypermetabolic or critically ill patients. In the absence of severe renal or hepatic dysfunction precluding the use of standard nutritional regimens, approximately 0.25 to 0.35 g of nitrogen per kilogram of body weight should be provided daily.141 Vitamins and Minerals The requirements for vitamins and essential trace minerals usually can be met easily in the average patient with an VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Nitrogen excretion (g/day) 24 52 Table 2-10 Caloric adjustments above basal energy expenditure (BEE) in hypermetabolic conditions PART I BASIC CONSIDERATIONS Condition kcal/kg per Day Adjustment above BEE Grams of Protein/ kg per Day Nonprotein Calories: Nitrogen Normal/moderate malnutrition 25–30 1.1 1.0 150:1 Mild stress 25–30 1.2 1.2 150:1 Moderate stress 30 1.4 1.5 120:1 Severe stress 30–35 1.6 2.0 90–120:1 Burns 35–40 2.0 2.5 90–100:1 uncomplicated postoperative course. Therefore, vitamins usually are not given in the absence of preoperative deficiencies. Patients maintained on elemental diets or parenteral hyperalimentation require complete vitamin and mineral supplementation. Commercial enteral diets contain varying amounts of essential minerals and vitamins. It is necessary to ensure that adequate replacement is available in the diet or by supplementation. Numerous commercial vitamin preparations are available for intravenous or intramuscular use, although most do not contain vitamin K and some do not contain vitamin B12 or folic acid. Supplemental trace minerals may be given intravenously via commercial preparations. Essential fatty acid supplementation also may be necessary, especially in patients with depletion of adipose stores. Overfeeding Overfeeding usually results from overestimation of caloric needs, as occurs when actual body weight is used to calculate the BEE in patient populations such as the critically ill with significant fluid overload and the obese. Indirect calorimetry can be used to quantify energy requirements but frequently overestimates BEE by 10% to 15% in stressed patients, particularly if they are receiving ventilatory support. In these instances, estimated dry weight should be obtained from preinjury records or family members. Adjusted lean body weight also can be calculated. Overfeeding may contribute to clinical deterioration via increased oxygen consumption, increased carbon dioxide production and prolonged need for ventilatory support, fatty liver, suppression of leukocyte function, hyperglycemia, and increased risk of infection. ENTERAL NUTRITION Rationale for Enteral Nutrition Enteral nutrition generally is preferred over parenteral nutrition based on the lower cost of enteral feeding and the associated risks of the intravenous route, including vascular access complications.142 Of further consideration are the consequences of gastrointestinal tract disuse, which include diminished secretory IgA production and cytokine production as well as bacterial overgrowth and altered mucosal defenses. For example, laboratory models have long demonstrated that luminal nutrient contact reduces intestinal mucosal atrophy compared with parenteral or no nutritional support. The benefits of enteral feeding in patients undergoing elective surgery appear to be linked to their preoperative nutritional status. Studies comparing postoperative enteral and parenteral nutrition in patients undergoing gastrointestinal surgery have demonstrated reduced infectious complications and acute-phase protein production in those fed by the enteral route. Yet prospectively randomized studies of patients with adequate nutritional status (albumin ≥4 g/dL) undergoing gastrointestinal surgery demonstrate no differences in outcome and complications between those administered enteral nutrition and those given maintenance intravenous fluids alone in the initial days after surgery.143 Furthermore, intestinal permeability studies in well-nourished patients undergoing upper gastrointestinal cancer surgery demonstrated normalization of intestinal permeability and barrier function by the fifth postoperative day.144 The data for critically ill or injured patients are more definitive as to the benefits of enteral nutrition. Meta-analysis of studies involving critically ill patients demonstrates a 44% reduction in infectious complications in those receiving enteral nutritional support compared with those receiving parenteral nutrition. Most prospectively randomized studies in patients with severe abdominal and thoracic trauma demonstrate significant reductions in infectious complications in patients given early enteral nutrition compared with those who were unfed or received parenteral nutrition. In critically ill patients, prospective studies have also demonstrated that early enteral nutrition is associated with better small-intestinal carbohydrate absorption, shorter duration of mechanical ventilation, and shorter time in the intensive care unit. The exception has been in studies of patients with 6 closed-head injury, in whom no significant differences in outcome were demonstrated between early jejunal feeding and other nutritional support modalities. Moreover, early gastric feeding after closed-head injury was frequently associated with underfeeding and calorie deficiency due to the difficulties in overcoming gastroparesis and the high risk of aspiration. While current evidence remains inconclusive about the benefits of “early” (as defined by feeding in the first 24 hours) versus “late” (as defined by feeding >24 hours after burn) enteral nutrition in burn patients as to its impact on mortality rates, there is reason to believe that early enteral nutrition may positively modulate the initial hypermetabolic response and help to maintain mucosal immunity. In summary, enteral nutrition is preferred for most critically ill patients—an evidence-based practice supported by clinical data involving a variety of critically ill patient populations, including those with trauma, burns, head injury, major surgery, and acute pancreatitis. For intensive care unit 7 patients who are hemodynamically stable and have a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ As noted earlier, critically ill and/or injured patients demonstrate increased resting energy expenditure associated with altered metabolism. While several methods exist to predict the energy requirement, the recommended caloric dose for critically ill patients varies, ranging from 25 to 30 kcal/kg. The perceived benefit of achieving the caloric target is to meet the patient’s energy needs and to avoid the loss of lean body mass. However, recent evidence supports the idea of caloric restriction, attributing its benefits to improved cellular function in terms of effects on mitochondrial free radical generation, the plasma membrane redox system, and insulin sensitivity. Further support was offered by a single-center, randomized controlled trial that compared permissive underfeeding with target enteral feeding (caloric goal: 60% to 70% compared with 90% to 100% of calculated requirement) in critically ill medical and surgical patients.146 This study demonstrated that permissive underfeeding was associated with lower mortality and morbidity than was target feeding. However, current guidelines do not recommend hypocaloric feeding without confirmation of these data from the multicenter trial that is currently ongoing. A recent study examined the use of trophic feedings in patients with acute lung injury. Trophic feedings refer to providing a minimal amount of enteral feedings, which are presumed to have beneficial effects despite not meeting daily caloric needs. When the trophic feeding group (enteral feeding at 10 mL/h) was compared with the 53 Enteral Formulas For most critically ill patients, the choice of enteral formula will be determined by a number of factors and will include a clinical judgment as to the “best fit” for the patients’ needs. In general, feeding formulas to consider are gastrointestinal tolerance-promoting, anti-inflammatory, immune-modulating, organ supportive, and standard enteral nutrition. In addition, guidelines from professional nutrition societies identify certain populations of patients who can benefit from formulations with specific pharmaconutrients.148 For many others, each physician must use his or her own clinical judgment about what formula will best meet the patient’s needs. The functional status of the gastrointestinal tract determines the type of enteral solutions to be used. Patients with an intact gastrointestinal tract will tolerate complex solutions, but patients who have not been fed via the gastrointestinal tract for prolonged periods are less likely to tolerate complex carbohydrates. In those patients who are having difficulty tolerating standard enteral formulas, peptide- and MCT-based formulas with prebiotics can lessen gastrointestinal tolerance problems. Additionally, in patients with demonstrated malabsorption issues, such as with inflammatory bowel diseases or short-bowel syndrome, current guidelines endorse the provision of hydrolyzed protein formulas to improve absorption. Guidelines have not yet been made with regard to the fiber content of enteral formulas. However, recent evidence indicates that supplementation of enteral formulas with soluble dietary fiber may be beneficial for improving stool consistency in patients suffering from diarrhea. Factors that influence the choice of enteral formula also include the extent of organ dysfunction (e.g., renal, pulmonary, hepatic, or gastrointestinal), the nutrients needed to restore optimal function and healing, and the cost of specific products. There are still no conclusive data to recommend one category of product over another, and nutritional support committees typically develop the most cost-efficient enteral formulary for the most commonly encountered disease categories within the institution. As discussed extensively in the first sections of this chapter, surgery and trauma result in a significant “sterile” inflammatory response that impacts the innate and adaptive immune systems. The provision of immune-modulating nutrients, termed “immunonutrition,” is one mechanism by which the immune response can be supported and an attempt made to lower infectious risk. At present, the best-studied immunonutrients are glutamine, arginine, and ω-3 PUFAs. “Immunonutrients.” Glutamine is the most abundant amino acid in the human body, comprising nearly two thirds of the free intracellular amino acid pool. Of this, 75% is found within the skeletal muscles. In healthy individuals, glutamine is considered a nonessential amino acid, because it is synthesized within the skeletal muscles and the lungs. Glutamine is a necessary substrate for nucleotide synthesis in most dividing cells and hence provides a major fuel source for enterocytes. It also serves as an important fuel source for immunocytes such as lymphocytes and macrophages and is a precursor for glutathione, a major intracellular antioxidant. During stress states such as sepsis, or in tumor-bearing hosts, peripheral glutamine stores are rapidly depleted, and the amino acid is preferentially shunted as a fuel VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Hypocaloric Enteral Nutrition full-feeding group (25 mL/h) over the first 6 days of feeding, there was no improvement in ventilator-free days, 60-day mortality, or infectious complications.147 CHAPTER 2 functioning gastrointestinal tract, early enteral feeding (within 24 to 48 hours of arrival in the intensive care unit) has become a recommended standard of care.145 For patients undergoing elective surgery, healthy patients without malnutrition who are undergoing uncomplicated surgery can tolerate 10 days of partial starvation (i.e., maintenance intravenous fluids only) before any clinically significant protein catabolism occurs. Earlier intervention is likely indicated for patients in whom preoperative protein-calorie malnutrition has been identified. Other clinical scenarios for which the benefits of enteral nutritional support have been substantiated include permanent neurologic impairment, oropharyngeal dysfunction, short-bowel syndrome, and bone marrow transplantation. Initiation of enteral nutrition should occur immediately after adequate resuscitation, most readily determined by adequate urine output. The presence of bowel sounds and the passage of flatus or stool are not absolute prerequisites for initiation of enteral nutrition, but in the setting of gastroparesis, feedings should be administered distal to the pylorus. Gastric residuals of 200 mL or more in a 4- to 6-hour period or abdominal distention requires cessation of feeding and adjustment of the infusion rate. Concomitant gastric decompression with distal small-bowel feedings may be appropriate in certain patients such as closedhead injury patients with gastroparesis. There is no evidence to support withholding enteric feedings for patients after bowel resection or for those with low-output enterocutaneous fistulas of <500 mL/d. In fact, a recent systematic review of studies of early enteral feeding (within 24 hours of gastrointestinal surgery) showed no effect on anastomotic leak and a reduction in mortality. Early enteral feeding is also associated with reduced incidence of fistula formation in patients with open abdomen. Enteral feeding should also be offered to patients with shortbowel syndrome or clinical malabsorption, but necessary calories, essential minerals, and vitamins should be supplemented using parenteral modalities. 54 PART I BASIC CONSIDERATIONS source toward the visceral organs and tumors, respectively.149 These situations create, at least experimentally, a glutaminedepleted environment, with consequences including enterocyte and immunocyte starvation. Glutamine metabolism during stress in humans, however, may be more complex than is indicated in previously reported animal data. Although it is hypothesized that provision of glutamine may preserve immune cell and enterocyte function and enhance nitrogen balance during injury or sepsis, the clinical outcome is very strongly dependent on the patient population, as will be discussed later. Arginine, also a nonessential amino acid in healthy subjects, first attracted attention for its immunoenhancing properties, wound-healing benefits, and association with improved survival in animal models of sepsis and injury.150 As with glutamine, the benefits of experimental arginine supplementation during stress states are diverse. In clinical studies involving critically ill and injured patients and patients who have undergone surgery for certain malignancies, enteral administration of arginine has led to net nitrogen retention and protein synthesis, whereas isonitrogenous diets have not. Some of these studies also provide in vitro evidence of enhanced immunocyte function. The clinical utility of arginine supplementation in improving overall patient outcome remains an area of investigation. As previously discussed, ω-3 PUFAs (canola oil or fish oil) displace ω-6 fatty acids in cell membranes, which theoretically reduces the proinflammatory response from prostaglandin production. Hence, there has been significant interest in reducing the ratio of ω-6 to ω-3 fatty acids. Low-Residue Isotonic Formulas. Most low-residue isotonic formulas provide a caloric density of 1.0 kcal/mL, and approximately 1500 to 1800 mL are required to meet daily requirements. These low-osmolarity compositions provide baseline carbohydrates, protein, electrolytes, water, fat, and fat-soluble vitamins (some do not have vitamin K) and typically have a nonprotein-calorie:nitrogen ratio of 150:1. These contain no fiber bulk and therefore leave minimum residue. These solutions usually are considered to be the standard or first-line formulas for stable patients with an intact gastrointestinal tract. Isotonic Formulas with Fiber. Isotonic formulas with fiber contain soluble and insoluble fiber, which is most often soy based. Physiologically, fiber-based solutions delay intestinal transit time and may reduce the incidence of diarrhea compared with nonfiber solutions. Fiber stimulates pancreatic lipase activity and is degraded by gut bacteria into short-chain fatty acids (SCFAs), an important fuel for colonocytes. Recent data have also demonstrated the expression of SCFA receptors on leukocytes, suggesting that fiber fermentation by the colonic microbiome may indirectly regulate immune cell function. Future work in this area is likely to demonstrate important links between fiber type, microbiome composition, and immune health. Immune-Enhancing Formulas. Immune-enhancing formulas are fortified with special nutrients that are purported to enhance various aspects of immune or solid organ function. Such additives include glutamine, arginine, ω-3 fatty acids, and nucleotides.151 Although several trials have proposed that one or more of these additives reduce surgical complications and improve outcome, these results have not been uniformly corroborated by other trials. The Canadian Clinical Practice Guidelines currently do not recommend the addition of arginine supplements for critically ill patients due to the potential for harm when used in septic patients.152 With regard to ω-3 PUFAs, results from the EDEN-Omega study demonstrated that twice-daily enteral supplementation of ω-3 fatty acids, α-linolenic acid, and antioxidants did not improve the primary endpoint of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful.153 Glutamine supplementation should be strictly guided by the individual patient condition. Enteral and parenteral supplementation with glutamine appears to have a harmful effect in critically ill patients with multiorgan failure as evidenced by significantly increased mortality (REDOXS study). However, for burn or trauma patients who are hemodynamically stable and without evidence of organ dysfunction, glutamine supplementation has been shown to be beneficial in terms of decreased LOS and infectious complications. Calorie-Dense Formulas. The primary distinction of caloriedense formulas is a greater caloric value for the same volume. Most commercial products of this variety provide 1.5 to 2 kcal/mL and therefore are suitable for patients requiring fluid restriction or those unable to tolerate large-volume infusions. As expected, these solutions have higher osmolality than standard formulas and are suitable for intragastric feedings. High-Protein Formulas. High-protein formulas are available in isotonic and nonisotonic mixtures and are proposed for critically ill or trauma patients with high protein requirements. These formulas have nonprotein-calorie:nitrogen ratios between 80:1 and 120:1. While some observational studies show improved outcomes with higher protein intakes in critically ill patients, there are limited data from randomized trials, which prevents making strong conclusions about the dose of protein in critically ill patients. Elemental Formulas. Elemental formulas contain predigested nutrients and provide proteins in the form of small peptides. Complex carbohydrates are limited, and fat content, in the form of MCTs and LCTs, is minimal. The primary advantage of such a formula is ease of absorption, but the inherent scarcity of fat, associated vitamins, and trace elements limits its long-term use as a primary source of nutrients. Due to its high osmolarity, dilution or slow infusion rates usually are necessary, particularly in critically ill patients. These formulas have been used frequently in patients with malabsorption, gut impairment, and pancreatitis, but their cost is significantly higher than that of standard formulas. To date, there has been no evidence of their benefit in routine use. Renal Failure Formulas. The primary benefits of renal formulas are the lower fluid volume and concentrations of potassium, phosphorus, and magnesium needed to meet daily calorie requirements. This type of formulation almost exclusively contains essential amino acids and has a high nonproteincalorie:nitrogen ratio; however, it does not contain trace elements or vitamins. Pulmonary Failure Formulas. In pulmonary failure formulas, fat content is usually increased to 50% of the total calories, with a corresponding reduction in carbohydrate content. The goal is to reduce carbon dioxide production and alleviate ventilation burden for failing lungs. Hepatic Failure Formulas. Close to 50% of the proteins in hepatic failure formulas are branched-chain amino acids (e.g., leucine, isoleucine, and valine). The goal of such a formula is to reduce aromatic amino acid levels and increase the levels of branched-chain amino acids, which can potentially reverse encephalopathy in patients with hepatic failure.154 The use of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Access for Enteral Nutritional Support Nasoenteric Tubes. Nasogastric feeding should be reserved for those with intact mentation and protective laryngeal reflexes to minimize risks of aspiration. Even in intubated patients, nasogastric feedings often can be recovered from tracheal suction. Nasojejunal feedings are associated with fewer pulmonary complications including risk of pneumonia, but access past the pylorus requires greater effort to accomplish. Therefore, routine use of small-bowel feedings is preferred in units where smallbowel access is readily feasible. Where there may be difficulties obtaining access, small-bowel feedings may be considered a priority for those patients at high risk for intolerance to enteral nutrition (e.g., high gastric residuals). Blind insertion of nasogastric feeding tubes is fraught with misplacement, and air instillation with auscultation is inaccurate for ascertaining proper positioning. Radiographic confirmation is usually required to verify the position of the nasogastric feeding tube. Several methods have been recommended for the passage of nasoenteric feeding tubes into the small bowel, including use of prokinetic agents, right lateral decubitus positioning, gastric insufflation, tube angulation, and application of clockwise torque. However, the successful placement of feeding tubes by these methods is highly variable and operator dependent. Percutaneous Endoscopic Gastrostomy. The most common indications for percutaneous endoscopic gastrostomy (PEG) include impaired swallowing mechanisms, oropharyngeal or esophageal obstruction, and major facial trauma. It is frequently used for debilitated patients requiring caloric supplementation, hydration, or frequent medication dosing. It is also appropriate for patients requiring passive gastric decompression. Relative contraindications for PEG placement include ascites, coagulopathy, gastric varices, gastric neoplasm, and lack of a suitable abdominal site. Most tubes are 18F to 28F in size and may be used for 12 to 24 months. Identification of the PEG site requires endoscopic transillumination of the anterior stomach against the abdominal wall. A 14-gauge angiocatheter is passed through the abdominal wall into the fully insufflated stomach. A guidewire is threaded through the angiocatheter, grasped by snares or forceps, and Table 2-11 Options for enteral feeding access Access Option Comments Nasogastric tube Short-term use only; aspiration risks; nasopharyngeal trauma; frequent dislodgment Nasoduodenal/nasojejunal tube Short-term use; lower aspiration risks in jejunum; placement challenges (radiographic assistance often necessary) Percutaneous endoscopic gastrostomy (PEG) Endoscopy skills required; may be used for gastric decompression or bolus feeds; aspiration risks; can last 12–24 mo; slightly higher complication rates with placement and site leaks Surgical gastrostomy Requires general anesthesia and small laparotomy; procedure may allow placement of extended duodenal/jejunal feeding ports; laparoscopic placement possible Fluoroscopic gastrostomy Blind placement using needle and T-prongs to anchor to stomach; can thread smaller catheter through gastrostomy into duodenum/jejunum under fluoroscopy PEG-jejunal tube Jejunal placement with regular endoscope is operator dependent; jejunal tube often dislodges retrograde; two-stage procedure with PEG placement, followed by fluoroscopic conversion with jejunal feeding tube through PEG Direct percutaneous endoscopic jejunostomy (DPEJ) Direct endoscopic tube placement with enteroscope; placement challenges; greater injury risks Surgical jejunostomy Commonly carried out during laparotomy; general anesthesia; laparoscopic placement usually requires assistant to thread catheter; laparoscopy offers direct visualization of catheter placement Fluoroscopic jejunostomy Difficult approach with injury risks; not commonly done VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 55 Systemic Response to Injury and Metabolic Support The available techniques and repertoire for enteral access have provided multiple options for feeding the gut. Presently used methods and preferred indications are summarized in Table 2-11.156 Furthermore, it is time consuming, and success rates for intubation past the duodenum into the jejunum by these methods are <20%. Fluoroscopy-guided intubation past the pylorus has a >90% success rate, and more than half of these intubations result in jejunal placement. Similarly, endoscopy-guided placement past the pylorus has high success rates, but attempts to advance the tube beyond the second portion of the duodenum using a standard gastroduodenoscope are unlikely to be successful. Small-bowel feeding is more reliable for delivering nutrition than nasogastric feeding. Furthermore, the risks of aspiration pneumonia can be reduced by 25% with small-bowel feeding compared with nasogastric feeding. The disadvantages of the use of nasoenteric feeding tubes are clogging, kinking, and inadvertent displacement or removal of the tube and nasopharyngeal complications. If nasoenteric feeding will be required for longer than 30 days, access should be converted to a percutaneous one.157 CHAPTER 2 these formulas is controversial, however, because no clear benefits have been proven by clinical trials. Protein restriction should be avoided in patients with end-stage liver disease, because such patients have significant protein-energy malnutrition that predisposes them to additional morbidity and mortality.155 56 PART I BASIC CONSIDERATIONS pulled out through the mouth. The tapered end of the PEG tube is secured to the guidewire and is pulled into position out of the abdominal wall. The PEG tube is secured without tension against the abdominal wall, and many have reported using the tube within hours of placement. It has been the practice of some to connect the PEG tube to a drainage bag for passive decompression for 24 hours before use, allowing more time for the stomach to seal against the peritoneum. If endoscopy is not available or technical obstacles preclude PEG placement, the interventional radiologist can attempt the procedure percutaneously under fluoroscopic guidance by first insufflating the stomach against the abdominal wall with a nasogastric tube. If this also is unsuccessful, surgical gastrostomy tube placement can be considered, particularly with minimally invasive methods. When surgery is contemplated, it may be wise to consider directly accessing the small bowel for nutrition delivery. Although PEG tubes enhance nutritional delivery, facilitate nursing care, and are superior to nasogastric tubes, serious complications occur in approximately 3% of patients. These complications include wound infection, necrotizing fasciitis, peritonitis, aspiration, leaks, dislodgment, bowel perforation, enteric fistulas, bleeding, and aspiration pneumonia.158 For patients with significant gastroparesis or gastric outlet obstruction, feedings through PEG tubes are hazardous. In such cases, the PEG tube can be used for decompression and allow access for converting the PEG tube to a transpyloric feeding tube. Percutaneous Endoscopic Gastrostomy-Jejunostomy and Direct Percutaneous Endoscopic Jejunostomy. Although gastric bolus feedings are more physiologic, patients who cannot tolerate gastric feedings or who have significant aspiration risks should be fed directly past the pylorus. In the percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) method, a 9F to 12F tube is passed through an existing PEG tube, past the pylorus, and into the duodenum. This can be achieved by endoscopic or fluoroscopic guidance. With weighted catheter tips and guidewires, the tube can be further advanced past the ligament of Treitz. However, the incidence of long-term PEG-J tube malfunction has been reported to be >50% as a result of retrograde tube migration into the stomach, kinking, or clogging. Direct percutaneous endoscopic jejunostomy (DPEJ) tube placement uses the same techniques as PEG tube placement but requires an enteroscope or colonoscope to reach the jejunum. DPEJ tube malfunctions are probably less frequent than PEG-J tube malfunctions, and kinking or clogging is usually averted by placement of larger-caliber catheters. The success rate of DPEJ tube placement is variable because of the complexity of endoscopic skills required to locate a suitable jejunal site. In such cases where endoscopic means are not feasible, surgical jejunostomy tube placement is more appropriate, especially when minimally invasive techniques are available. Surgical Gastrostomy and Jejunostomy. For a patient undergoing complex abdominal or trauma surgery, thought should be given during surgery to the possible routes for subsequent nutritional support, because laparotomy affords direct access to the stomach or small bowel. The only absolute contraindication to feeding jejunostomy is distal intestinal obstruction. Relative contraindications include severe edema of the intestinal wall, radiation enteritis, inflammatory bowel disease, ascites, severe immunodeficiency, and bowel ischemia. Needle-catheter jejunostomies also can be done with a minimal learning curve. The biggest drawback usually is possible clogging and knotting of the 6F catheter.159 Abdominal distention and cramps are common adverse effects of early enteral nutrition. Some have also reported impaired respiratory mechanics as a result of intolerance to enteral feedings. These are mostly correctable by temporarily discontinuing feedings and resuming at a lower infusion rate. Pneumatosis intestinalis and small-bowel necrosis are infrequent but significant problems in patients receiving jejunal tube feedings. Several contributing factors have been proposed, including the hyperosmolarity of enteral solutions, bacterial overgrowth, fermentation, and accumulation of metabolic breakdown products. The common pathophysiology is believed to be bowel distention and consequent reduction in bowel wall perfusion. Risk factors for these complications include cardiogenic and circulatory shock, vasopressor use, diabetes mellitus, and chronic obstructive pulmonary disease. Therefore, enteral feedings in the critically ill patient should be delayed until adequate resuscitation has been achieved. As alternatives, diluting standard enteral formula, delaying the progression to goal infusion rates, or using monomeric solutions with low osmolality requiring less digestion by the gastrointestinal tract all have been successfully used. PARENTERAL NUTRITION Parenteral nutrition is the continuous infusion of a hyperosmolar solution containing carbohydrates, proteins, fat, and other necessary nutrients through an indwelling catheter inserted into the superior vena cava. To obtain the maximum benefit, the calorie:protein ratio must be adequate (at least 100 to 150 kcal/g nitrogen), and both carbohydrates and proteins must be infused simultaneously. When the sources of calories and nitrogen are given at different times, there is a significant decrease in nitrogen utilization. These nutrients can be given in quantities considerably greater than the basic caloric and nitrogen requirements, and this method has proved to be highly successful in achieving growth and development, positive nitrogen balance, and weight gain in a variety of clinical situations. Clinical trials and meta-analysis of studies of parenteral feeding in the perioperative period have suggested that preoperative nutritional support may benefit some surgical patients, particularly those with extensive malnutrition. Short-term use of parenteral nutrition in critically ill patients (i.e., duration of <7 days) when enteral nutrition may have been instituted is associated with higher rates of infectious complications. After severe injury, parenteral nutrition is associated with higher rates of infectious risks than is enteral feeding (Table 2-12). Clinical studies have demonstrated that parenteral feeding with complete bowel rest results in augmented stress hormone and inflammatory mediator response to an antigenic challenge. However, parenteral feeding still is associated with fewer infectious complications than no feeding at all. In cancer patients, delivery of parenteral nutrition has not been shown to benefit clinical response, prolong survival, or ameliorate the toxic effects of chemotherapy, and infectious complications are increased. Rationale for Parenteral Nutrition The principal indications for parenteral nutrition are malnutrition, sepsis, or surgical or traumatic injury in seriously ill patients for whom use of the gastrointestinal tract for feedings is not possible. In some instances, intravenous nutrition may be used to supplement inadequate oral intake. The safe and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 57 Table 2-12 Incidence of septic morbidity in parenterally and enterally fed trauma patients Complication TEN n = 48 TPN n = 44 Penetrating Trauma TEN n = 38 TPN n = 48 Total TEN n = 44 TPN n = 84 2 1 2 6 4 7 4 10 1 2 5 12 Wound infection 0 2 3 1 3 3 Bacteremia 1 4 0 1 1 5 Urinary tract 1 1 0 1 1 2 Other 5 4 1 1 6 5 Total complications 13 22 7 12 20 34 % Complications per patient group 27% 50% 18% 30% 23% 39% Source: Reproduced with permission from Moore FA, Feliciano DV, Andrassy RJ et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications. Ann Surg. 1992;216(2):172-183. successful use of parenteral nutrition requires proper selection of patients with specific nutritional needs, experience with the technique, and an awareness of the associated complications. In patients with significant malnutrition, parenteral nutrition can rapidly improve nitrogen balance, which may enhance immune function. Routine postoperative use of parenteral nutrition is not shown to have clinical benefit and may be associated with a significant increase in complication rate. As with enteral nutrition, the fundamental goals are to provide sufficient calories and nitrogen substrate to promote tissue repair and to maintain the integrity or growth of lean tissue mass. The following are patient groups for whom parenteral nutrition has been used in an effort to achieve these goals: 1. Newborn infants with catastrophic gastrointestinal anomalies, such as tracheoesophageal fistula, gastroschisis, omphalocele, or massive intestinal atresia 2. Infants who fail to thrive due to gastrointestinal insufficiency associated with short-bowel syndrome, malabsorption, enzyme deficiency, meconium ileus, or idiopathic diarrhea 3. Adult patients with short-bowel syndrome secondary to massive small-bowel resection (<100 cm without colon or ileocecal valve or <50 cm with intact ileocecal valve and colon) 4. Patients with enteroenteric, enterocolic, enterovesical, or high-output enterocutaneous fistulas (>500 mL/d) 5. Surgical patients with prolonged paralytic ileus after major operations (>7 to 10 days), multiple injuries, or blunt or open abdominal trauma, or patients with reflex ileus complicating various medical diseases 6. Patients with normal bowel length but with malabsorption secondary to sprue, hypoproteinemia, enzyme or pancreatic insufficiency, regional enteritis, or ulcerative colitis 7. Adult patients with functional gastrointestinal disorders such as esophageal dyskinesia after cerebrovascular accident, idiopathic diarrhea, psychogenic vomiting, or anorexia nervosa 8. Patients with granulomatous colitis, ulcerative colitis, or tuberculous enteritis in whom major portions of the absorptive mucosa are diseased 9. Patients with malignancy, with or without cachexia, in whom malnutrition might jeopardize successful use of a therapeutic option 10. Patients in whom attempts to provide adequate calories by enteral tube feedings or high residuals have failed 11. Critically ill patients who are hypermetabolic for >5 days or for whom enteral nutrition is not feasible Patients in whom hyperalimentation is contraindicated include the following: 1.  Patients for whom a specific goal for patient management is lacking or for whom, instead of extending a meaningful life, inevitable dying would be delayed 2.  Patients experiencing hemodynamic instability or severe metabolic derangement (e.g., severe hyperglycemia, azotemia, encephalopathy, hyperosmolality, and fluid-electrolyte disturbances) requiring control or correction before hypertonic intravenous feeding is attempted 3.  Patients for whom gastrointestinal tract feeding is feasible; in the vast majority of instances, this is the best route by which to provide nutrition 4. Patients with good nutritional status 5.  Infants with <8 cm of small bowel, because virtually all have been unable to adapt sufficiently despite prolonged periods of parenteral nutrition 6.  Patients who are irreversibly decerebrate or otherwise dehumanized Total Parenteral Nutrition Total parenteral nutrition (TPN), also referred to as central parenteral nutrition, requires access to a large-diameter vein to deliver the entire nutritional requirements of the individual. Dextrose content of the solution is high (15% to 25%), and all other macronutrients and micronutrients are deliverable by this route. Peripheral Parenteral Nutrition The lower osmolarity of the solution used for peripheral parenteral nutrition (PPN), secondary to reduced levels of dextrose (5% to 10%) and protein (3%), allows its administration VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Systemic Response to Injury and Metabolic Support Abdominal abscess Pneumonia CHAPTER 2 Blunt Trauma 58 PART I via peripheral veins. Some nutrients cannot be supplemented because they cannot be concentrated into small volumes. Therefore, PPN is not appropriate for repleting patients with severe malnutrition. It can be considered if central routes are not available or if supplemental nutritional support is required. Typically, PPN is used for short periods (<2 weeks). Beyond this time, TPN should be instituted. Initiation of Parenteral Nutrition BASIC CONSIDERATIONS The basic solution for parenteral nutrition contains a final concentration of 15% to 25% dextrose and 3% to 5% crystalline amino acids. The solutions usually are prepared in sterile conditions in the pharmacy from commercially available kits containing the component solutions and transfer apparatus. Preparation in the pharmacy under laminar flow hoods reduces the incidence of bacterial contamination of the solution. Proper preparation with suitable quality control is absolutely essential to avoid septic complications. The proper provision of electrolytes and amino acids must take into account routes of fluid and electrolyte loss, renal function, metabolic rate, cardiac function, and the underlying disease state. Intravenous vitamin preparations also should be added to parenteral formulas. Vitamin deficiencies are rare occurrences if such preparations are used. In addition, because vitamin K is not part of any commercially prepared vitamin solution, it should be supplemented on a weekly basis. During prolonged parenteral nutrition with fat-free solutions, essential fatty acid deficiency may become clinically apparent and manifests as dry, scaly dermatitis and loss of hair. The syndrome may be prevented by periodic infusion of a fat emulsion at a rate equivalent to 10% to 15% of total calories. Essential trace minerals may be required after prolonged TPN and may be supplied by direct addition of commercial preparations. The most frequent presentation of trace mineral deficiencies is the eczematoid rash developing both diffusely and at intertriginous areas in zincdeficient patients. Other rare trace mineral deficiencies include a microcytic anemia associated with copper deficiency and glucose intolerance presumably related to chromium deficiency. The latter complications are seldom seen except in patients receiving parenteral nutrition for extended periods. The daily administration of commercially available trace mineral supplements will obviate most such problems. Depending on fluid and nitrogen tolerance, parenteral nutrition solutions generally can be increased over 2 to 3 days to achieve the desired infusion rate. Insulin may be supplemented as necessary to ensure glucose tolerance. Administration of additional intravenous fluids and electrolytes may occasionally be necessary in patients with persistently high fluid losses. The patient should be carefully monitored for development of electrolyte, volume, acid-base, and septic complications. Vital signs and urinary output should be measured regularly, and the patient should be weighed regularly. Frequent adjustments of the volume and composition of the solutions are necessary during the course of therapy. Samples for measurement of electrolytes are drawn daily until levels are stable and every 2 or 3 days thereafter. Blood counts, blood urea nitrogen level, levels of liver function indicators, and phosphate and magnesium levels are determined at least weekly. The urine or capillary blood glucose level is checked every 6 hours, and serum glucose concentration is checked at least once daily during the first few days of the infusion and at frequent intervals thereafter. Relative glucose intolerance, which often manifests as glycosuria, may occur after initiation of parenteral nutrition. If blood glucose levels remain elevated or glycosuria persists, the dextrose concentration may be decreased, the infusion rate slowed, or regular insulin added to each bottle. The rise in blood glucose concentration observed after initiating parenteral nutrition may be temporary, as the normal pancreas increases its output of insulin in response to the continuous carbohydrate infusion. In patients with diabetes mellitus, additional insulin may be required. Potassium is essential to achieve positive nitrogen balance and replace depleted intracellular stores. In addition, a significant shift of potassium ion from the extracellular to the intracellular space may take place because of the large glucose infusion, with resultant hypokalemia, metabolic alkalosis, and poor glucose utilization. In some cases as much as 240 mEq of potassium ion daily may be required. Hypokalemia may cause glycosuria, which would be treated with potassium, not insulin. Thus, before giving insulin, the serum potassium level must be checked to avoid exacerbating the hypokalemia. Patients with insulin-dependent diabetes mellitus may exhibit wide fluctuations in blood glucose levels while receiving parenteral nutrition. This may require protocol-driven intravenous insulin therapy. In addition, partial replacement of dextrose calories with lipid emulsions may alleviate these problems in selected patients. Lipid emulsions derived from soybean or safflower oils are widely used as an adjunctive nutrient to prevent the development of essential fatty acid deficiency, although recent data support reducing the overall ω-6 PUFA load in favor of ω-3 PUFAs or MCTs. There is no evidence of enhanced metabolic benefit when >10% to 15% of calories are provided as lipid emulsions. Although the administration of 500 mL of 20% fat emulsion one to three times a week is sufficient to prevent essential fatty acid deficiency, it is common to provide fat emulsions on a daily basis to provide additional calories. The triple mix of carbohydrate, fat, and amino acids is infused at a constant rate during a 24-hour period. The theoretical advantages of a constant fat infusion rate include increased efficiency of lipid utilization and reduction in the impairment of reticuloendothelial function normally identified with bolus lipid infusions. The addition of lipids to an infusion bag may alter the stability of some micronutrients in a dextrose–amino acid preparation. The delivery of parenteral nutrition requires central intravenous access. Temporary or short-term access can be achieved with a 16-gauge percutaneous catheter inserted into a subclavian or internal jugular vein and threaded into the superior vena cava. More permanent access with the intention of providing longterm or home parenteral nutrition can be achieved by placement of a catheter with a subcutaneous port for access by tunneling a catheter with a substantial subcutaneous length or threading a long catheter through the basilic or cephalic vein into the superior vena cava. Complications of Parenteral Nutrition Technical Complications. One of the more common and serious complications associated with long-term parenteral feeding is sepsis secondary to contamination of the central venous catheter. Contamination of solutions should be also considered but is rare when proper pharmacy protocols have been followed. Central line–associated bloodstream infections (CLABSI) occur as a consequence of hematogenous seeding of the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Intestinal Atrophy. Lack of intestinal stimulation is associated with intestinal mucosal atrophy, diminished villous height, bacterial overgrowth, reduced lymphoid tissue size, reduced IgA production, and impaired gut immunity. The full clinical implications of these changes are not well realized, although bacterial translocation has been demonstrated in animal models. The most efficacious method to prevent these changes is to provide at least some nutrients enterally. In patients requiring TPN, it may be feasible to infuse small amounts of feedings via the gastrointestinal tract. References Entries highlighted in bright blue are key references.   1. Minei JP, Cuschieri J, Sperry J, et al. The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock. Crit Care Med. 2012;40(4):1129-1135.    2. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13): 2581-2590.   3. Bone RC. The pathogenesis of sepsis. Ann Intern Med. 1991;115(6):457-469.   4. Lowry SF. Human endotoxemia: a model for mechanistic insight and therapeutic targeting. Shock. 2005;24(Suppl 1): 94-100.   5. Pugin J. How tissue injury alarms the immune system and causes a systemic inflammatory response syndrome. Ann Intensive Care. 2012;2(1):27.    6. Manson J, Thiemermann C, Brohi K. Trauma alarmins as activators of damage-induced inflammation. Br J Surg. 2012;99(Suppl 1):12-20.   7. Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711-2719.   8.  Lu B, Wang H, Andersson U, Tracey KJ. Regulation of HMGB1 release by inflammasomes. Protein Cell. 2013;4(3):163-167.    9. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139-162. 10. Yang H, Hreggvidsdottir HS, Palmblad K, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA. 2010;107(26):11942-11947. 11. Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013;93(6):865-873. 12. Peltz ED, Moore EE, Eckels PC, et al. HMGB1 is markedly elevated within 6 hours of mechanical trauma in humans. Shock. 2009;32(1):17-22. 13. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104-107. 14. West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. 2011;11(6):389-402. 15. Moreth K, Iozzo RV, Schaefer L. Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation. Cell Cycle. 2012;11(11):2084-2091. 16. Babelova A, Moreth K, Tsalastra-Greul W, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem. 2009;284(36): 24035-24048. 17. Haimovich B, Reddell MT, Calvano JE, et al. A novel model of common Toll-like receptor 4- and injury-induced VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 59 Systemic Response to Injury and Metabolic Support Metabolic Complications. Hyperglycemia may develop with normal rates of infusion in patients with impaired glucose tolerance or in any patient if the hypertonic solutions are administered too rapidly. This is a particularly common complication in patients with latent diabetes and in patients subjected to severe surgical stress or trauma. Treatment of the condition consists of volume replacement with correction of electrolyte abnormalities and the administration of insulin. This complication can be avoided with careful attention to daily fluid balance and frequent monitoring of blood glucose levels and serum electrolytes. Increasing experience has emphasized the importance of not overfeeding the parenterally nourished patient. This is particularly true for the depleted patient in whom excess calorie infusion may result in carbon dioxide retention and respiratory insufficiency. In addition, excess feeding also has been related to the development of hepatic steatosis or marked glycogen deposition in selected patients. Cholestasis and formation of gallstones are common in patients receiving long-term parenteral nutrition. Mild but transient abnormalities of serum transaminase, alkaline phosphatase, and bilirubin levels occur in many parenterally nourished patients. Failure of the liver enzymes to plateau or return to normal over 7 to 14 days should suggest another etiology. CHAPTER 2 catheter with bacteria. One of the earliest signs of systemic sepsis from CLA-BSI may be the sudden development of glucose intolerance (with or without temperature increase) in a patient who previously has been maintained on parenteral alimentation without difficulty. When this occurs, or if high fever (>38.5°C [101.3°F]) develops without obvious cause, a diligent search for a potential septic focus is indicated. Other causes of fever should also be investigated. If fever persists, the infusion catheter should be removed and submitted for culture. If the catheter is the cause of the fever, removal of the infectious source is usually followed by rapid defervescence. Some centers are now replacing catheters considered at low risk for infection over a guidewire. However, if blood cultures are positive and the catheter tip is also positive, then the catheter should be removed and placed in a new site. Should evidence of infection persist over 24 to 48 hours without a definable source, the catheter should be replaced into the opposite subclavian vein or into one of the internal jugular veins and the infusion restarted.160 The use of multilumen catheters may be associated with a slightly increased risk of infection. This is most likely associated with greater catheter manipulation and intensive use. The rate of catheter infection is highest for those placed in the femoral vein, lower for those in the jugular vein, and lowest for those in the subclavian vein. When catheters are indwelling for <3 days, infection risks are negligible. If indwelling time is 3 to 7 days, the infection risk is 3% to 5%. Indwelling times of >7 days are associated with a catheter infection risk of 5% to 10%. Strict adherence to barrier precautions also reduces the rate of infection, as can the implementation of procedure checklists to ensure compliance with evidence-based guidelines shown to reduce infectious risk.161 Other complications related to catheter placement include the development of pneumothorax, hemothorax, hydrothorax, subclavian artery injury, thoracic duct injury, cardiac arrhythmia, air embolism, catheter embolism, and cardiac perforation with tamponade. All of these complications may be avoided by strict adherence to proper techniques. Further, the use of ultrasonographic guidance during central venous line placement has been demonstrated to significantly decrease the failure rate, complication rate, and number of attempts required for successful access.162 60 PART I BASIC CONSIDERATIONS transcriptional themes in human leukocytes. Crit Care. 2010;14(5):R177. 18. McGhan LJ, Jaroszewski DE. 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Mast cells as effector cells: a costimulating question. Trends Immunol. 2007;28(8):360-365. 117.  Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis, and disease. Nature. 2013;496(7446):445-455. 118. Cavaillon JM, Adib-Conquy M. Monocytes/macrophages and sepsis. Crit Care Med. 2005;33(12 Suppl):S506-S509. 119.  Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. 2012;189(6):2689-2695. 120. Alves-Filho JC, Tavares-Murta BM, Barja-Fidalgo C, et al. Neutrophil function in severe sepsis. Endocr Metab Immune Disord Drug Targets. 2006;6(2):151-158. 121.  Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159-175. 122. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7(9):678-689. 123. Fortin CF, McDonald PP, Fulop T, Lesur O. Sepsis, leukocytes, and nitric oxide (NO): an intricate affair. Shock. 2010;33(4):344-352. 124. Darwiche SS, Pfeifer R, Menzel C, et al. Inducible nitric oxide synthase contributes to immune dysfunction following trauma. Shock. 2012;38(5):499-507. 125. Cauwels A. Nitric oxide in shock. Kidney Int. 2007;72(5): 557-565. 126. Su F, Huang H, Akieda K, et al. Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock. Shock. 2010;34(3):243-249. 127. Zardi EM, Zardi DM, Dobrina A, Afeltra A. Prostacyclin in sepsis: a systematic review. Prostaglandins Other Lipid Mediat. 2007;83(1-2):1-24. 128. Yeager ME, Belchenko DD, Nguyen CM, Colvin KL, Ivy DD, Stenmark KR. Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2012;46(1):14-22. 129. Piechota M, Banach M, Irzmanski R, et al. Plasma endothelin-1 levels in septic patients. J Intensive Care Med. 2007; 22(4):232-239. 130. Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res. 2013;112(11):1506-1519. 131. Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med. 2002;30(5 Suppl):S294-S301. 132. Varpula M, Pulkki K, Karlsson S, Ruokonen E, Pettila V. Predictive value of N-terminal pro-brain natriuretic peptide in severe sepsis and septic shock. Crit Care Med. 2007;35(5):1277-1283. 133. Mitch WE, Price SR. Mechanisms activating proteolysis to cause muscle atrophy in catabolic conditions. J Ren Nutr. 2003;13(2):149-152. 134. Guirao X. Impact of the inflammatory reaction on intermediary metabolism and nutrition status. Nutrition. 2002;18 (11-12):949-952. 135. Souba WW. Nutritional support. N Engl J Med. 1997;336(1): 41-48. 136. Bistrian BR. Clinical aspects of essential fatty acid metabolism: Jonathan Rhoads Lecture. JPEN J Parenter Enteral Nutr. 2003;27(3):168-175. 137. Dahn MS, Mitchell RA, Lange MP, Smith S, Jacobs LA. Hepatic metabolic response to injury and sepsis. Surgery. 1995;117(5):520-530. 138. Vidal-Puig A, O’Rahilly S. Metabolism. Controlling the glucose factory. Nature. 2001;413(6852):125-126. 139. Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med. 2013;34(2-3): 121-138. 140. Volpi E, Sheffield-Moore M, Rasmussen BB, Wolfe RR. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA. 2001;286(10): 1206-1212. 141. Chernoff R. Normal aging, nutrition assessment, and clinical practice. Nutr Clin Pract. 2003;18(1):12-20. 142. Heslin MJ, Brennan MF. Advances in perioperative nutrition: cancer. World J Surg. 2000;24(12):1477-1485. 143. Heslin MJ, Latkany L, Leung D, et al. A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg. 1997;226(4):567-577; discussion 77-80. 144. Brooks AD, Hochwald SN, Heslin MJ, Harrison LE, Burt M, Brennan MF. Intestinal permeability after early postoperative enteral nutrition in patients with upper gastrointestinal malignancy. JPEN J Parenter Enteral Nutr. 1999;23(2):75-79. 145. Abunnaja S, Cuviello A, Sanchez JA. Enteral and parenteral nutrition in the perioperative period: state of the art. Nutrients. 2013;5(2):608-623. 146. Arabi YM, Tamim HM, Dhar GS, et al. Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial. Am J Clin Nutr. 2011;93(3): 569-577. 147. Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307(8):795-803. 148. Bankhead R, Boullata J, Brantley S, et al. Enteral nutrition practice recommendations. JPEN J Parenter Enteral Nutr. 2009;33(2):122-167. 149. Exner R, Tamandl D, Goetzinger P, et al. Perioperative GLYGLN infusion diminishes the surgery-induced period of immunosuppression: accelerated restoration of the lipopolysaccharide-stimulated tumor necrosis factor-alpha response. Ann Surg. 2003;237(1):110-115. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 63 Systemic Response to Injury and Metabolic Support 157. Heyland DK, Drover JW, Dhaliwal R, Greenwood J. Optimizing the benefits and minimizing the risks of enteral nutrition in the critically ill: role of small bowel feeding. JPEN J Parenter Enteral Nutr. 2002;26(6 Suppl):S51-S55; discussion S6-S7. 158. Scolapio JS. Methods for decreasing risk of aspiration pneumonia in critically ill patients. JPEN J Parenter Enteral Nutr. 2002;26(6 Suppl):S58-S61. 159. Vanek VW. Ins and outs of enteral access: part 2—long term access: esophagostomy and gastrostomy. Nutr Clin Pract. 2003;18(1):50-74. 160. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45. 161. Agency for Healthcare Research and Quality. Tools for Reducing Central Line-Associated Blood Stream Infections. http://www.ahrq.gov/legacy/qual/clabsitools/ clabsitoolshtm-purpose. 162. Maecken T, Grau T. Ultrasound imaging in vascular access. Crit Care Med. 2007;35(5 Suppl):S178-S185. CHAPTER 2 150. Luiking YC, Ten Have GA, Wolfe RR, Deutz NE. Arginine de novo and nitric oxide production in disease states. Am J Physiol Endocrinol Metab. 2012;303(10):E1177-E1189. 151. Marik PE, Flemmer M. Immunonutrition in the surgical patient. Minerva Anestesiol. 2012;78(3):336-342. 152.  Canadian Clinical Practice Guidelines. Enteral Feeding Guidelines. 2013. Available at: http://www.criticalcarenutrition.com/docs/cpgs2012/Summary%20CPGs%202013%20 vs%202009_24April2013.pdf. 153. Pontes-Arruda A, Martins LF, de Lima SM, et al. Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT study. Crit Care. 2011;15(3):R144. 154. Btaiche IF. Branched-chain amino acids in patients with hepatic encephalopathy. 1982. Nutr Clin Pract. 2003;18(1): 97-100. 155. Patton KM, Aranda-Michel J. Nutritional aspects in liver disease and liver transplantation. Nutr Clin Pract. 2002;17(6):332-340. 156. DiSario JA, Baskin WN, Brown RD, et al. Endoscopic approaches to enteral nutritional support. Gastrointest Endosc. 2002;55(7):901-908. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 3 Fluid and Electrolyte Management of the Surgical Patient chapter Introduction Body Fluids G. Tom Shires III 65 65 Total Body Water / 65 Fluid Compartments / 65 Composition of Fluid Compartments / 65 Osmotic Pressure / 66 Body Fluid Changes Fluid and Electrolyte Therapy 67 Normal Exchange of Fluid and Electrolytes / 67 Classification of Body Fluid Changes / 67 Disturbances in Fluid Balance / 68 Parenteral Solutions / 76 Alternative Resuscitative Fluids / 76 Correction of Life-Threatening Electrolyte Abnormalities / 77 Preoperative Fluid Therapy / 78 Intraoperative Fluid Therapy / 80 INTRODUCTION Fluid and electrolyte management is paramount to the care of the surgical patient. Changes in both fluid volume and electrolyte composition occur preoperatively, intraoperatively, and postoperatively, as well as in response to trauma and sepsis. The sections that follow review the normal anatomy of body fluids, electrolyte composition and concentration abnormalities and common metabolic derangements, and alterna1 treatments, tive resuscitative fluids. These concepts are then discussed in relationship to management of specific surgical patients and their commonly encountered fluid and electrolyte abnormalities. BODY FLUIDS Total Body Water Postoperative Fluid Therapy / 80 Special Considerations for the Postoperative Patient / 80 Volume Control / 68 Concentration Changes / 69 Composition Changes: Etiology and Diagnosis / 70 Acid-Base Balance / 73 Water constitutes approximately 50% to 60% of total body weight. The relationship between total body weight and total body water (TBW) is relatively constant for an individual and is primarily a reflection of body fat. Lean tissues such as muscle and solid organs have higher water content than fat and bone. As a result, young, lean males have a higher proportion of body weight as water than elderly or obese individuals. Deuterium oxide and tritiated water have been used in clinical research to measure TBW by indicator dilution methods. In an average young adult male, TBW accounts for 60% of total body weight, whereas in an average young adult female, it is 50%.1 The lower percentage of TBW in females correlates with a higher percentage of adipose tissue and lower percentage of muscle mass in most. Estimates of percentage of TBW should be adjusted downward approximately 10% to 20% for obese individuals and upward by 10% for malnourished individuals. The highest percentage of TBW is found in newborns, with approximately 80% Electrolyte Abnormalities in Specific Surgical Patients 76 80 Neurologic Patients / 80 Malnourished Patients: Refeeding Syndrome / 81 Acute Renal Failure Patients / 81 Cancer Patients / 81 of their total body weight comprised of water. This decreases to approximately 65% by 1 year of age and thereafter remains fairly constant. Fluid Compartments TBW is divided into three functional fluid compartments: plasma, extravascular interstitial fluid, and intracellular fluid (Fig. 3-1). The extracellular fluids (ECF), plasma and interstitial fluid, together compose about one third of the TBW, and the intracellular compartment composes the remaining two thirds. The extracellular water composes 20% of the total body weight and is divided between plasma (5% of body weight) and interstitial fluid (15% of body weight). Intracellular water makes up approximately 40% of an individual’s total body weight, with the largest proportion in the skeletal muscle mass. ECF is measured using indicator dilution methods. The distribution volumes of NaBr and radioactive sulfate have been used to measure ECF in clinical research. Measurement of the intracellular compartment is then determined indirectly by subtracting the measured ECF from the simultaneous TBW measurement. Composition of Fluid Compartments The normal chemical composition of the body fluid compartments is shown in Fig. 3-2. The ECF compartment is bal2 anced between sodium, the principal cation, and chloride and bicarbonate, the principal anions. The intracellular fluid compartment is composed primarily of the cations potassium and magnesium, and the anions phosphate and sulfate, and proteins. The concentration gradient between compartments is maintained by adenosine triphosphate–driven sodium-potassium pumps located with in the cell membranes. The composition of the plasma and interstitial fluid differs only slightly in ionic composition. The slightly higher protein content (organic anions) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 Proper management of fluid and electrolytes facilitates crucial homeostasis that allows cardiovascular perfusion, organ system function, and cellular mechanisms to respond to surgical illness. Knowledge of the compartmentalization of body fluids forms the basis for understanding pathologic shifts in these fluid spaces in disease states. Although difficult to quantify, a deficiency in the functional extracellular fluid compartment often requires resuscitation with isotonic fluids in surgical and trauma patients. Alterations in the concentration of serum sodium have profound effects on cellular function due to water shifts between the intracellular and extracellular spaces. Different rates of compensation between respiratory and metabolic components of acid-base homeostasis require frequent laboratory reassessment during therapy. in plasma results in a higher plasma cation composition relative to the interstitial fluid, as explained by the Gibbs-Donnan equilibrium equation. Proteins add to the osmolality of the plasma and contribute to the balance of forces that determine fluid balance across the capillary endothelium. Although the movement of ions and proteins between the various fluid compartments is restricted, water is freely diffusible. Water is distributed evenly throughout all fluid compartments of the body so that a given volume of water increases the volume of any one compartment relatively little. Sodium, however, is confined to the ECF compartment, and because of its osmotic and electrical properties, it remains associated with water. Therefore, sodium-containing fluids are distributed throughout the ECF and add to the volume of both the intravascular and interstitial spaces. Although the administration of sodium-containing fluids expands the intravascular volume, it also expands the interstitial space by approximately three times as much as the plasma. Osmotic Pressure The physiologic activity of electrolytes in solution depends on the number of particles per unit volume (millimoles per liter, or mmol/L), the number of electric charges per unit volume % of Total body weight Volume of TBW Plasma 5% Extracellular volume Interstitial fluid 15% Intracellular volume 40% 5 6 7 Although active investigation continues, alternative resuscitation fluids have limited clinical utility, other than the correction of specific electrolyte abnormalities. Most acute surgical illnesses are accompanied by some degree of volume loss or redistribution. Consequently, isotonic fluid administration is the most common initial intravenous fluid strategy, while attention is being given to alterations in concentration and composition. Some surgical patients with neurologic illness, malnutrition, acute renal failure, or cancer require special attention to well-defined, disease-specific abnormalities in fluid and electrolyte status. (milliequivalents per liter, or mEq/L), and the number of osmotically active ions per unit volume (milliosmoles per liter, or mOsm/L). The concentration of electrolytes usually is expressed in terms of the chemical combining activity, or equivalents. An equivalent of an ion is its atomic weight expressed in grams divided by the valence: Equivalent = atomic weight (g)/valence For univalent ions such as sodium, 1 mEq is the same as 1 mmol. For divalent ions such as magnesium, 1 mmol equals 2 mEq. The number of milliequivalents of cations must be balanced by the same number of milliequivalents of anions. However, the expression of molar equivalents alone does not allow a physiologic comparison of solutes in a solution. The movement of water across a cell membrane depends primarily on osmosis. To achieve osmotic equilibrium, water moves across a semipermeable membrane to equalize the concentration on both sides. This movement is determined by the concentration of the solutes on each side of the membrane. Osmotic pressure is measured in units of osmoles (osm) or milliosmoles (mOsm) that refer to the actual number of osmotically Male (70 kg) Female (60 kg) 14,000 mL 10,000 mL 3500 mL 2500 mL Interstitial 10,500 mL 7500 mL Intracellular volume 28,000 mL 20,000 mL 42,000 mL 30,000 mL Plasma Figure 3-1. Functional body fluid compartments. TBW = total body water. 66 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 154 mEq/L 153 mEq/L 153 mEq/L CATIONS ANIONS CATIONS ANIONS Na+ 142 CI− 103 Na+ 144 CI− 200 mEq/L CATIONS ANIONS K+ 150 HPO43– SO 42– 67 CHAPTER 3 154 mEq/L 200 mEq/L 150 114 SO4 2– PO43– HCO3− 30 3 K+ K+ 4 4 Ca2+ 5 Organic Acids 5 Mg2+ 3 Protein 16 Plasma SO42– PO43– HCO3− 10 3 Ca2+ 3 Organic Acids 5 Mg2+ 2 Protein 1 Interstitial fluid active particles. For example, 1 mmol of sodium chloride contributes to 2 mOsm (one from sodium and one from chloride). The principal determinants of osmolality are the concentrations of sodium, glucose, and urea (blood urea nitrogen, or BUN): Calculated serum osmolality = 2 sodium + (glucose/18) + (BUN/2.8) The osmolality of the intracellular and extracellular fluids is maintained between 290 and 310 mOsm in each compartment. Because cell membranes are permeable to water, any change in osmotic pressure in one compartment is accompanied by a redistribution of water until the effective osmotic pressure between compartments is equal. For example, if the ECF concentration of sodium increases, there will be a net movement of water from the intracellular to the extracellular compartment. Conversely, if the ECF concentration of sodium decreases, water will move into the cells. Although the intracellular fluid shares in losses that involve a change in concentration or composition of the ECF, an isotonic change in volume in either one of the compartments is not accompanied by the net movement of water as long as the ionic concentration remains the same. For practical clinical purposes, most significant gains and losses of body fluid are directly from the extracellular compartment. BODY FLUID CHANGES Normal Exchange of Fluid and Electrolytes The healthy person consumes an average of 2000 mL of water per day, approximately 75% from oral intake and the rest Mg2+ 40 Na+ 10 Protein 40 Intracellular fluid Figure 3-2. Chemical composition of body fluid compartments. extracted from solid foods. Daily water losses include 800 to 1200 mL in urine, 250 mL in stool, and 600 mL in insensible losses. Insensible losses of water occur through both the skin (75%) and lungs (25%) and can be increased by such factors as fever, hypermetabolism, and hyperventilation. Sensible water losses such as sweating or pathologic loss of gastrointestinal (GI) fluids vary widely, but these include the loss of electrolytes as well as water (Table 3-1). To clear the products of metabolism, the kidneys must excrete a minimum of 500 to 800 mL of urine per day, regardless of the amount of oral intake. The typical individual consumes 3 to 5 g of dietary salt per day, with the balance maintained by the kidneys. With hyponatremia or hypovolemia, sodium excretion can be reduced to as little as 1 mEq/d or maximized to as much as 5000 mEq/d to achieve balance except in people with salt-wasting kidneys. Sweat is hypotonic, and sweating usually results in only a small sodium loss. GI losses are isotonic to slightly hypotonic and contribute little to net gain or loss of free water when measured and appropriately replaced by isotonic salt solutions. Classification of Body Fluid Changes Disorders in fluid balance may be classified into three general categories: disturbances in (a) volume, (b) concentration, and (c) composition. Although each of these may occur simultaneously, each is a separate entity with unique mechanisms demanding individual correction. Isotonic gain or loss of salt solution results in extracellular volume changes, with little impact on intracellular fluid volume. If free water is added or lost from the ECF, water will pass between the ECF and intracellular fluid until solute concentration or osmolarity is equalized between VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fluid and Electrolyte Management of the Surgical Patient HCO3 − 27 68 Table 3-1 Water exchange (60- to 80-kg man) PART I Routes Average Daily Volume (mL) Minimal (mL) Maximal (mL) H2O gain: Sensible: BASIC CONSIDERATIONS   Oral fluids 800–1500 0 1500/h   Solid foods 500–700 0 1500    Water of oxidation 250 125 800    Water of solution 0 0 500   Urine 800–1500 300 1400/h   Intestinal 0–250 0 2500/h   Sweat 0 0 4000/h 600 600 1500 Insensible: H2O loss: Sensible: Insensible:    Lungs and skin the compartments. Unlike with sodium, the concentration of most other ions in the ECF can be altered without significant change in the total number of osmotically active particles, producing only a compositional change. For instance, doubling the serum potassium concentration will profoundly alter myocardial function without significantly altering volume or concentration of the fluid spaces. Disturbances in Fluid Balance Extracellular volume deficit is the most common fluid disorder in surgical patients and can be either acute or chronic. Acute volume deficit is associated with cardiovascular and central nervous system signs, whereas chronic deficits display tissue signs, such as a decrease in skin turgor and sunken eyes, in addition to cardiovascular and central nervous system signs (Table 3-2). Laboratory examination may reveal an elevated blood urea nitrogen level if the deficit is severe enough to reduce glomerular filtration and hemoconcentration. Urine osmolality usually will be higher than serum osmolality, and urine sodium will be low, typically <20 mEq/L. Serum sodium concentration does not necessarily reflect volume status and therefore may be high, normal, or low when a volume deficit is present. The most common cause of volume deficit in surgical patients is a loss of GI fluids (Table 3-3) from nasogastric suction, vomiting, diarrhea, or enterocutaneous fistula. In addition, sequestration secondary to soft tissue injuries, burns, and intra-abdominal processes such as peritonitis, obstruction, or prolonged surgery can also lead to massive volume deficits. Extracellular volume excess may be iatrogenic or secondary to renal dysfunction, congestive heart failure, or cirrhosis. Both plasma and interstitial volumes usually are increased. Symptoms are primarily pulmonary and cardiovascular (see Table 3-2). In fit patients, edema and hyperdynamic circulation are common and well tolerated. However, the elderly and patients with cardiac disease may quickly develop congestive heart failure and pulmonary edema in response to only a moderate volume excess. Volume Control Volume changes are sensed by both osmoreceptors and baroreceptors. Osmoreceptors are specialized sensors that detect even small changes in fluid osmolality and drive changes in thirst and diuresis through the kidneys.2 For example, when plasma osmolality is increased, thirst is stimulated and water consumption increases, although the exact cell mechanism is not known.3 Additionally, the hypothalamus is stimulated to secrete vasopressin, which increases water reabsorption in the kidneys. Table 3-2 Signs and symptoms of volume disturbances System Volume Deficit Volume Excess Generalized Weight loss Weight gain Decreased skin turgor Peripheral edema Cardiac Tachycardia Increased cardiac output Orthostasis/ hypotension Increased central venous pressure Collapsed neck veins Distended neck veins Murmur Renal Oliguria — Azotemia GI Ileus Bowel edema Pulmonary — Pulmonary edema VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 69 Table 3-3 Composition of GI secretions Na (mEq/L) K (mEq/L) Cl (mEq/L) HCO3− (mEq/L) Stomach 1000–2000 60–90 10–30 100–130 0 Small intestine 2000–3000 120–140 5–10 90–120 30–40 Colon — 60 30 40 0 Pancreas 600–800 135–145 5–10 70–90 95–115 Bile 300–800 135–145 5–10 90–110 30–40 Together, these two mechanisms return the plasma osmolality to normal. Baroreceptors also modulate volume in response to changes in pressure and circulating volume through specialized pressure sensors located in the aortic arch and carotid sinuses.4 Baroreceptor responses are both neural, through sympathetic and parasympathetic pathways, and hormonal, through substances including renin-angiotensin, aldosterone, atrial natriuretic peptide, and renal prostaglandins. The net result of alterations in renal sodium excretion and free water reabsorption is restoration of volume to the normal state. Concentration Changes Changes in serum sodium concentration are inversely proportional to TBW. Therefore, abnormalities in TBW are 3 reflected by abnormalities in serum sodium levels. Hyponatremia. A low serum sodium level occurs when there is an excess of extracellular water relative to sodium. Extracellular volume can be high, normal, or low (Fig. 3-3). In most cases of hyponatremia, sodium concentration is decreased as a consequence of either sodium depletion or dilution.5 Dilutional hyponatremia frequently results from excess extracellular water and therefore is associated with a high extracellular volume status. Excessive oral water intake or iatrogenic intravenous (IV) excess free water administration can cause hyponatremia. Postoperative patients are particularly prone to increased secretion of antidiuretic hormone (ADH), which increases reabsorption of free water from the kidneys with subsequent volume expansion and hyponatremia. This is usually self-limiting in that both hyponatremia and volume expansion decrease ADH secretion. Additionally, a number of drugs can cause water retention and subsequent hyponatremia, such as the antipsychotics and tricyclic antidepressants as well as angiotensin-converting enzyme inhibitors. The elderly are particularly susceptible to druginduced hyponatremia. Physical signs of volume overload usually are absent, and laboratory evaluation reveals hemodilution. Depletional causes of hyponatremia are associated with either a decreased intake or increased loss of sodium-containing fluids. A concomitant ECF volume deficit is common. Causes include decreased sodium intake, such as consumption of a low-sodium diet or use of enteral feeds, which are typically low in sodium; GI losses from vomiting, prolonged nasogastric suctioning, or diarrhea; and renal losses due to diuretic use or primary renal disease. Hyponatremia also can be seen with an excess of solute relative to free water, such as with untreated hyperglycemia or mannitol administration. Glucose exerts an osmotic force in the extracellular compartment, causing a shift of water from the intracellular to the extracellular space. Hyponatremia therefore can be seen when the effective osmotic pressure of the extracellular compartment is normal or even high. When hyponatremia in the presence of hyperglycemia is being evaluated, the corrected sodium concentration should be calculated as follows: For every 100-mg/dL increment in plasma glucose above normal, the plasma sodium should decrease by 1.6 mEq/L Lastly, extreme elevations in plasma lipids and proteins can cause pseudohyponatremia, because there is no true decrease in extracellular sodium relative to water. Signs and symptoms of hyponatremia (Table 3-4) are dependent on the degree of hyponatremia and the rapidity with which it occurred. Clinical manifestations primarily have a central nervous system origin and are related to cellular water intoxication and associated increases in intracranial pressure. Oliguric renal failure also can be a rapid complication in the setting of severe hyponatremia. A systematic review of the etiology of hyponatremia should reveal its cause in a given instance. Hyperosmolar causes, including hyperglycemia or mannitol infusion and pseudohyponatremia, should be easily excluded. Next, depletional versus dilutional causes of hyponatremia are evaluated. In the absence of renal disease, depletion is associated with low urine sodium levels (<20 mEq/L), whereas renal sodium wasting shows high urine sodium levels (>20 mEq/L). Dilutional causes of hyponatremia usually are associated with hypervolemic circulation. A normal volume status in the setting of hyponatremia should prompt an evaluation for a syndrome of inappropriate secretion of ADH. Hypernatremia. Hypernatremia results from either a loss of free water or a gain of sodium in excess of water. Like hyponatremia, it can be associated with an increased, normal, or decreased extracellular volume (see Fig. 3-3). Hypervolemic hypernatremia usually is caused either by iatrogenic administration of sodium-containing fluids, including sodium bicarbonate, or mineralocorticoid excess as seen in hyperaldosteronism, Cushing’s syndrome, and congenital adrenal hyperplasia. Urine sodium concentration is typically >20 mEq/L, and urine osmolarity is >300 mOsm/L. Normovolemic hypernatremia can result from renal causes, including diabetes insipidus, diuretic use, and renal disease, or from nonrenal water loss from the GI tract or skin, although the same conditions can result in hypovolemic hypernatremia. When hypovolemia is present, the urine sodium concentration is <20 mEq/L and urine osmolarity VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fluid and Electrolyte Management of the Surgical Patient Volume (mL/24 h) CHAPTER 3 Type of Secretion 70 Hyponatremia Volume status PART I BASIC CONSIDERATIONS High Normal Increased intake Hyperglycemia Decreased sodium intake Postoperative ADH secretion ↑ Plasma Iipids/proteins GI losses Drugs Low SIADH Renal losses Water intoxication Diuretics Diuretics Primary renal disease Hypernatremia Volume status High Iatrogenic sodium administration Normal Nonrenal water loss Low Nonrenal water loss Mineralocorticoid excess Skin Skin Aldosteronism GI GI Cushing’s disease Renal water loss Renal water loss Congenital adrenal hyperplasia Renal disease Renal (tubular) disease Diuretics Osmotic diuretics Diabetes insipidus Diabetes insipidus Adrenal failure is <300 to 400 mOsm/L. Nonrenal water loss can occur secondary to relatively isotonic GI fluid losses such as that caused by diarrhea, to hypotonic skin fluid losses such as loss due to fever, or to losses via tracheotomies during hyperventilation. Additionally, thyrotoxicosis can cause water loss, as can the use of hypertonic glucose solutions for peritoneal dialysis. With nonrenal water loss, the urine sodium concentration is <15 mEq/L and the urine osmolarity is >400 mOsm/L. Symptomatic hypernatremia usually occurs only in patients with impaired thirst or restricted access to fluid, because thirst will result in increased water intake. Symptoms are rare until the serum sodium concentration exceeds 160 mEq/L but, once present, are associated with significant morbidity and mortality. Because symptoms are related to hyperosmolarity, central nervous system effects predominate (see Table 3-4). Water shifts from the intracellular to the extracellular space in response to a hyperosmolar extracellular space, which results in cellular dehydration. This can put traction on the cerebral vessels and lead to subarachnoid hemorrhage. Central nervous system symptoms Figure 3-3. Evaluation of sodium abnormalities. ADH = antidiuretic hormone; SIADH = syndrome of inappropriate secretion of antidiuretic hormone. can range from restlessness and irritability to seizures, coma, and death. The classic signs of hypovolemic hypernatremia, (tachycardia, orthostasis, and hypotension) may be present, as well as the unique findings of dry, sticky mucous membranes. Composition Changes: Etiology and Diagnosis Potassium Abnormalities. The average dietary intake of potassium is approximately 50 to 100 mEq/d, which in the absence of hypokalemia is excreted primarily in the urine. Extracellular potassium is maintained within a narrow range, principally by renal excretion of potassium, which can range from 10 to 700 mEq/d. Although only 2% of the total body potassium (4.5 mEq/L × 14 L = 63 mEq) is located within the extracellular compartment, this small amount is critical to cardiac and neuromuscular function; thus, even minor changes can have major effects on cardiac activity. The intracellular and extracellular distribution of potassium is influenced by a number of factors, including surgical stress, injury, acidosis, and tissue catabolism. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 71 Table 3-5 Clinical manifestations of abnormalities in serum sodium level Etiology of potassium abnormalities Hyponatremia Central nervous system Headache, confusion, hyperactive or hypoactive deep tendon reflexes, seizures, coma, increased intracranial pressure Musculoskeletal Weakness, fatigue, muscle cramps/ twitching GI Anorexia, nausea, vomiting, watery diarrhea Cardiovascular Hypertension and bradycardia if intracranial pressure increases significantly Tissue Lacrimation, salivation Renal Oliguria Body System Hypernatremia Central nervous system Restlessness, lethargy, ataxia, irritability, tonic spasms, delirium, seizures, coma Musculoskeletal Weakness Cardiovascular Tachycardia, hypotension, syncope Tissue Dry sticky mucous membranes, red swollen tongue, decreased saliva and tears Renal Oliguria Metabolic Fever Hyperkalemia Hyperkalemia is defined as a serum potassium concentration above the normal range of 3.5 to 5.0 mEq/L. It is caused by excessive potassium intake, increased release of potassium from cells, or impaired potassium excretion by the kidneys (Table 3-5).6 Increased intake can be either from oral or IV supplementation, or from red cell lysis after transfusion. Hemolysis, rhabdomyolysis, and crush injuries can disrupt cell membranes and release intracellular potassium into the ECF. Acidosis and a rapid rise in extracellular osmolality from hyperglycemia or IV mannitol can raise serum potassium levels by causing a shift of potassium ions to the extracellular compartment.7 Because 98% of total body potassium is in the intracellular fluid compartment, even small shifts of intracellular potassium out of the intracellular fluid compartment can lead to a significant rise in extracellular potassium. A number of medications can contribute to hyperkalemia, particularly in the presence of renal insufficiency, including potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Spironolactone and angiotensin-converting enzyme inhibitors interfere with aldosterone activity, inhibiting the normal renal mechanism of potassium excretion. Acute and chronic renal insufficiency also impairs potassium excretion. Symptoms of hyperkalemia are primarily GI, neuromuscular, and cardiovascular (Table 3-6). GI symptoms include nausea, vomiting, intestinal colic, and diarrhea. Neuromuscular symptoms range from weakness to ascending paralysis to respiratory failure. Early cardiovascular signs may be apparent from electrocardiogram (ECG) changes and eventually lead Hypokalemia Inadequate intake  Dietary, potassium-free intravenous fluids, potassiumdeficient TPN Excessive potassium excretion Hyperaldosteronism Medications GI losses Direct loss of potassium from GI fluid (diarrhea)  Renal loss of potassium (to conserve sodium in response to gastric losses) to hemodynamic symptoms of arrhythmia and cardiac arrest. ECG changes that may be seen with hyperkalemia include high peaked T waves (early), widened QRS complex, flattened P wave, prolonged PR interval (first-degree block), sine wave formation, and ventricular fibrillation. Hypokalemia Hypokalemia is much more common than hyperkalemia in the surgical patient. It may be caused by inadequate potassium intake; excessive renal potassium excretion; potassium loss in pathologic GI secretions, such as with diarrhea, fistulas, vomiting, or high nasogastric output; or intracellular shifts from metabolic alkalosis or insulin therapy (see Table 3-5). The change in potassium associated with alkalosis can be calculated by the following formula: Potassium decreases by 0.3 mEq/L for every 0.1 increase in pH above normal. Additionally, drugs such as amphotericin, aminoglycosides, cisplatin, and ifosfamide that induce magnesium depletion cause renal potassium wastage.8,9 In cases in which potassium deficiency is due to magnesium depletion,10 potassium repletion is difficult unless hypomagnesemia is first corrected. The symptoms of hypokalemia (see Table 3-6), like those of hyperkalemia, are primarily related to failure of normal contractility of GI smooth muscle, skeletal muscle, and cardiac muscle. Findings may include ileus, constipation, weakness, fatigue, diminished tendon reflexes, paralysis, and cardiac arrest. In the setting of ECF depletion, symptoms may be masked initially and then worsened by further dilution during volume repletion. ECG changes suggestive of hypokalemia include U waves, T-wave flattening, ST-segment changes, and arrhythmias (with digitalis therapy). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fluid and Electrolyte Management of the Surgical Patient Body System Hyperkalemia Increased intake Potassium supplementation Blood transfusions  Endogenous load/destruction: hemolysis, rhabdomyolysis, crush injury, gastrointestinal hemorrhage Increased release Acidosis  Rapid rise of extracellular osmolality (hyperglycemia or mannitol) Impaired excretion Potassium-sparing diuretics Renal insufficiency/failure CHAPTER 3 Table 3-4 72 Table 3-6 Clinical manifestations of abnormalities in potassium, magnesium, and calcium levels PART I Increased Serum Levels BASIC CONSIDERATIONS System Potassium Magnesium Calcium GI Nausea/vomiting, colic, diarrhea Nausea/vomiting Anorexia, nausea/vomiting, abdominal pain Neuromuscular Weakness, paralysis, respiratory failure Weakness, lethargy, decreased reflexes Weakness, confusion, coma, bone pain Cardiovascular Arrhythmia, arrest Hypotension, arrest Hypertension, arrhythmia, polyuria Renal — — Polydipsia Decreased Serum Levels System Potassium Magnesium Calcium GI Ileus, constipation — — Neuromuscular Decreased reflexes, fatigue, weakness, paralysis Hyperactive reflexes, muscle tremors, tetany, seizures Hyperactive reflexes, paresthesias, carpopedal spasm, seizures Cardiovascular Arrest Arrhythmia Heart failure Calcium Abnormalities. The vast majority of the body’s calcium is contained within the bone matrix, with <1% found in the ECF. Serum calcium is distributed among three forms: protein found (40%), complexed to phosphate and other anions (10%), and ionized (50%). It is the ionized fraction that is responsible for neuromuscular stability and can be measured directly. When total serum calcium levels are measured, the albumin concentration must be taken into consideration: Adjust total serum calcium down by 0.8 mg/dL for every 1 g/dL decrease in albumin. Unlike changes in albumin, changes in pH will affect the ionized calcium concentration. Acidosis decreases protein binding, thereby increasing the ionized fraction of calcium. Daily calcium intake is 1 to 3 g/d. Most of this is excreted via the bowel, with urinary excretion relatively low. Total body calcium balance is under complex hormonal control, but disturbances in metabolism are relatively long term and less important in the acute surgical setting. However, attention to the critical role of ionized calcium in neuromuscular function often is required. Hypercalcemia Hypercalcemia is defined as a serum calcium level above the normal range of 8.5 to 10.5 mEq/L or an increase in the ionized calcium level above 4.2 to 4.8 mg/dL. Primary hyperparathyroidism in the outpatient setting and malignancy in hospitalized patients, from either bony metastasis or secretion of parathyroid hormone–related protein, account for most cases of symptomatic hypercalcemia.11 Symptoms of hypercalcemia (see Table 3-6), which vary with the degree of severity, include neurologic impairment, musculoskeletal weakness and pain, renal dysfunction, and GI symptoms of nausea, vomiting, and abdominal pain. Cardiac symptoms can be manifest as hypertension, cardiac arrhythmias, and a worsening of digitalis toxicity. ECG changes in hypercalcemia include shortened QT interval, prolonged PR and QRS intervals, increased QRS voltage, T-wave flattening and widening, and atrioventricular block (which can progress to complete heart block and cardiac arrest). Hypocalcemia Hypocalcemia is defined as a serum calcium level below 8.5 mEq/L or a decrease in the ionized calcium level below 4.2 mg/dL. The causes of hypocalcemia include pancreatitis, massive soft tissue infections such as necrotizing fasciitis, renal failure, pancreatic and small bowel fistulas, hypoparathyroidism, toxic shock syndrome, abnormalities in magnesium levels, and tumor lysis syndrome. In addition, transient hypocalcemia commonly occurs after removal of a parathyroid adenoma due to atrophy of the remaining glands and avid bone remineralization, and sometimes requires high-dose calcium supplementation.12 Additionally, malignancies associated with increased osteoblastic activity, such as breast and prostate cancer, can lead to hypocalcemia from increased bone formation.13 Calcium precipitation with organic anions is also a cause of hypocalcemia and may occur during hyperphosphatemia from tumor lysis syndrome or rhabdomyolysis. Pancreatitis may sequester calcium via chelation with free fatty acids. Massive blood transfusion with citrate binding is another mechanism.14,15 Hypocalcemia rarely results solely from decreased intake, because bone reabsorption can maintain normal levels for prolonged periods. Asymptomatic hypocalcemia may occur when hypoproteinemia results in a normal ionized calcium level. Conversely, symptoms can develop with a normal serum calcium level during alkalosis, which decreases ionized calcium. In general, neuromuscular and cardiac symptoms do not occur until the ionized fraction falls below 2.5 mg/dL (see Table 3-6). Clinical findings may include paresthesias of the face and extremities, muscle cramps, carpopedal spasm, stridor, tetany, and seizures. Patients will demonstrate hyperreflexia and may exhibit positive Chvostek’s sign (spasm resulting from tapping over the facial nerve) and Trousseau’s sign (spasm resulting from pressure applied to the nerves and vessels of the upper extremity with a blood pressure cuff). Hypocalcemia may lead to decreased cardiac contractility and heart failure. ECG changes of hypocalcemia include prolonged QT interval, T-wave inversion, heart block, and ventricular fibrillation. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Hyperphosphatemia Hyperphosphatemia can be due to Hypophosphatemia Hypophosphatemia can be due to a decrease in phosphorus intake, an intracellular shift of phosphorus, or an increase in phosphorus excretion. Decreased GI uptake due to malabsorption or administration of phosphate binders and decreased dietary intake from malnutrition are causes of chronic hypophosphatemia. Most acute cases are due to an intracellular shift of phosphorus in association with respiratory alkalosis, insulin therapy, refeeding syndrome, and hungry bone syndrome. Clinical manifestations of hypophosphatemia usually are absent until levels fall significantly. In general, symptoms are related to adverse effects on the oxygen availability of tissue and to a decrease in high-energy phosphates, and can be manifested as cardiac dysfunction or muscle weakness. Magnesium Abnormalities. Magnesium is the fourth most common mineral in the body and, like potassium, is found primarily in the intracellular compartments. Approximately one half of the total body content of 2000 mEq is incorporated in bone and is slowly exchangeable. Of the fraction found in the extracellular space, one third is bound to serum albumin. Therefore, the plasma level of magnesium may be a poor indicator of total body stores in the presence of hypoalbuminemia. Magnesium should be replaced until levels are in the upper limit of normal. The normal dietary intake is approximately 20 mEq/d and is excreted in both the feces and urine. The kidneys have a remarkable ability to conserve magnesium, with renal excretion <1 mEq/d during magnesium deficiency. Hypermagnesemia Hypermagnesemia is rare but can be seen with severe renal insufficiency and parallel changes in potassium excretion. Magnesium-containing antacids and laxatives can produce toxic levels in patients with renal failure. Excess intake in conjunction with total parenteral nutrition (TPN), or rarely massive trauma, thermal injury, and severe acidosis, may be associated with symptomatic hypermagnesemia. Clinical examination (see Table 3-6) may find nausea and vomiting; neuromuscular dysfunction with weakness, lethargy, and hyporeflexia; and impaired cardiac conduction leading to hypotension and arrest. ECG changes are similar to those seen with hyperkalemia and include increased PR interval, widened QRS complex, and elevated T waves. lem in hospitalized patients, particularly in the critically ill.16 The kidney is primarily responsible for magnesium homeostasis through regulation by calcium/magnesium receptors on the renal tubular cells that respond to serum magnesium concentrations.17 Hypomagnesemia may result from alterations of intake, renal excretion, and pathologic losses. Poor intake may occur in cases of starvation, alcoholism, prolonged IV fluid therapy, and TPN with inadequate supplementation of magnesium. Losses are seen in cases of increased renal excretion from alcohol abuse, diuretic use, administration of amphotericin B, and primary aldosteronism, as well as GI losses from diarrhea, malabsorption, and acute pancreatitis. The magnesium ion is essential for proper function of many enzyme systems. Depletion is characterized by neuromuscular and central nervous system hyperactivity. Symptoms are similar to those of calcium deficiency, including hyperactive reflexes, muscle tremors, tetany, and positive Chvostek’s and Trousseau’s signs (see Table 3-6). Severe deficiencies can lead to delirium and seizures. A number of ECG changes also can occur and include prolonged QT and PR intervals, ST-segment depression, flattening or inversion of P waves, torsades de pointes, and arrhythmias. Hypomagnesemia is important not only because of its direct effects on the nervous system but also because it can produce hypocalcemia and lead to persistent hypokalemia. When hypokalemia or hypocalcemia coexists with hypomagnesemia, magnesium should be aggressively replaced to assist in restoring potassium or calcium homeostasis. Acid-Base Balance Acid-Base Homeostasis. The pH of body fluids is maintained within a narrow range despite the ability of the kidneys to generate large amounts of HCO3− and the normal large acid load produced as a by-product of metabolism. This endogenous acid load is efficiently neutralized by buffer systems and ultimately excreted by the lungs and kidneys. Important buffers include intracellular proteins and phosphates and the extracellular bicarbonate–carbonic acid system. Compensation for acid-base derangements can be by respiratory mechanisms (for metabolic derangements) or metabolic mechanisms (for respiratory derangements). Changes in ventilation in response to metabolic abnormalities are mediated by hydrogensensitive chemoreceptors found in the carotid body and brain stem. Acidosis stimulates the chemoreceptors to increase ventilation, whereas alkalosis decreases the activity of the chemoreceptors and thus decreases ventilation. The kidneys provide compensation for respiratory abnormalities by either increasing or decreasing bicarbonate reabsorption in response to respiratory acidosis or alkalosis, respectively. Unlike the prompt change in ventilation that occurs with metabolic abnormalities, the compensatory response in the kidneys to respiratory abnormalities is delayed. Significant compensation may not begin for 6 hours and then may continue for several days. Because of this delayed compensatory response, respiratory acid-base derangements before renal compensation are classified as acute, whereas those persisting after renal compensation are categorized as chronic. predicted compensatory changes in response to meta4 The bolic or respiratory derangements are listed in Table 3-7.18 If the predicted change in pH is exceeded, then a mixed acidbase abnormality may be present (Table 3-8). Metabolic Derangements Metabolic Acidosis Metabolic acidosis results from an increased intake of acids, an increased generation of acids, or an VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 73 Fluid and Electrolyte Management of the Surgical Patient decreased urinary excretion, increased intake, or endogenous mobilization of phosphorus. Most cases of hyperphosphatemia are seen in patients with impaired renal function. Hypoparathyroidism or hyperthyroidism also can decrease urinary excretion of phosphorus and thus lead to hyperphosphatemia. Increased release of endogenous phosphorus can be seen in association with any clinical condition that results in cell destruction, including rhabdomyolysis, tumor lysis syndrome, hemolysis, sepsis, severe hypothermia, and malignant hyperthermia. Excessive phosphate administration from IV hyperalimentation solutions or phosphoruscontaining laxatives may also lead to elevated phosphate levels. Most cases of hyperphosphatemia are asymptomatic, but significant prolonged hyperphosphatemia can lead to metastatic deposition of soft tissue calcium-phosphorus complexes. Hypomagnesemia Magnesium depletion is a common prob- CHAPTER 3 Phosphorus Abnormalities. Phosphorus is the primary intracellular divalent anion and is abundant in metabolically active cells. Phosphorus is involved in energy production during glycolysis and is found in high-energy phosphate products such as adenosine triphosphate. Serum phosphate levels are tightly controlled by renal excretion. 74 • β-Hydroxybutyrate and acetoacetate in ketoacidosis • Lactate in lactic acidosis • Organic acids in renal insufficiency Table 3-7 Predicted changes in acid-base disorders PART I Disorder Predicted Change Metabolic Metabolic acidosis Metabolic alkalosis Pco2 = 1.5 × HCO3− + 8 Pco2 = 0.7 × HCO3− + 21 BASIC CONSIDERATIONS Respiratory Acute respiratory acidosis  Chronic respiratory acidosis Acute respiratory alkalosis  Chronic respiratory alkalosis Δ pH = (Pco2 – 40) × 0.008 Δ pH = (Pco2 – 40) × 0.003 Δ pH = (40 – Pco2) × 0.008 Δ pH = (40 – Pco2) × 0.017 Pco2 = partial pressure of carbon dioxide. increased loss of bicarbonate (Table 3-9). The body responds by several mechanisms, including producing buffers (extracellular bicarbonate and intracellular buffers from bone and muscle), increasing ventilation (Kussmaul’s respirations), and increasing renal reabsorption and generation of bicarbonate. The kidney also will increase secretion of hydrogen and thus increase urinary excretion of NH4+ (H+ + NH3+ = NH4+). Evaluation of a patient with a low serum bicarbonate level and metabolic acidosis includes determination of the anion gap (AG), an index of unmeasured anions. AG = (Na) – (Cl + HCO3) The normal AG is <12 mmol/L and is due primarily to the albumin effect, so that the estimated AG must be adjusted for albumin (hypoalbuminemia reduces the AG).19 Corrected AG = actual AG – [2.5(4.5 – albumin)] Metabolic acidosis with an increased AG occurs either from ingestion of exogenous acid such as from ethylene glycol, salicylates, or methanol, or from increased endogenous acid production of the following: A common cause of severe metabolic acidosis in surgical patients is lactic acidosis. In circulatory shock, lactate is produced in the presence of hypoxia from inadequate tissue perfusion. The treatment is to restore perfusion with volume resuscitation rather than to attempt to correct the abnormality with exogenous bicarbonate. With adequate perfusion, the lactic acid is rapidly metabolized by the liver and the pH level returns to normal. In clinical studies of lactic acidosis and ketoacidosis, the administration of bicarbonate has not reduced morbidity or mortality or improved cellular function.20 The overzealous administration of bicarbonate can lead to metabolic alkalosis, which shifts the oxyhemoglobin dissociation curve to the left; this interferes with oxygen unloading at the tissue level and can be associated with arrhythmias that are difficult to treat. An additional disadvantage is that sodium bicarbonate actually can exacerbate intracellular acidosis. Administered bicarbonate can combine with the excess hydrogen ions to form carbonic acid; this is then converted to CO2 and water, which thus raises the partial pressure of CO2 (Pco2). This hypercarbia could compound ventilation abnormalities in patients with underlying acute respiratory distress syndrome. This CO2 can diffuse into cells, but bicarbonate remains extracellular, which thus worsens intracellular acidosis. Clinically, lactate levels may not be useful in directing resuscitation, although lactate levels may be higher in nonsurvivors of serious injury.21 Metabolic acidosis with a normal AG results from exogenous acid administration (HCl or NH4+), from loss of bicarbonate due to GI disorders such as diarrhea and fistulas or ureterosigmoidostomy, or from renal losses. In these settings, the bicarbonate loss is accompanied by a gain of chloride; thus, the AG remains unchanged. To determine whether the loss of bicarbonate has a renal cause, the urinary [NH4+] can be measured. A low urinary [NH4+] in the face of hyperchloremic acidosis would indicate that the kidney is the site of loss, and evaluation for renal tubular acidosis should be undertaken. Proximal renal tubular acidosis results from decreased tubular reabsorption of HCO3−, whereas distal renal tubular acidosis results from decreased acid excretion. The carbonic anhydrase Table 3-8 Respiratory and metabolic components of acid-base disorders Acute Uncompensated Chronic (Partially Compensated) Type of Acid-Base Disorder pH Pco2 (Respiratory Component) Plasma HCO3−a (Metabolic Component) pH Pco2 (Respiratory Component) Plasma HCO3−a (Metabolic Component) Respiratory acidosis ↓↓ ↑↑ N ↓ ↑↑ ↑ Respiratory alkalosis ↑↑ ↓↓ N ↑ ↓↓ ↓ Metabolic acidosis ↓↓ N ↓↓ ↓ ↓ ↓ Metabolic alkalosis ↑↑ N ↑↑ ↑ ↑? ↑ aMeasured as standard bicarbonate, whole blood buffer base, CO content, or CO combining power. The base excess value is positive when the standard 2 2 bicarbonate is above normal and negative when the standard bicarbonate is below normal. N = normal; Pco2 = partial pressure of carbon dioxide. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Etiology of metabolic acidosis Normal Anion Gap Acid administration (HCl) Loss of bicarbonate GI losses (diarrhea, fistulas) Ureterosigmoidostomy Renal tubular acidosis Carbonic anhydrase inhibitor Respiratory Derangements. Under normal circumstances inhibitor acetazolamide also causes bicarbonate loss from the kidneys. Metabolic Alkalosis Normal acid-base homeostasis prevents metabolic alkalosis from developing unless both an increase in bicarbonate generation and impaired renal excretion of bicarbonate occur (Table 3-10). Metabolic alkalosis results from the loss of fixed acids or the gain of bicarbonate and is worsened by potassium depletion. The majority of patients also will have hypokalemia, because extracellular potassium ions exchange with intracellular hydrogen ions and allow the hydrogen ions to buffer excess HCO3–. Hypochloremic and hypokalemic metabolic alkalosis can occur from isolated loss of gastric contents in infants with pyloric stenosis or adults with duodenal ulcer disease. Unlike vomiting associated with an open pylorus, Table 3-10 Etiology of metabolic alkalosis Increased bicarbonate generation 1. Chloride losing (urinary chloride >20 mEq/L) Mineralocorticoid excess Profound potassium depletion 2. Chloride sparing (urinary chloride <20 mEq/L) Loss from gastric secretions (emesis or nasogastric suction) Diuretics 3. Excess administration of alkali Acetate in parenteral nutrition Citrate in blood transfusions Antacids Bicarbonate Milk-alkali syndrome Impaired bicarbonate excretion 1. Decreased glomerular filtration 2. Increased bicarbonate reabsorption (hypercarbia or potassium depletion) blood Pco2 is tightly maintained by alveolar ventilation, controlled by the respiratory centers in the pons and medulla oblongata. Respiratory Acidosis Respiratory acidosis is associated with the retention of CO2 secondary to decreased alveolar ventilation. The principal causes are listed in Table 3-11. Because compensation is primarily a renal mechanism, it is a delayed response. Treatment of acute respiratory acidosis is directed at the underlying cause. Measures to ensure adequate ventilation are also initiated. This may entail patient-initiated volume expansion using noninvasive bilevel positive airway pressure or may require endotracheal intubation to increase minute ventilation. In the chronic form of respiratory acidosis, the partial pressure of arterial CO2 remains elevated and the bicarbonate concentration rises slowly as renal compensation occurs. Respiratory Alkalosis In the surgical patient, most cases of respiratory alkalosis are acute and secondary to alveolar hyperventilation. Causes include pain, anxiety, and neurologic disorders, including central nervous system injury and assisted ventilation. Drugs such as salicylates, fever, gram-negative bacteremia, thyrotoxicosis, and hypoxemia are other possibilities. Acute hypocapnia can cause an uptake of potassium and phosphate into cells and increased binding of calcium to albumin, leading to symptomatic hypokalemia, hypophosphatemia, and hypocalcemia with subsequent arrhythmias, paresthesias, muscle cramps, and seizures. Treatment should be directed at the underlying cause, but direct treatment of the hyperventilation using controlled ventilation may also be required. Table 3-11 Etiology of respiratory acidosis: hypoventilation Narcotics Central nervous system injury Pulmonary: significant Secretions Atelectasis Mucus plug Pneumonia Pleural effusion Pain from abdominal or thoracic injuries or incisions Limited diaphragmatic excursion from intra-abdominal pathology Abdominal distention Abdominal compartment syndrome Ascites VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fluid and Electrolyte Management of the Surgical Patient Increased Anion Gap Metabolic Acidosis Exogenous acid ingestion Ethylene glycol Salicylate Methanol Endogenous acid production Ketoacidosis Lactic acidosis Renal insufficiency 75 CHAPTER 3 which involves a loss of gastric as well as pancreatic, biliary, and intestinal secretions, vomiting with an obstructed pylorus results only in the loss of gastric fluid, which is high in chloride and hydrogen, and therefore results in a hypochloremic alkalosis. Initially the urinary bicarbonate level is high in compensation for the alkalosis. Hydrogen ion reabsorption also ensues, with an accompanied potassium ion excretion. In response to the associated volume deficit, aldosterone-mediated sodium reabsorption increases potassium excretion. The resulting hypokalemia leads to the excretion of hydrogen ions in the face of alkalosis, a paradoxic aciduria. Treatment includes replacement of the volume deficit with isotonic saline and then potassium replacement once adequate urine output is achieved. Table 3-9 76 Table 3-12 Electrolyte solutions for parenteral administration PART I Electrolyte Composition (mEq/L) BASIC CONSIDERATIONS Solution Na Cl K HCO3− Ca Mg mOsm Extracellular fluid 142 103 4 27 5 3 280–310 Lactated Ringer’s 130 109 4 28 3 0.9% Sodium chloride 154 154 308 D5 0.45% Sodium chloride 77 77 407 273 D5W 3% Sodium chloride 253 513 513 1026 D5 = 5% dextrose; D5W = 5% dextrose in water. FLUID AND ELECTROLYTE THERAPY Parenteral Solutions Alternative Resuscitative Fluids A number of commercially available electrolyte solutions are available for parenteral administration. The most commonly used solutions are listed in Table 3-12. The type of fluid administered depends on the patient’s volume status and the type of concentration or compositional abnormality present. Both lactated Ringer’s solution and normal saline are considered isotonic and are useful in replacing GI losses and correcting extracellular volume deficits. Lactated Ringer’s is slightly hypotonic in that it contains 130 mEq of lactate. Lactate is used rather than bicarbonate because it is more stable in IV fluids during storage. It is converted into bicarbonate by the liver after infusion, even in the face of hemorrhagic shock. Evidence has suggested that resuscitation using lactated Ringer’s may be deleterious because it activates the inflammatory response and induces apoptosis. The component that has been implicated is the D isomer of lactate, which unlike the L isomer is not a normal intermediary in mammalian metabolism.22 However, subsequent in vivo studies showed significantly lower levels of apoptosis in lung and liver tissue after resuscitation with any of the various Ringer’s formulations.23 Sodium chloride is mildly hypertonic, containing 154 mEq of sodium that is balanced by 154 mEq of chloride. The high chloride concentration imposes a significant chloride load on the kidneys and may lead to a hyperchloremic metabolic acidosis. Sodium chloride is an ideal solution, however, for correcting volume deficits associated with hyponatremia, hypochloremia, and metabolic alkalosis. The less concentrated sodium solutions, such as 0.45% sodium chloride, are useful for replacement of ongoing GI losses as well as for maintenance fluid therapy in the postoperative period. This solution provides sufficient free water for insensible losses and enough sodium to aid the kidneys in adjustment of serum sodium levels. The addition of 5% dextrose (50 g of dextrose per liter) supplies 200 kcal/L, and dextrose is always added to solutions containing <0.45% sodium chloride to maintain osmolality and thus prevent the lysis of red blood cells that may occur with rapid infusion of hypotonic fluids. The addition of potassium is useful once adequate renal function and urine output are established. A number of alternative solutions for volume expansion and resuscitation are available (Table 3-13).24 Hypertonic saline solutions (3.5% and 5%) are used for correction of 5 severe sodium deficits and are discussed elsewhere in this chapter. Hypertonic saline (7.5%) has been used as a treatment modality in patients with closed head injuries. It has been shown to increase cerebral perfusion and decrease intracranial pressure, thus decreasing brain edema.25 However, there have also been concerns about increased bleeding, because hypertonic saline is an arteriolar vasodilator. A trial of 853 patients receiving hypertonic saline versus hypertonic saline/dextran 70 vs. 0.9% saline as initial resuscitation in the field showed a higher 28-day mortality in both hypertonic saline groups compared to 0.9% saline.26 Colloids also are used in surgical patients, and their effectiveness as volume expanders compared with isotonic crystalloids has long been debated. Due to their molecular weight, they are confined to the intravascular space, and their infusion results in more efficient transient plasma volume expansion. However, under conditions of Table 3-13 Alternative resuscitative fluids Solution Molecular Osmolality Weight (mOsm/L) Sodium (mEq/L) Hypertonic saline — (7.5%) 2565 1283 Albumin 5% 70,000 300 130–160 Albumin 25% 70,000 1500 130–160 Dextran 40 40,000 308 154 Dextran 70 70,000 308 154 Hetastarch 450,000 310 154 Hextend 670,000 307 143 Gelofusine 30,000 NA 154 NA = not available. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Correction of Life-Threatening Electrolyte Abnormalities Sodium Hypernatremia Treatment of hypernatremia usually consists of Water deficit (L) = serum sodium − 140 × TBW 140 Estimate TBW as 50% of lean body mass in men and 40% in women The rate of fluid administration should be titrated to achieve a decrease in serum sodium concentration of no more than 1 mEq/h and 12 mEq/d for the treatment of acute symptomatic hypernatremia. Even slower correction should be undertaken for chronic hypernatremia (0.7 mEq/h), because overly rapid correction can lead to cerebral edema and herniation. The type of fluid used depends on the severity and ease of correction. Oral or enteral replacement is acceptable in most cases, or IV replacement with half- or quarter-normal saline can be used. Caution also should be exercised when using 5% dextrose in water to avoid overly rapid correction. Frequent neurologic evaluation as well as frequent evaluation of serum sodium levels also should be performed. Hypernatremia is less common than hyponatremia, but has a worse prognosis, and is an independent predictor of mortality in critical illness.38 Hyponatremia Most cases of hyponatremia can be treated by free water restriction and, if severe, the administration of sodium. In patients with normal renal function, symptomatic hyponatremia usually does not occur until the serum sodium level is ≤120 mEq/L. If neurologic symptoms are present, 3% normal saline should be used to increase the sodium by no more than 1 mEq/L per hour until the serum sodium level reaches 130 mEq/L or neurologic symptoms are improved. Correction of asymptomatic hyponatremia should increase the sodium level by no more than 0.5 mEq/L per hour to a maximum increase of 12 mEq/L per day, and even more slowly in chronic hyponatremia. The rapid correction of hyponatremia can lead to pontine myelinolysis,39 with seizures, weakness, paresis, akinetic movements, and unresponsiveness, and may result in permanent brain damage and death. Serial magnetic resonance imaging may be necessary to confirm the diagnosis.40 Potassium Hyperkalemia Treatment options for symptomatic hyperkalemia are listed in Table 3-14. The goals of therapy include reducing the total body potassium, shifting potassium from the extracellular to the intracellular space, and protecting the cells from the effects of increased potassium. For all patients, exogenous sources of potassium should be removed, including potassium supplementation in IV fluids and enteral and parenteral solutions. Potassium can be removed from the body using a cation-exchange resin such as Kayexalate that binds potassium in exchange for sodium. It can be administered either VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fluid and Electrolyte Management of the Surgical Patient treatment of the associated water deficit. In hypovolemic patients, volume should be restored with normal saline before the concentration abnormality is addressed. Once adequate volume has been achieved, the water deficit is replaced using a hypotonic fluid such as 5% dextrose, 5% dextrose in ¼ normal saline, or enterally administered water. The formula used to estimate the amount of water required to correct hypernatremia is as follows: 77 CHAPTER 3 severe hemorrhagic shock, capillary membrane permeability increases; this permits colloids to enter the interstitial space, which can worsen edema and impair tissue oxygenation. The theory that these high molecular weight agents “plug” capillary leaks, which occur during neutrophil-mediated organ injury, has not been confirmed.27,28 Four major types of colloids are available—albumin, dextrans, hetastarch, and gelatins—that are described by their molecular weight and size in Table 3-13. Colloid solutions with smaller particles and lower molecular weights exert a greater oncotic effect but are retained within the circulation for a shorter period of time than larger and higher molecular weight colloids. Albumin (molecular weight 70,000) is prepared from heat-sterilized pooled human plasma. It is typically available as either a 5% solution (osmolality of 300 mOsm/L) or 25% solution (osmolality of 1500 mOsm/L). Because it is a derivative of blood, it can be associated with allergic reactions. Albumin has been shown to induce renal failure and impair pulmonary function when used for resuscitation in hemorrhagic shock.29 Dextrans are glucose polymers produced by bacteria grown on sucrose media and are available as either 40,000 or 70,000 molecular weight solutions. They lead to initial volume expansion due to their osmotic effect but are associated with alterations in blood viscosity. Thus dextrans are used primarily to lower blood viscosity rather than as volume expanders. Dextrans have been used, in association with hypertonic saline, to help maintain intravascular volume. Hydroxyethyl starch solutions are another group of alternative plasma expanders and volume replacement solutions. Hetastarches are produced by the hydrolysis of insoluble amylopectin, followed by a varying number of substitutions of hydroxyl groups for carbon groups on the glucose molecules. The molecular weights can range from 1000 to 3,000,000. The high molecular weight hydroxyethyl starch hetastarch, which comes as a 6% solution, is the only hydroxyethyl starch approved for use in the United States. Administration of hetastarch can cause hemostatic derangements related to decreases in von Willebrand’s factor and factor VIII:C, and its use has been associated with postoperative bleeding in cardiac and neurosurgery patients.30,31 Hetastarch also can induce renal dysfunction in patients with septic shock and was associated with a significant increased risk of mortality and acute kidney injury in the critically ill.32,33 Currently, hetastarch has a limited role in massive resuscitation because of the associated coagulopathy and hyperchloremic acidosis (due to its high chloride content). Hextend is a modified, balanced, high molecular weight hydroxyethyl starch that is suspended in a lactate-buffered solution, rather than in saline. A phase III clinical study comparing Hextend to a similar 6% hydroxyethyl starch in patients undergoing major abdominal surgery demonstrated no adverse effects on coagulation with Hextend other than the known effects of hemodilution.34 Hextend has not been tested for use in massive resuscitation, and not all clinical studies show consistent results.35 Gelatins are the fourth group of colloids and are produced from bovine collagen. The two major types are urea-linked gelatin and succinylated gelatin (modified fluid gelatin, Gelofusine). Gelofusine has been used abroad with mixed results.36 Like many other artificial plasma volume expanders, it has been shown to impair whole blood coagulation time in human volunteers.37 78 Table 3-14 Treatment of symptomatic hyperkalemia PART I Potassium removal Kayexalate   Oral administration is 15–30 g in 50–100 mL of 20% sorbitol    Rectal administration is 50 g in 200 mL of 20% sorbitol Dialysis BASIC CONSIDERATIONS Shift potassium Glucose 1 ampule of D50 and regular insulin 5–10 units IV Bicarbonate 1 ampule IV Counteract cardiac effects Calcium gluconate 5–10 mL of 10% solution Hypocalcemia will be refractory to treatment if coexisting hypomagnesemia is not corrected first. Routine calcium supplementation is no longer recommended in association with massive blood transfusions.41 Phosphorus Hyperphosphatemia Phosphate binders such as sucralfate or aluminum-containing antacids can be used to lower serum phosphorus levels. Calcium acetate tablets also are useful when hypocalcemia is simultaneously present. Dialysis usually is reserved for patients with renal failure. Hypophosphatemia Depending on the level of depletion and tolerance to oral supplementation, a number of enteral and parenteral repletion strategies are effective for the treatment of hypophosphatemia (see Table 3-15). Magnesium Hypermagnesemia Treatment for hypermagnesemia consists D50 = 50% dextrose. orally, in alert patients, or rectally. Immediate measures also should include attempts to shift potassium intracellularly with glucose and bicarbonate infusion. Nebulized albuterol (10 to 20 mg) may also be used. Use of glucose alone will cause a rise in insulin secretion, but in the acutely ill, this response may be blunted, and therefore both glucose and insulin may be necessary. Circulatory overload and hypernatremia may result from the administration of Kayexalate and bicarbonate, so care should be exercised when administering these agents to patients with fragile cardiac function. When ECG changes are present, calcium chloride or calcium gluconate (5–10 mL of 10% solution) should be administered immediately to counteract the myocardial effects of hyperkalemia. Calcium infusion should be used cautiously in patients receiving digitalis, because digitalis toxicity may be precipitated. All of the aforementioned measures are temporary, lasting from 1 to approximately 4 hours. Dialysis should be considered in severe hyperkalemia when conservative measures fail. Hypokalemia Treatment for hypokalemia consists of potassium repletion, the rate of which is determined by the symptoms (Table 3-15). Oral repletion is adequate for mild, asymptomatic hypokalemia. If IV repletion is required, usually no more than 10 mEq/h is advisable in an unmonitored setting. This amount can be increased to 40 mEq/h when accompanied by continuous ECG monitoring, and even more in the case of imminent cardiac arrest from a malignant arrhythmia-associated hypokalemia. Caution should be exercised when oliguria or impaired renal function is coexistent. Calcium Hypercalcemia Treatment is required when hypercalcemia is symptomatic, which usually occurs when the serum level exceeds 12 mg/dL. The critical level for serum calcium is 15 mg/dL, when symptoms noted earlier may rapidly progress to death. The initial treatment is aimed at repleting the associated volume deficit and then inducing a brisk diuresis with normal saline. Treatment of hypercalcemia associated with malignancies is discussed later in this chapter. Hypocalcemia Asymptomatic hypocalcemia can be treated with oral or IV calcium (see Table 3-15). Acute symptomatic hypocalcemia should be treated with IV 10% calcium gluconate to achieve a serum concentration of 7 to 9 mg/dL. Associated deficits in magnesium, potassium, and pH must also be corrected. of measures to eliminate exogenous sources of magnesium, correct concurrent volume deficits, and correct acidosis if present. To manage acute symptoms, calcium chloride (5 to 10 mL) should be administered to immediately antagonize the cardiovascular effects. If elevated levels or symptoms persist, hemodialysis may be necessary. Hypomagnesemia Correction of magnesium depletion can be oral if asymptomatic and mild. Otherwise, IV repletion is indicated and depends on severity (see Table 3-15) and clinical symptoms. For those with severe deficits (<1.0 mEq/L) or those who are symptomatic, 1 to 2 g of magnesium sulfate may be administered IV over 15 minutes. Under ECG monitoring, it may be given over 2 minutes if necessary to correct torsades de pointes (irregular ventricular rhythm). Caution should be taken when giving large amounts of magnesium, because magnesium toxicity may develop. The simultaneous administration of calcium gluconate will counteract the adverse side effects of a rapidly rising magnesium level and correct hypocalcemia, which is frequently associated with hypomagnesemia. Preoperative Fluid Therapy The administration of maintenance fluids should be all that is required in an otherwise healthy individual who may be under orders to receive nothing by mouth for some period before the time of surgery. This does not, however, include replenishment of a pre-existing deficit or ongoing fluid losses. The following is a frequently used formula for calculating the volume of maintenance fluids in the absence of pre-existing abnormalities: For the first 0–10 kg For the next 10–20 kg For weight >20 kg Give 100 mL/kg per day Give an additional 50 mL/ kg per day Give an additional 20 mL/ kg per day For example, a 60-kg female would receive a total of 2300 mL of fluid daily: 1000 mL for the first 10 kg of body weight (10 kg × 100 mL/kg per day), 500 mL for the next 20 kg (10 kg × 50 mL/kg per day), and 800 mL for the last 40 kg (40 kg × 20 mL/kg per day). An alternative approach is to replace the calculated daily water losses in urine, stool, and insensible loss with a hypotonic saline solution rather than water alone, which allows VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 79 Table 3-15 Electrolyte replacement therapy protocol Calcium Ionized calcium level <4.0 mg/dL:  With gastric access and tolerating enteral nutrition: Calcium carbonate suspension 1250 mg/5 mL q6h per gastric access; recheck ionized calcium level in 3 d  Without gastric access or not tolerating enteral nutrition: Calcium gluconate 2 g IV over 1 h × 1 dose; recheck ionized calcium level in 3 d Phosphate Phosphate level 1.0–2.5 mg/dL: Tolerating enteral nutrition: Neutra-Phos 2 packets q6h per gastric tube or feeding tube No enteral nutrition: KPHO4 or NaPO4 0.15 mmol/kg IV over 6 h × 1 dose Recheck phosphate level in 3 d Phosphate level <1.0 mg/dL: Tolerating enteral nutrition: KPHO4 or NaPO4 0.25 mmol/kg over 6 h × 1 dose Recheck phosphate level 4 h after end of infusion; if <2.5 mg/dL, begin Neutra-Phos 2 packets q6h  Not tolerating enteral nutrition: KPHO4 or NaPO4 0.25 mmol/kg (LBW) over 6 h × 1 dose; recheck phosphate level 4 h after end of infusion; if <2.5 mg/dL, then KPHO4 or NaPO4 0.15 mmol/kg (LBW) IV over 6 h × 1 dose 3 mmol KPHO4 = 3 mmol Phos and 4.4 mEq K+ = 1 mL 3 mmol NaPO4 = 3 mmol Phos and 4 mEq Na+ = 1 mL Neutra-Phos 1 packet = 8 mmol Phos, 7 mEq K+, 7 mEq Na+ Use patient’s lean body weight (LBW) in kilograms for all calculations. Disregard protocol if patient has renal failure, is on dialysis, or has a creatinine clearance <30 mL/min. the kidney some sodium excess to adjust for concentration. Although there should be no “routine” maintenance fluid orders, both of these methods would yield an appropriate choice of 5% dextrose in 0.45% sodium chloride at 100 mL/h as initial therapy, with potassium added for patients with normal renal function. However, many surgical patients have volume and/or electrolyte abnormalities associated with their surgical disease. Preoperative evaluation of a patient’s volume status and preexisting electrolyte abnormalities is an important part of overall preoperative assessment and care. Volume deficits should be considered in patients who have obvious GI losses, such as through emesis or diarrhea, as well as in patients with poor oral intake secondary to their disease. Less obvious are those fluid losses known as third-space or nonfunctional ECF losses that occur with GI obstruction, peritoneal or bowel inflammation, ascites, crush injuries, burns, and severe soft tissue infections such as necrotizing fasciitis. The diagnosis of an acute volume deficit is primarily clinical (see Table 3-2), although the physical signs may vary with the duration of the deficit. Cardiovascular signs of tachycardia and orthostasis predominate with acute volume loss, usually accompanied by oliguria and hemoconcentration. Acute volume deficits should be corrected as much as possible before the time of operation. Once a volume deficit is diagnosed, prompt fluid replacement should be instituted, usually with an isotonic crystalloid, depending on the measured serum electrolyte values. Patients with cardiovascular signs of volume deficit should receive a bolus of 1 to 2 L of isotonic fluid followed by a continuous infusion. Close monitoring during this period is imperative. Resuscitation should be guided by the reversal of the signs of volume deficit, such as restoration of acceptable values for vital signs, maintenance of adequate urine output (½–1 mL/kg per hour in an adult), and correction of base deficit. Patients whose volume deficit is not corrected after this initial volume challenge and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fluid and Electrolyte Management of the Surgical Patient Magnesium Magnesium level 1.0–1.8 mEq/L: Magnesium sulfate 0.5 mEq/kg in normal saline 250 mL infused IV over 24 h × 3 d Recheck magnesium level in 3 d Magnesium level <1.0 mEq/L:  Magnesium sulfate 1 mEq/kg in normal saline 250 mL infused IV over 24 h × 1 d, then 0.5 mEq/kg in normal saline 250 mL infused IV over 24 h × 2 d Recheck magnesium level in 3 d If patient has gastric access and needs a bowel regimen: Milk of magnesia 15 mL (approximately 49 mEq magnesium) q24h per gastric tube; hold for diarrhea CHAPTER 3 Potassium Serum potassium level <4.0 mEq/L: Asymptomatic, tolerating enteral nutrition: KCl 40 mEq per enteral access × 1 dose Asymptomatic, not tolerating enteral nutrition: KCl 20 mEq IV q2h × 2 doses Symptomatic: KCl 20 mEq IV q1h × 4 doses Recheck potassium level 2 h after end of infusion; if <3.5 mEq/L and asymptomatic, replace as per above protocol 80 PART I BASIC CONSIDERATIONS those with impaired renal function and the elderly should be considered for more intensive monitoring in an intensive care unit setting. In these patients, early invasive monitoring of central venous pressure or cardiac output may be necessary. If symptomatic electrolyte abnormalities accompany volume deficit, the abnormality should be corrected to the point that the acute symptom is relieved before surgical intervention. For correction of severe hypernatremia associated with a volume deficit, an unsafe rapid fall in extracellular osmolarity from 5% dextrose infusion is avoided by slowly correcting the hypernatremia with 0.45% saline or even lactated Ringer’s solution rather than 5% dextrose alone. This will safely and slowly correct the hypernatremia while also correcting the associated volume deficit. Intraoperative Fluid Therapy With the induction of anesthesia, compensatory mechanisms are lost, and hypotension will develop if volume deficits are not appropriately corrected before the time of surgery. Hemodynamic instability during anesthesia is best avoided by correcting known fluid losses, replacing ongoing losses, and providing adequate maintenance fluid therapy preoperatively. In addition to measured blood loss, major open abdominal surgeries are associated with continued extracellular losses in the form of bowel wall edema, peritoneal fluid, and the wound edema during surgery. Large soft tissue wounds, complex fractures with associated soft tissue injury, and burns are all associated with additional third-space losses that must be considered in the operating room. These represent distributional shifts, in that the functional volume of ECF is reduced but fluid is not externally lost from the body. These functional losses have been referred to as parasitic losses, sequestration, or third-space edema, because the lost volume no longer participates in the normal functions of the ECF. Until the 1960s saline solutions were withheld during surgery. Administered saline was retained and was felt to be an inappropriate challenge to a physiologic response of intraoperative salt intolerance. Basic and clinical research began to change this concept,42,43 eventually leading to the current concept that saline administration is necessary to restore the obligate ECF losses noted earlier. Although no accurate formula can predict intraoperative fluid needs, replacement of ECF during surgery often requires 500 to 1000 mL/h of a balanced salt solution to support homeostasis. The addition of albumin or other colloidcontaining solutions to intraoperative fluid therapy is not necessary. Manipulation of colloid oncotic forces by albumin infusion during major vascular surgery showed no advantage in supporting cardiac function or avoiding the accumulation of extravascular lung water.44 Postoperative Fluid Therapy Postoperative fluid therapy should be based on the patient’s current estimated volume status and projected ongoing fluid losses. Any deficits from either preoperative or intraoperative losses should be corrected, and ongoing requirements should be included along with maintenance fluids. Third-space losses, although difficult to measure, should be included in fluid replacement strategies. In the initial postoperative period, an isotonic solution should be administered. The adequacy of resuscitation should be guided by the restoration of acceptable values for vital signs and urine output and, in more complicated cases, by the correction of base deficit or lactate. If uncertainty exists, particularly in patients with renal or cardiac dysfunction, a central venous catheter or Swan-Ganz catheter may be inserted to help guide fluid therapy. After the initial 24 to 48 hours, fluids can be changed to 5% dextrose in 0.45% saline in patients unable to tolerate enteral nutrition. If normal renal function and adequate urine output are present, potassium may be added to the IV fluids. Daily fluid orders should begin with assessment of the patient’s volume status and assessment of electrolyte abnormalities. There is rarely a need to check electrolyte levels in the first few days of an uncomplicated postoperative course. However, postoperative diuresis may require attention to replacement of urinary potassium loss. All measured losses, including losses through vomiting, nasogastric suctioning, drains, and urine output, as well as insensible losses, are replaced with the appropriate parenteral solutions as previously reviewed. Special Considerations for the Postoperative Patient Volume excess is a common disorder in the postoperative period. The administration of isotonic fluids in excess of actual needs may result in excess volume expansion. This may be due to the overestimation of third-space losses or to ongoing GI losses that are difficult to measure accurately. The earliest sign of volume overload is weight gain. The average postoperative patient who is not receiving nutritional support should lose approximately 0.25 to 0.5 lb/d (0.11 to 0.23 kg/d) from catabolism. Additional signs of volume excess may also be present as listed in Table 3-2. Peripheral edema may not necessarily be associated with intravascular volume overload, because overexpansion of total ECF may exist in association with a deficit in the circulating plasma volume. Volume deficits also can be encountered in surgical patients if preoperative losses were not completely corrected, intraoperative losses were underestimated, or postoperative losses were greater than appreciated. The clinical manifestations are described in Table 3-2 and include tachycardia, orthostasis, and oliguria. Hemoconcentration also may be present. Treatment will depend on the amount and composition of fluid lost. In most cases of volume depletion, replacement with an isotonic fluid will be sufficient while alterations in concentration 6 and composition are being evaluated. ELECTROLYTE ABNORMALITIES IN SPECIFIC SURGICAL PATIENTS Neurologic Patients Syndrome of Inappropriate Secretion of Antidiuretic Hormone. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) can occur after head injury or surgery to the central nervous system, but it also is seen in association with administration of drugs such as morphine, nonsteroidals, and oxytocin, and in a number of pulmonary and endocrine diseases, including hypothyroidism and glucocorticoid deficiency. Additionally, it can be seen in association with a number of malignancies, most often small cell cancer of the lung but also pancreatic carcinoma, thymoma, and Hodgkin’s dis7 ease.45 SIADH should be considered in patients who are euvolemic and hyponatremic with elevated urine sodium levels and urine osmolality. ADH secretion is considered inappropriate when it is not in response to osmotic or volume-related conditions. Correction of the underlying problem should be attempted VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ ADH stimulation and is manifested by dilute urine in the case of hypernatremia. Central DI results from a defect in ADH secretion, and nephrogenic DI results from a defect in end-organ responsiveness to ADH. Central DI is frequently seen in association with pituitary surgery, closed head injury, and anoxic encephalopathy.46 Nephrogenic DI occurs in association with hypokalemia, administration of radiocontrast dye, and use of certain drugs such as aminoglycosides and amphotericin B. In patients tolerating oral intake, volume status usually is normal because thirst stimulates increased intake. However, volume depletion can occur rapidly in patients incapable of oral intake. The diagnosis can be confirmed by documenting a paradoxical increase in urine osmolality in response to a period of water deprivation. In mild cases, free water replacement may be adequate therapy. In more severe cases, vasopressin can be added. The usual dosage of vasopressin is 5 U subcutaneously every 6 to 8 hours. However, serum electrolytes and osmolality should be monitored to avoid excess vasopressin administration with resulting iatrogenic SIADH. Cerebral Salt Wasting. Cerebral salt wasting is a diagnosis of exclusion that occurs in patients with a cerebral lesion and renal wasting of sodium and chloride with no other identifiable cause.47 Natriuresis in a patient with a contracted extracellular volume should prompt the possible diagnosis of cerebral salt wasting. Hyponatremia is frequently observed but is nonspecific and occurs as a secondary event, which differentiates it from SIADH. Malnourished Patients: Refeeding Syndrome Refeeding syndrome is a potentially lethal condition that can occur with rapid and excessive feeding of patients with severe underlying malnutrition due to starvation, alcoholism, delayed nutritional support, anorexia nervosa, or massive weight loss in obese patients.48 With refeeding, a shift in metabolism from fat to carbohydrate substrate stimulates insulin release, which results in the cellular uptake of electrolytes, particularly phosphate, magnesium, potassium, and calcium. However, severe hyperglycemia may result from blunted basal insulin secretion. The refeeding syndrome can be associated with enteral or parenteral refeeding, and symptoms from electrolyte abnormalities include cardiac arrhythmias, confusion, respiratory failure, and even death. To prevent the development of refeeding syndrome, underlying electrolyte and volume deficits should be corrected. Additionally, thiamine should be administered before the initiation of feeding. Caloric repletion should be instituted slowly and should gradually increase over the first week.49 Vital signs, fluid balance, and electrolytes should be closely monitored and any deficits corrected as they evolve. A number of fluid and electrolyte abnormalities are specific to patients with acute renal failure. With the onset of renal failure, an accurate assessment of volume status must be made. If prerenal azotemia is present, prompt correction of the underlying volume deficit is mandatory. Once acute tubular necrosis is established, measures should be taken to restrict daily fluid intake to match urine output and insensible and GI losses. Oliguric renal failure requires close monitoring of serum potassium levels. Measures to correct hyperkalemia as reviewed in Table 3-14 should be instituted early, including consideration of early hemodialysis. Hyponatremia is common in established renal failure as a result of the breakdown of proteins, carbohydrates, and fats, as well the administration of free water. Dialysis may be required for severe hyponatremia. Hypocalcemia, hypermagnesemia, and hyperphosphatemia also are associated with acute renal failure. Hypocalcemia should be verified by measuring ionized calcium, because many patients also are hypoalbuminemic. Phosphate binders can be used to control hyperphosphatemia, but dialysis may be required in more severe cases. Metabolic acidosis is commonly seen with renal failure, as the kidneys lose their ability to clear acid by-products. Bicarbonate can be useful, but dialysis often is needed. Although dialysis may be either intermittent or continuous, renal recovery may be improved by continuous renal replacement.50 Cancer Patients Fluid and electrolyte abnormalities are common in patients with cancer. The causes may be common to all patient populations or may be specific to cancer patients and their treatment.51 Hyponatremia is frequently hypovolemic due to renal loss of sodium caused by diuretics or salt-wasting nephropathy as seen with some chemotherapeutic agents such as cisplatin. Cerebral salt wasting also can occur in patients with intracerebral lesions. Normovolemic hyponatremia may occur in association with SIADH from cervical cancer, lymphoma, and leukemia, or from certain chemotherapeutic agents. Hypernatremia in cancer patients most often is due to poor oral intake or GI volume losses, which are common side effects of chemotherapy. Central DI also can lead to hypernatremia in patients with central nervous system lesions. Hypokalemia can develop from GI losses associated with diarrhea caused by radiation enteritis or chemotherapy, or from tumors such as villous adenomas of the colon. Tumor lysis syndrome can precipitate severe hyperkalemia from massive tumor cell destruction. Hypocalcemia can be seen after removal of a thyroid or parathyroid tumor or after a central neck dissection, which can damage the parathyroid glands. Hungry bone syndrome produces acute and profound hypocalcemia after parathyroid surgery for secondary or tertiary hyperparathyroidism because calcium is rapidly taken up by bones. Prostate and breast cancer can result in increased osteoblastic activity, which decreases serum calcium by increasing bone formation. Acute hypocalcemia also can occur with hyperphosphatemia, because phosphorus complexes with calcium. Hypomagnesemia is a side effect of ifosfamide and cisplatin therapy. Hypophosphatemia can be seen in hyperparathyroidism, due to decreased phosphorus reabsorption, and in oncogenic osteomalacia, which increases the urinary excretion of phosphorus. Other causes of hypophosphatemia in cancer patients include renal tubular dysfunction from multiple myeloma, Bence Jones proteins, and certain chemotherapeutic agents. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 81 Fluid and Electrolyte Management of the Surgical Patient Diabetes Insipidus. Diabetes insipidus (DI) is a disorder of Acute Renal Failure Patients CHAPTER 3 when possible. In most cases, restriction of free water will improve the hyponatremia. The goal is to achieve net water balance while avoiding volume depletion that may compromise renal function. Furosemide also can be used to induce free water loss. If hyponatremia persists after fluid restriction, the addition of isotonic or hypertonic fluids may be effective. The administration of isotonic saline may sometimes worsen the problem if the urinary sodium concentration is higher than the infused sodium concentration. The use of loop diuretics may be helpful in this situation by preventing further urine concentration. In chronic SIADH, when long-term fluid restriction is difficult to maintain or is ineffective, demeclocycline and lithium can be used to induce free water loss. 82 PART I BASIC CONSIDERATIONS Acute hypophosphatemia can occur as rapidly proliferating malignant cells take up phosphorus in acute leukemia. Tumor lysis syndrome or the use of bisphosphonates to treat hypercalcemia also can result in hyperphosphatemia. Malignancy is the most common cause of hypercalcemia in hospitalized patients and is due to increased bone resorption or decreased renal excretion. Bone destruction occurs from bony metastasis as seen in breast or renal cell cancer but also can occur in multiple myeloma. With Hodgkin’s and non-Hodgkin’s lymphoma, hypercalcemia results from increased calcitriol formation, which increases both absorption of calcium from the GI tract and mobilization from bone. Humoral hypercalcemia of malignancy is a common cause of hypercalcemia in cancer patients. As in primary hyperparathyroidism, a parathyroidrelated protein is secreted that binds to parathyroid receptors, stimulating calcium resorption from bone and decreasing renal excretion of calcium. The treatment of hypercalcemia of malignancy should begin with saline volume expansion, which will decrease renal reabsorption of calcium as the associated volume deficit is corrected. Once an adequate volume status has been achieved, a loop diuretic may be added. Unfortunately, these measures are only temporary, and additional treatment is often necessary. A variety of drugs are available with varying times of onset, durations of action, and side effects.52 The bisphosphonates etidronate and pamidronate inhibit bone resorption and osteoclastic activity. They have a slow onset of action, but effects can last for 2 weeks. Calcitonin also is effective, inhibiting bone resorption and increasing renal excretion of calcium. It acts quickly, within 2 to 4 hours, but its use is limited by the development of tachyphylaxis. Corticosteroids may decrease tachyphylaxis in response to calcitonin and can be used alone to treat hypercalcemia. Gallium nitrates are potent inhibitors of bone resorption. They display a long duration of action but can cause nephrotoxicity. Mithramycin is an antibiotic that blocks osteoclastic activity, but it can be associated with liver, renal, and hematologic abnormalities, which limits its use to the treatment of Paget’s disease of bone. For patients with severe, refractory hypercalcemia who are unable to tolerate volume expansion due to pulmonary edema or congestive heart failure, dialysis is an option. Tumor lysis syndrome results when the release of intracellular metabolites overwhelms the kidneys’ excretory capacity. This rapid release of uric acid, potassium, and phosphorus can result in marked hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, and acute renal failure. It is typically seen with poorly differentiated lymphomas and leukemias but also can occur with a number of solid tumor malignancies. Tumor lysis syndrome most commonly develops during treatment with chemotherapy or radiotherapy. Once it develops, volume expansion should be undertaken and any associated electrolyte abnormalities corrected. In this setting, hypocalcemia should not be treated unless it is symptomatic to avoid metastatic calcifications. Dialysis may be required for management of impaired renal function or correction of electrolyte abnormalities. REFERENCES Entries highlighted in blue are key references. 1. Aloia JF, Vaswani A, Flaster E, et al. Relationship of body water compartment to age, race and fat-free mass. J Lab Clin Med. 1998;132:483. 2. Bourque CW, Oliet SHR. 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Admission serum lactate levels do not predict mortality in the acutely injured patient. J Trauma. 2006;60:583. 22. Koustova E, Standon K, Gushchin V, et al. Effects of lactated Ringer’s solution on human leukocytes. J Trauma. 2002;53:782. 23. Shires GT, Browder LK, Steljes TP, et al. The effect of shock resuscitation fluids on apoptosis. Am J Surg. 2005;189:85. 24. Roberts JS, Bratton SL. Colloid volume expanders: problems, pitfalls, and possibilities. Drugs. 1998;55:621. 25. Cottenceau V, Masson F, Mahamid E, et al. Comparison effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma. 2011;28(10):2003. 26. Bulger EM, May S, Kerby JD, et al. Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo-controlled trial. Ann Surg. 2011;253(3):431. 27. Ley K. Plugging the leaks. Nat Med. 2001;7:1105. 28. Conhaim RL, Watson KE, Potenza BM, et al. Pulmonary capillary sieving of hetastarch is not altered by LPS-induced sepsis. J Trauma. 1999;46:800. 29. Lucas CE. The water of life: a century of confusion. J Am Coll Surg. 2001;192:86. 30. de Jonge E, Levi M. Effects of different plasma substitutes on blood coagulation: a comparative review. Crit Care Med. 2001;291:1261. 31. Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a metaanalysis of randomized trilals. J Thorac Cardiovasc Surg. 2012;144(4):223. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 83 Fluid and Electrolyte Management of the Surgical Patient 42. Shires GT, Williams J, Brown F. Acute changes in extracellular fluids associated with major surgical procedures. Ann Surg. 1961;154:803. 43. Shires GT, Jackson DE. Postoperative salt tolerance. Arch Surg. 1962;84:703. 44. Shires GT III, Peitzman AB, Albert SA, et al. Response of extravascular lung water to intraoperative fluids. Ann Surg. 1983;197:515. 45. Ellison DH, Burl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064. 46. Tisdall M, Crocker M, Watkiss J, et al. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol. 2006;18(1):57. 47. Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting: pathophysiology, diagnosis, and treatment. Neurosurg Clin N Am. 2010;21(2):339. 48. Kozar RA, McQuiggan MM, Moore FA. Nutritional support in trauma patients. In: Shikora SA, Martindale RG, Schwaitzberg SD, eds. Nutritional Considerations in the Intensive Care Unit. 1st ed. Dubuque, IA: Kendall/Hunt Publishing; 2002:229. 49. Boateng AA, Sriram K, Mequid MM, et al. Refeeding syndrome: treatment considerations based on collective analysis of literature case reports. Nutrition. 2010;26(2):156. 50. Glassford NJ, Bellomo R. Acute kidney injury: how can we facilitate recovery? Curr Opin Crit Care. 2011;17(6):562. 51. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin. 2002;17:503. 52. Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011; 18(6)339. CHAPTER 3 32. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicenter randomized study. Lancet. 2001;357:911. 33. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;309(7):678. 34. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. Hextend, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Anesth Analg. 1999;88:992. 35. Boldt J, Haisch G, Suttner S, et al. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation. Br J Anaesth. 2002;89:772. 36. Rittoo D, Gosling P, Bonnici C, et al. Splanchnic oxygenation in patients undergoing abdominal aortic aneurysm repair and volume expansion with eloHAES. Cardiovasc Surg. 2002;10:128. 37. Coats TJ, Brazil E, Heron M, et al. Impairment of coagulation by commonly used resuscitation fluids in human volunteers. Emerg Med J. 2006;23:846. 38. Overgaard-Steensen C, Ring T. Clinical Review: Practical approach to hyponatremia and hypernatremia in critically ill patients. Crit Care. 2013;17(1):206. 39. Norenberg MD. Central pontine myelinolysis: historical and mechanistic considerations. Metab Brain Dis. 2010;25(1):97. 40. Graff-Radford J, Fugate JE, Kauffmann TJ. Clinical and radiologic correlations of central pontine myelinolysis syndrome. Mayo Clin Proc. 2011;86(11):1063. 41. American College of Surgeons. Shock. In: American College of Surgeons Advanced Trauma Life Support Manual. 9th ed. Chicago: American College of Surgeons; 2012. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 4 Hemostasis, Surgical Bleeding, and Transfusion chapter Biology of Hemostasis Bryan Cotton, John B. Holcomb, Matthew Pommerening, Kenneth Jastrow, and Rosemary A. Kozar 85 Vascular Constriction / 85 Platelet Function / 85 Coagulation / 86 Fibrinolysis / 88 Congenital Factor Deficiencies 88 Coagulation Factor Deficiencies / 88 Platelet Functional Defects / 89 Acquired Hemostatic Defects 90 Transfusion 96 Background / 96 Replacement Therapy / 96 Platelet Abnormalities / 90 BIOLOGY OF HEMOSTASIS Hemostasis is a complex process whose function is to limit blood loss from an injured vessel. Four major physiologic events participate in the hemostatic process: vascular constriction, platelet plug formation, fibrin formation, and fibrinolysis. Although each tends to be activated in order, the four processes are interrelated so that there is a continuum and multiple reinforcements. The process is shown schematically in Fig. 4-1. Vascular Constriction Vascular constriction is the initial response to vessel injury. It is more pronounced in vessels with medial smooth muscles and is dependent on local contraction of smooth muscle. Vasoconstriction is subsequently linked to platelet plug formation. Thromboxane A2 (TXA2) is produced locally at the site if injury via the release of arachidonic acid from platelet membranes and is a potent constrictor of smooth muscle. Similarly, endothelin synthesized by injured endothelium and serotonin (5-hydroxytryptamine [5-HT]) released during platelet aggregation are potent vasoconstrictors. Lastly, bradykinin and fibrinopeptides, which are involved in the coagulation schema, are also capable of contracting vascular smooth muscle. The extent of vasoconstriction varies with the degree of vessel injury. A small artery with a lateral incision may remain open due to physical forces, whereas a similarly sized vessel that is completely transected may contract to the extent that bleeding ceases spontaneously. Platelet Function Indications for Replacement of Blood and Its Elements / 97 Volume Replacement / 98 New Concepts in Resuscitation / 98 Complications of Transfusion / 100 Acquired Hypofibrinogenemia / 92 Myeloproliferative Diseases / 92 Coagulopathy of Liver Disease / 92 Coagulopathy of Trauma / 93 Acquired Coagulation Inhibitors / 93 Anticoagulation and Bleeding / 94 Platelets are anucleate fragments of megakaryocytes. The normal circulating number of platelets ranges between 150,000 and 400,000/μL. Up to 30% of circulating platelets may be sequestered in the spleen. If not consumed in a clotting reaction, Tests of Hemostasis and Blood Coagulation Evaluation of Excessive Intraoperative or Postoperative Bleeding 102 104 platelets are normally removed by the spleen and have an average life span of 7 to 10 days. Platelets play an integral role in hemostasis by forming a hemostatic plug and by contributing to thrombin formation (Fig. 4-2). Platelets do not normally adhere to each other or to the vessel wall but can form a plug that aids in cessation of bleeding when vascular disruption occurs. Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere. This process requires von Willebrand factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand’s disease. vWF binds to glycoprotein (GP) I/IX/V on the platelet membrane. Following adhesion, platelets initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel. Up to this point, this process is known as primary hemostasis. Platelet aggregation is reversible and is not associated with secretion. Additionally, heparin does not interfere with this reaction, and thus, hemostasis can occur in the heparinized patient. Adenosine diphosphate (ADP) and serotonin are the principal mediators in platelet aggregation. Arachidonic acid released from the platelet membranes is converted by cyclooxygenase to prostaglandin G2 (PGG2) and then to prostaglandin H2 (PGH2), which, in turn, is converted to TXA2. TXA2 has potent vasoconstriction and platelet aggregation effects. Arachidonic acid may also be shuttled to adjacent endothelial cells and converted to prostacyclin (PGI2), which is a vasodilator and acts to inhibit platelet aggregation. Platelet cyclooxygenase is irreversibly inhibited by aspirin and reversibly blocked by nonsteroidal anti-inflammatory agents, but is not affected by cyclooxygenase-2 (COX-2) inhibitors. In the second wave of platelet aggregation, a release reaction occurs in which several substances including ADP, Ca2+, serotonin, TXA2, and α-granule proteins are discharged. Fibrinogen is a required cofactor for this process, acting as a bridge for VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 The life span of platelets ranges from 7 to 10 days. Drugs that interfere with platelet function include aspirin, clopidogrel, prasugrel, dipyridamole, and the glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors. Approximately 5 to 7 days should pass from the time the drug is stopped until an elective procedure is performed. The acute coagulopathy of trauma results from a combination of activation of protein C and hyperfibrinolysis. It is distinct from disseminated intravascular coagulation, is present on arrival to the emergency department, and is associated with an increase in mortality. Newer anticoagulants like dabigatran and rivaroxaban have no readily available method of detection of the degree of anticoagulation and may not be readily reversible. the GP IIb/IIIa receptor on the activated platelets. The release reaction results in compaction of the platelets into a plug, a process that is no longer reversible. Thrombospondin, another protein secreted by the α-granule, stabilizes fibrinogen binding to the activated platelet surface and strengthens the platelet-platelet interactions. Platelet factor 4 (PF4) and α-thromboglobulin are also secreted during the release reaction. PF4 is a potent heparin antagonist. The second wave of platelet aggregation is inhibited by aspirin and nonsteroidal anti-inflammatory drugs, by cyclic adenosine monophosphate (cAMP), and by nitric oxide. As a consequence of the release reaction, alterations occur in the phospholipids of the platelet membrane that allow calcium and clotting factors to bind to the platelet surface, forming enzymatically active complexes. The altered lipoprotein surface (sometimes referred to as platelet factor 3) catalyzes reactions that are involved in the conversion of prothrombin (factor II) to 1. Vascular phase (Vasoconstriction) 4 5 6 Therapeutic anticoagulation preoperatively and postoperatively is becoming increasingly more common. The patient’s risk of intraoperative and postoperative bleeding should guide the need for reversal of anticoagulation therapy preoperatively and the timing of its reinstatement postoperatively. Damage control resuscitation has three basic components: permissive hypotension, minimizing crystalloid-based resuscitation, and the administration of predefined blood products. The need for massive transfusion should be anticipated, and guidelines should be in place to provide early and increased amounts of red blood cells, plasma, and platelets. thrombin (factor IIa) by activated factor X (Xa) in the presence of factor V and calcium, and it is involved in the reaction by which activated factor IX (IXa), factor VIII, and calcium activate factor X. Platelets may also play a role in the initial activation of factors XI and XII. Coagulation Hemostasis involves a complex interplay and combination of interactions between platelets, the endothelium, and multiple circulating or membrane-bound coagulation factors. While a bit simplistic and not reflective of the depth or complexity of these interactions, the coagulation cascade has traditionally been depicted as two possible pathways converging into a single common pathway (Fig. 4-3). While this pathway reflects the basic process and sequences that lead to the formation of a clot, the numerous feedback loops, endothelial interplay, and platelet 2. Platelet phase (Platelets aggregate) Common pathway Prothrombin Intrinsic pathway CA2+v Clotting factors VIII, IX, X, XI, XII Thrombin Extrinsic pathway CA2+ Clotting factors VII Fibrin 3. Coagulation phase (Clot formation) 86 (Clot retraction) 4. Fibrinolysis (Clot destruction) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 4-1. Biology of hemostasis. The four physiologic processes that interrelate to limit blood loss from an injured vessel are illustrated and include vascular constriction, platelet plug formation, fibrin clot formation, and fibrinolysis. Platelet hemostatic function Vasoconstriction Subendothelial collagen Platelet adhesion secretion (Reversible) Platelet aggregation secretion ADP, serotonin, Ca2+, fibrinogen (Irreversible) Coagulation activation via tissue factorfactor VIIa IXa, Xa Complexes on activated platelets Platelet aggregation Thrombin + Fibrinogen Platelet-fibrin thrombus Figure 4-2. Schematic of platelet activation and thrombus function. functions are not included. The intrinsic pathway begins with the activation of factor XII that subsequently activates factors XI, IX, and VIII. In this pathway, each of the primary factors is “intrinsic” to the circulating plasma, whereby no surface is required to initiate the process. In the extrinsic pathway, tissue factor (TF) is released or exposed on the surface of the endothelium, binding to circulating factor VII, facilitating its activation to VIIa. Each of these pathways continues on to a common sequence that begins with the activation of factor X to Xa (in the presence of VIIIa). Subsequently, Xa (with the help of factor Va) converts factor II (prothrombin) to thrombin and then factor I (fibrinogen) to fibrin. Clot formation occurs after fibrin monomers are cross-linked to polymers with the assistance of factor XIII. One convenient feature of depicting the coagulation cascade with two merging arms is that commonly used laboratory Extrinsic Intrinsic Vascular injury Surface Factor XIIa Factor XII Tissue factor + factor VII Kallikrein Tissue factor-Factor VIIa Factor XIa ? Physiologic Factor XI 2+ Ca Factor IX Ca Prekallikrein HMW kininogen Surface Inflammation Complement activation Fibrinolysis 2+ Factor X Factor IXa Factor VIIIa Ca2+ Factor Xa Phospholipid Factor Va Ca2+ Phospholipid Prothrombin (factor II) Factor VIII Factor V Thrombin (factor IIa) Factor XIII Ca2+ Fibrinogen Fibrin Fibrin Factor XIIIa X-Linked fibrin VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 4-3. Schematic of the coagulation system. HMW = high molecular weight. Hemostasis, Surgical Bleeding, and Transfusion ADP, serotonin, Ca2+, fibrinogen 87 CHAPTER 4 tests segregate abnormalities of clotting to one of the two arms. An elevated activated partial thromboplastin time (aPTT) is associated with abnormal function of the intrinsic arm of the cascade (II, IX, X, XI, XII), while the prothrombin time (PT) is associated with the extrinsic arm (II, VII, X). Vitamin K deficiency or warfarin use affects factors II, VII, IX, and X Expanding from the basic concept of Fig. 4-3, the primary pathway for coagulation is initiated by TF exposure following subendothelial injury. Clot propagation ensues with what is a sequence of four similar enzymatic reactions, each involving a proteolytic enzyme generating the next enzyme by cleaving its proenzyme, a phospholipid surface (e.g., platelet membrane) in the presence of ionized calcium, and a helper protein. TF binds to VIIa, and this complex catalyzes the activation of factor X to Xa. This complex is four orders of magnitude more active at converting factor X than is factor VIIa alone and also activates factor IX to IXa. Factor Xa, together with Va, calcium, and phospholipid, composes the prothrombinase complex that converts prothrombin to thrombin. The prothrombinase complex is significantly more effective at catalyzing its substrate than is factor Xa alone. Thrombin is then involved with the conversion of fibrinogen to fibrin and activation of factors V, VII, VIII, XI, and XIII. In building on the redundancy inherent in the coagulation system, factor VIIIa combines with IXa to form the intrinsic factor complex. Factor IXa is responsible for the bulk of the conversion of factor X to Xa. This complex (VIIIa-IXa) is 50 times more effective at catalyzing factor X activation than is the extrinsic (TF-VIIa) complex and five to six orders of magnitude more effective than factor IXa alone. Once formed, thrombin leaves the membrane surface and converts fibrinogen by two cleavage steps into fibrin and two small peptides termed fibrinopeptides A and B. Removal of fibrinopeptide A permits end-to-end polymerization of the fibrin molecules, whereas cleavage of fibrinopeptide B allows side-to-side polymerization of the fibrin clot. This latter step is facilitated by thrombin-activatable fibrinolysis inhibitor (TAFI), which acts to stabilize the resultant clot. Vascular endothelial injury 88 PART I BASIC CONSIDERATIONS In seeking to balance profound bleeding with overwhelming clot burden, several related processes exist to prevent propagation of the clot beyond the site of injury.1 First, feedback inhibition on the coagulation cascade deactivates the enzyme complexes leading to thrombin formation. Thrombomodulin (TM) presented by the endothelium serves as a “thrombin sink” by forming a complex with thrombin, rendering it no longer available to cleave fibrinogen. This then activates protein C (APC) and reduces further thrombin generation by inhibiting factors V and VIII. Second, tissue plasminogen activator (tPA) is released from the endothelium following injury, cleaving plasminogen to initiate fibrinolysis. APC then consumes plasminogen activator inhibitor-1 (PAI-1), leading to increased tPA activity and fibrinolysis. Building on the anticoagulant response to inhibit thrombin formation, tissue factor pathway inhibitor (TFPI) is released, blocking the TF-VIIa complex and reducing the production of factors Xa and IXa. Antithrombin III (ATIII) then neutralizes all of the procoagulant serine proteases and also inhibits the TF-VIIa complex. The most potent mechanism of thrombin inhibition involves the APC system. APC forms a complex with its cofactor, protein S, on a phospholipid surface. This complex then cleaves factors Va and VIIIa so they are no longer able to participate in the formation of TF-VIIa or prothrombinase complexes. This is of interest clinically in the form of a genetic mutation, called factor V Leiden. In this setting, factor V is resistant to cleavage by APC, thereby remaining active as a procoagulant. Patients with factor V Leiden are predisposed to venous thromboembolic events. Degradation of fibrin clot is accomplished by plasmin, a serine protease derived from the proenzyme plasminogen. Plasmin formation occurs as a result of one of several plasminogen activators. tPA is made by the endothelium and other cells of the vascular wall and is the main circulating form of this family of enzymes. tPA is selective for fibrin-bound plasminogen so that endogenous fibrinolytic activity occurs predominately at the site of clot formation. The other major plasminogen activator, urokinase plasminogen activator (uPA), also produced by endothelial cells as well as by urothelium, is not selective for fibrin-bound plasminogen. Of note, the thrombin-TM complex activates TAFI, leading to a mixed effect on clot stability. In addition to inhibiting fibrinolysis directly, removal of the terminal lysine on the fibrin molecule by TAFI renders the clot more susceptible to lysis by plasmin. Fibrinolysis Fibrin clot breakdown (lysis) allows restoration of blood flow during the healing process following injury and begins at the same time clot formation is initiated. Fibrin polymers are degraded by plasmin, a serine protease derived from the proenzyme plasminogen. Plasminogen is converted to plasmin by one of several plasminogen activators, including tPA. Plasmin then degrades the fibrin mesh at various places, leading to the production of circulating fragments, termed fibrin degradation products (FDPs), cleared by other proteases or by the kidney and liver (Fig. 4-4). Fibrinolysis is directed by circulating kinases, tissue activators, and kallikrein present in vascular endothelium. tPA is synthesized by endothelial cells and released by the cells on thrombin stimulation. Bradykinin, a potent endothelialdependent vasodilator, is cleaved from high molecular weight kininogen by kallikrein and enhances the release of tPA. Both tPA and plasminogen bind to fibrin as it forms, and this trimolecular complex cleaves fibrin very efficiently. After plasmin is generated, however, it cleaves fibrin somewhat less efficiently. Platelet Thrombin Fibrin FDP Plasminogen Plasmin tPA Endothelium Figure 4-4. Formation of fibrin degradation products (FDPs). tPA = tissue plasminogen activator. As with clot formation, fibrinolysis is also kept in check through several robust mechanisms. tPA activates plasminogen more efficiently when it is bound to fibrin, so that plasmin is formed selectively on the clot. Plasmin is inhibited by α2antiplasmin, a protein that is cross-linked to fibrin by factor XIII, which helps to ensure that clot lysis does not occur too quickly. Any circulating plasmin is also inhibited by α2-antiplasmin and circulating tPA or urokinase. Clot lysis yields FDPs including E-nodules and D-dimers. These smaller fragments interfere with normal platelet aggregation, and the larger fragments may be incorporated into the clot in lieu of normal fibrin monomers. This may result in an unstable clot as seen in cases of severe coagulopathy such as hyperfibrinolysis associated with traumainduced coagulopathy or disseminated intravascular coagulopathy. The presence of D-dimers in the circulation may serve as a marker of thrombosis or other conditions in which a significant activation of the fibrinolytic system is present. Another inhibitor of the fibrinolytic system is TAFI, which removes lysine residues from fibrin that are essential for binding plasminogen. CONGENITAL FACTOR DEFICIENCIES Coagulation Factor Deficiencies Inherited deficiencies of all of the coagulation factors are seen. However, the three most frequent are factor VIII deficiency (hemophilia A and von Willebrand’s disease), factor IX deficiency (hemophilia B or Christmas disease), and factor XI deficiency. Hemophilia A and hemophilia B are inherited as sex-linked recessive disorders with males being affected almost exclusively. The clinical severity of hemophilia A and hemophilia B depends on the measurable level of factor VIII or factor IX in the patient’s plasma. Plasma factor levels less than 1% of normal are considered severe disease, factor levels between 1% and 5% moderately severe disease, and levels between 5% and 30% mild disease. Patients with severe hemophilia have spontaneous bleeds, frequently into joints, leading to crippling arthropathies. Intracranial bleeding, intramuscular hematomas, retroperitoneal hematomas, and gastrointestinal, genitourinary, and retropharyngeal bleeding are added clinical sequelae seen with severe disease. Patients with moderately severe hemophilia have less spontaneous bleeding but are likely to bleed severely after trauma or surgery. Mild hemophiliacs do not bleed spontaneously and have only minor bleeding after major trauma or surgery. Since platelet function is normal in hemophiliacs, patients may not bleed immediately after an injury or minor surgery as VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Factor XI Deficiency. Factor XI deficiency, an autosomal recessive inherited condition sometimes referred to as hemophilia C, is more prevalent in the Ashkenazi Jewish population but found in all races. Spontaneous bleeding is rare, but bleeding may occur after surgery, trauma, or invasive procedures. Treatment of patients with factor XI deficiency who present with bleeding or in whom surgery is planned and who are known to have bled previously is with fresh frozen plasma (FFP). Each milliliter of plasma contains 1 unit of factor XI activity, so the volume needed depends on the patient’s baseline level, the desired level, and the plasma volume. Antifibrinolytics may be useful in patients with menorrhagia. Factor VIIa is recommended for patients with anti-factor XI antibodies, although thrombosis has been reported.4 There has been renewed interest in factor XI inhibitors as antithrombotic agents, because patients with factor XI deficiency generally have only minimal bleeding risk unless a severe deficiency is present and seem to be protected from thrombosis.5 Deficiency of Factors II (Prothrombin), V, and X. Inherited deficiencies of factors II, V, and X are rare. These deficiencies are inherited as autosomal recessive. Significant bleeding in homozygotes with less than 1% of normal activity is encountered. Bleeding with any of these deficiencies is treated with FFP. Similar to factor XI, FFP contains one unit of activity Factor VII Deficiency. Inherited factor VII deficiency is a rare autosomal recessive disorder. Clinical bleeding can vary widely and does not always correlate with the level of FVII coagulant activity in plasma. Bleeding is uncommon unless the level is less than 3%. The most common bleeding manifestations involve easy bruising and mucosal bleeding, particularly epistaxis or oral mucosal bleeding. Postoperative bleeding is also common, reported in 30% of surgical procedures.6 Treatment is with FFP or recombinant factor VIIa. The half-life of recombinant factor VIIa is only approximately 2 hours, but excellent hemostasis can be achieved with frequent infusions. The half-life of factor VII in FFP is up to 4 hours. Factor XIII Deficiency. Congenital factor XIII (FXIII) deficiency, originally recognized by Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis.7 The male-to-female ratio is 1:1. Although acquired FXIII deficiency has been described in association with hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant association with bleeding in children is the inherited deficiency.8 Bleeding is typically delayed because clots form normally but are susceptible to fibrinolysis. Umbilical stump bleeding is characteristic, and there is a high risk of intracranial bleeding. Spontaneous abortion is usual in women with factor XIII deficiency unless they receive replacement therapy. Replacement can be accomplished with FFP, cryoprecipitate, or a factor XIII concentrate. Levels of 1% to 2% are usually adequate for hemostasis. Platelet Functional Defects Inherited platelet functional defects include abnormalities of platelet surface proteins, abnormalities of platelet granules, and enzyme defects. The major surface protein abnormalities are thrombasthenia and Bernard-Soulier syndrome. Thrombasthenia, or Glanzmann thrombasthenia, is a rare genetic platelet disorder, inherited in an autosomal recessive pattern, in which the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex is either lacking or present but dysfunctional. This defect leads to faulty platelet aggregation and subsequent bleeding. The disorder was first described by Dr. Eduard Glanzmann in 1918.9 Bleeding in thrombasthenic patients must be treated with platelet transfusions. The Bernard-Soulier syndrome is caused by a defect in the GP Ib/IX/V receptor for vWF, which is necessary for platelet adhesion to the subendothelium. Transfusion of normal platelets is required for bleeding in these patients. The most common intrinsic platelet defect is storage pool disease. It involves loss of dense granules (storage sites for ADP, adenosine triphosphate [ATP], Ca2+, and inorganic phosphate) and α-granules. Dense granule deficiency is the most prevalent of these. It may be an isolated defect or occur with VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 89 Hemostasis, Surgical Bleeding, and Transfusion von Willebrand’s Disease. von Willebrand’s disease (vWD), the most common congenital bleeding disorder, is characterized by a quantitative or qualitative defect in vWF, a large glycoprotein responsible for carrying factor VIII and platelet adhesion. The latter is important for normal platelet adhesion to exposed subendothelium and for aggregation under high shear conditions. Patients with vWD have bleeding that is characteristic of platelet disorders such as easy bruising and mucosal bleeding. Menorrhagia is common in women. vWD is classified into three types. Type I is a partial quantitative deficiency, type II is a qualitative defect, and type III is total deficiency. For bleeding, type I patients usually respond well to desmopressin (DDAVP). Type II patients may respond, depending on the particular defect. Type III patients are usually unresponsive. These patients may require vWF concentrates.3 of each per milliliter. However, factor V activity is decreased because of its inherent instability. The half-life of prothrombin (factor II) is long (approximately 72 hours), and only about 25% of a normal level is needed for hemostasis. Prothrombin complex concentrates can be used to treat deficiencies of prothrombin or factor X. Daily infusions of FFP are used to treat bleeding in factor V deficiency, with a goal of 20% to 25% activity. Factor V deficiency may be coinherited with factor VIII deficiency. Treatment of bleeding in individuals with the combined deficiency requires factor VIII concentrate and FFP. Some patients with factor V deficiency are also lacking the factor V normally present in platelets and may need platelet transfusions as well as FFP. CHAPTER 4 they have a normal response with platelet activation and formation of a platelet plug. At times, the diagnosis of hemophilia is not made in these patients until after their first minor procedure (e.g., tooth extraction or tonsillectomy). Patients with hemophilia A or B are treated with factor VIII or factor IX concentrate, respectively. Recombinant factor VIII is strongly recommended for patients not treated previously and is generally recommended for patients who are both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) seronegative. For factor IX replacement, the preferred products are recombinant or high-purity factor IX. In general, activity levels should be restored to 30% to 40% for mild hemorrhage, 50% for severe bleeding, and 80% to 100% for life-threatening bleeding. Up to 20% of hemophiliacs with factor VIII deficiency develop inhibitors that can neutralize FVIII. For patients with low titers, inhibitors can be overcome with higher doses of factor VIII. For patients with high titer inhibitors, alternate treatments should be used and may include porcine factor VIII, prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa. For patients undergoing elective surgical procedures, a multidisciplinary approach with preoperative planning and replacement is recommended.2 90 PART I BASIC CONSIDERATIONS partial albinism in the Hermansky-Pudlak syndrome. Bleeding is variable, depending on the severity of the granule defect. Bleeding is caused by the decreased release of ADP from these platelets. A few patients have been reported who have decreased numbers of both dense and α-granules. They have a more severe bleeding disorder. Patients with mild bleeding as a consequence of a form of storage pool disease can be treated with DDAVP. It is likely that the high levels of vWF in the plasma after DDAVP somehow compensate for the intrinsic platelet defect. With more severe bleeding, platelet transfusion is required. Acquired Hemostatic Defects Platelet Abnormalities Acquired abnormalities of platelets are much more common than acquired defects and may be quantitative or qualitative, although some patients have both types of defects. Quantitative defects may be a result of failure of production, shortened survival, or sequestration. Failure of production is generally a result of bone marrow disorders such as leukemia, myelodysplastic syndrome, severe vitamin B12 or folate deficiency, chemotherapeutic drugs, radiation, acute ethanol intoxication, or viral infection. If a quantitative abnormality exists and treatment is indicated either due to symptoms or the need for an invasive procedure, platelet transfusion is utilized. The etiologies of both qualitative and quantitative defects are reviewed in Table 4-1. Table 4-1 Etiology of platelet disorders A. Quantitative Disorders 1. Failure of production: related to impairment in bone marrow function a. Leukemia b. Myeloproliferative disorders c. B12 or folate deficiencies d. Chemotherapy or radiation therapy e. Acute alcohol intoxication f. Viral infections 2. Decreased survival a. Immune-mediated 1) Idiopathic thrombocytopenia (ITP) 2) Heparin-induced thrombocytopenia 3) Autoimmune disorders or B-cell malignancies 4) Secondary thrombocytopenia b. Disseminated intravascular coagulation (DIC) c. Related to platelet thrombi 1) Thrombocytopenic purpura (TTP) 2) Hemolytic uremic syndrome (HS) 3. Sequestration a. Portal hypertension b. Sarcoid c. Lymphoma d. Gaucher’s Disease B. Qualitative Disorders 1. Massive transfusion 2. Therapeutic platelet inhibitors 3. Disease states a. Myeloproliferative disorders b. Monoclonal gammopathies c. Liver disease Quantitative Defects. Shortened platelet survival is seen in immune thrombocytopenia, disseminated intravascular coagulation, or disorders characterized by platelet thrombi such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Immune thrombocytopenia may be idiopathic or associated with other autoimmune disorders or low-grade B-cell malignancies, and it may also be secondary to viral infections (including HIV) or drugs. Secondary immune thrombocytopenia often presents with a very low platelet count, petechiae and purpura, and epistaxis. Large platelets are seen on peripheral smear. Initial treatment consists of corticosteroids, intravenous gamma globulin, or anti-D immunoglobulin in patients who are Rh positive. Both gamma globulin and anti-D immunoglobulin are rapid in onset. Platelet transfusions are not usually needed unless central nervous system bleeding or active bleeding from other sites occurs. Survival of the transfused platelets is usually short. Primary immune thrombocytopenia is also known as idiopathic thrombocytopenic purpura (ITP). In children, it is usually acute in onset, short lived, and typically follows a viral illness. In contrast, ITP in adults is gradual in onset, chronic in nature, and has no identifiable cause. Because the circulating platelets in ITP are young and functional, bleeding is less for a given platelet count than when there is failure of platelet production. The pathophysiology of ITP is believed to involve both impaired platelet production and T cell–mediated platelet destruction.10 Management options are summarized in Table 4-2.11 Treatment of drug-induced immune thrombocytopenia may simply entail withdrawal of the offending drug, but corticosteroids, gamma globulin, and anti-D immunoglobulin may hasten recovery of the count. Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia. It is an immunologic event during which antibodies against platelet factor 4 (PF4) formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.12 The platelet count typically begins to fall 5 to 7 days after Table 4-2 Management of idiopathic thrombocytopenic purpura (ITP) in adults First Line a. Corticosteroids: The majority of patients respond but only a few long term b. Intravenous immunoglobulin (IVIG) or anti-D immunoglobulin: indicated for clinical bleeding Second Line. Required in most patients a. Splenectomy: open or laparoscopic. Criteria include severe thrombocytopenia, high risk of bleeding, and continued need for steroids. Failure may be due to retained accessory splenic tissue. b. Rituximab, an anti-CD 20 monoclonal antibody c. Thrombopoietin (TPO) receptor agonists such as romiplostim and eltrombopag Third Line. To be used after failure of splenectomy and rituximab a. TPO receptor agonists b. Immunosuppressive agents. For failure of TPO receptor agonists VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Qualitative Platelet Defects. Impaired platelet function often accompanies thrombocytopenia but may also occur in the presence of a normal platelet count. The importance of this is obvious when one considers that 80% of overall strength is related to platelet function. The life span of platelets ranges from 7 to 10 days, placing them at increased risk for impairment by medical disorders and prescription and over-the-counter medications. Impairment of ADP-stimulated aggregation occurs with 1 massive transfusion of blood products. Uremia may be associated with increased bleeding time and impaired aggregation. Defective aggregation and platelet dysfunction are also seen in patients with thrombocythemia, polycythemia vera, and myelofibrosis. Drugs that interfere with platelet function include aspirin, clopidogrel, prasugrel, dipyridamole, and GP IIb/IIIa inhibitors. Aspirin, clopidogrel, and prasugrel all irreversibly inhibit VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 91 Hemostasis, Surgical Bleeding, and Transfusion is frequently used, but it is not clear what etiologic factor is being removed by the pheresis. Sequestration is another important cause of thrombocytopenia and usually involves trapping of platelets in an enlarged spleen typically related to portal hypertension, sarcoid, lymphoma, or Gaucher’s disease. The total body platelet mass is essentially normal in patients with hypersplenism, but a much larger fraction of the platelets are in the enlarged spleen. Platelet survival is mildly decreased. Bleeding is less than anticipated from the count because sequestered platelets can be mobilized to some extent and enter the circulation. Platelet transfusion does not increase the platelet count as much as it would in a normal person because the transfused platelets are similarly sequestered in the spleen. Splenectomy is not indicated to correct the thrombocytopenia of hypersplenism caused by portal hypertension. Thrombocytopenia is the most common abnormality of hemostasis that results in bleeding in the surgical patient. The patient may have a reduced platelet count as a result of a variety of disease processes, as discussed earlier. In these circumstances, the marrow usually demonstrates a normal or increased number of megakaryocytes. By contrast, when thrombocytopenia occurs in patients with leukemia or uremia and in patients on cytotoxic therapy, there are generally a reduced number of megakaryocytes in the marrow. Thrombocytopenia also occurs in surgical patients as a result of massive blood loss with product replacement deficient in platelets. Thrombocytopenia may also be induced by heparin administration during cardiac and vascular cases, as in the case of HIT, or may be associated with thrombotic and hemorrhagic complications. When thrombocytopenia is present in a patient for whom an elective operation is being considered, management is contingent upon the extent and cause of platelet reduction. A count of greater than 50,000/μL generally requires no specific therapy. Early platelet administration has now become part of massive transfusion protocols.18,19 Platelets are also administered preoperatively to rapidly increase the platelet count in surgical patients with underlying thrombocytopenia. One unit of platelet concentrate contains approximately 5.5 × 1010 platelets and would be expected to increase the circulating platelet count by about 10,000/μL in the average 70-kg person. Fever, infection, hepatosplenomegaly, and the presence of antiplatelet alloantibodies decrease the effectiveness of platelet transfusions. In patients refractory to standard platelet transfusion, the use of human leukocyte antigen (HLA)-compatible platelets coupled with special processors has proved effective. CHAPTER 4 heparin has been started, but if it is a re-exposure, the decrease in count may occur within 1 to 2 days. HIT should be suspected if the platelet count falls to less than 100,000 or if it drops by 50% from baseline in a patient receiving heparin. While HIT is more common with full-dose unfractionated heparin (1%– 3%), it can also occur with prophylactic doses or with low molecular weight heparins. Interestingly, approximately 17% of patients receiving unfractionated heparin and 8% receiving low molecular weight heparin develop antibodies against PF4, yet a much smaller percentage develop thrombocytopenia and even fewer develop clinical HIT.13 In addition to the mild to moderate thrombocytopenia, this disorder is characterized by a high incidence of thrombosis that may be arterial or venous. Importantly, the absence of thrombocytopenia in these patients does not preclude the diagnosis of HIT. The diagnosis of HIT may be made by using either a serotonin release assay (SRA) or an enzyme-linked immunosorbent assay (ELISA). The SRA is highly specific but not sensitive, so a positive test supports the diagnosis but a negative test does not exclude HIT.12 On the other hand, the ELISA has a low specificity, so although a positive ELISA confirms the presence of anti-heparin-PF4, it does not help in the diagnosis of clinical HIT. A negative ELISA, however, essentially rules out HIT. The initial treatment of suspected HIT is to stop heparin and begin an alternative anticoagulant. Stopping heparin without addition of another anticoagulant is not adequate to prevent thrombosis in this setting. Alternative anticoagulants are primarily thrombin inhibitors. The most recent guideline by the American College of Chest Physicians recommends lepirudin, argatroban, or danaparoid for patients with normal renal function and argatroban for patients with renal insufficiency.14 Because of warfarin’s early induction of a hypercoagulable state, warfarin should be instituted only once full anticoagulation with an alternative agent has been accomplished and the platelet count has begun to recover. These are also disorders in which thrombocytopenia is a result of platelet activation and formation of platelet thrombi. In thrombotic thrombocytopenic purpura (TTP), large vWF molecules interact with platelets, leading to activation. These large molecules result from inhibition of a metalloproteinase enzyme, ADAMtS13, which cleaves the large vWF molecules.15 TTP is classically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal and neurologic signs or symptoms. The finding of schistocytes on a peripheral blood smear aids in the diagnosis. Plasma exchange with replacement of FFP is the treatment for acute TTP.16 Additionally, rituximab, a monoclonal antibody against the CD20 protein on B lymphocytes, has shown promise as an immunomodulatory therapy directed against patients with acquired TTP, of which the majority are autoimmune mediated.17 Hemolytic uremic syndrome (HUS) often occurs secondary to infection by Escherichia coli 0157:H7 or other Shiga toxin-producing bacteria. The metalloproteinase is normal in these cases. HUS is usually associated with some degree of renal failure, with many patients requiring renal replacement therapy. Neurologic symptoms are less frequent. A number of patients develop features of both TTP and HUS. This may occur with autoimmune diseases, especially systemic lupus erythematosus and HIV infection, or in association with certain drugs (such as ticlopidine, mitomycin C, gemcitabine) or immunosuppressive agents (such as cyclosporine and tacrolimus). Discontinuation of the involved drug is the mainstay of therapy. Plasmapheresis 92 PART I BASIC CONSIDERATIONS platelet function. Clopidogrel and prasugrel do so through selective irreversible inhibition of ADP-induced platelet aggregation.20 Aspirin works through irreversible acetylation of platelet prostaglandin synthase. There are no prospective randomized trials in general surgical patients to guide the timing of surgery in patients on aspirin, clopidogrel, or prasugrel.21 The general recommendation is that approximately 5 to 7 days should pass from the time the drug is stopped until an elective procedure is performed.22 Timing of urgent and emergent surgeries is even more unclear. Preoperative platelet transfusions may be beneficial, but there are no good data to guide their administration. However, new functional tests are becoming available that may better demonstrate defects in platelet function and may serve to guide the timing of operation or when platelet transfusions might be indicated. Other disorders associated with abnormal platelet function include uremia, myeloproliferative disorders, monoclonal gammopathies, and liver disease. In the surgical patient, platelet dysfunction of uremia can often be corrected by dialysis or the administration of DDAVP. Platelet transfusion may not be helpful if the patient is uremic when the platelets are given and only serve to increase antibodies. Platelet dysfunction in myeloproliferative disorders is intrinsic to the platelets and usually improves if the platelet count can be reduced to normal with chemotherapy. If possible, surgery should be delayed until the count has been decreased. These patients are at risk for both bleeding and thrombosis. Platelet dysfunction in patients with monoclonal gammopathies is a result of interaction of the monoclonal protein with platelets. Treatment with chemotherapy or, occasionally, plasmapheresis to lower the amount of monoclonal protein improves hemostasis. Acquired Hypofibrinogenemia Disseminated Intravascular Coagulation (DIC). DIC is an acquired syndrome characterized by systemic activation of coagulation pathways that result in excessive thrombin generation and the diffuse formation of microthrombi. This disturbance ultimately leads to consumption and depletion of platelets and coagulation factors with the resultant classic picture of diffuse bleeding. Fibrin thrombi developing in the microcirculation may cause microvascular ischemia and subsequent end-organ failure if severe. There are many different conditions that predispose a patient to DIC, and the presence of an underlying condition is required for the diagnosis. For example, injuries resulting in embolization of materials such as brain matter, bone marrow, or amniotic fluid can act as potent thromboplastins that activate the DIC cascade.23 Additional etiologies include malignancy, organ injury (such as severe pancreatitis), liver failure, certain vascular abnormalities (such as large aneurysms), snake bites, illicit drugs, transfusion reactions, transplant rejection, and sepsis.24 In fact, DIC frequently accompanies sepsis and may be associated with multiple organ failure. As of yet, scoring systems for organ failure do not routinely incorporate DIC. The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut et al who showed that activated protein C was effective in septic patients with DIC.25 The diagnosis of DIC is made based on an inciting etiology with associated thrombocytopenia, prolongation of the prothrombin time, a low fibrinogen level, and elevated fibrin markers (FDPs, D-dimer, soluble fibrin monomers). A scoring system developed by the International Society for Thrombosis and Hemostasis has been shown to have high sensitivity and specificity for diagnosing DIC as well as a strong correlation between an increasing DIC score and mortality, especially in patients with infections.26 The most important facets of treatment are relieving the patient’s causative primary medical or surgical problem and maintaining adequate perfusion. If there is active bleeding, hemostatic factors should be replaced with FFP, which is usually sufficient to correct the hypofibrinogenemia, although cryoprecipitate, fibrinogen concentrates, or platelet concentrates may also be needed. Given the formation of microthrombi in DIC, heparin therapy has also been proposed. Most studies, however, have shown that heparin is not helpful in acute forms of DIC, but may be indicated in cases where thrombosis predominates, such as arterial or venous thromboembolism and severe purpura fulminans. Primary Fibrinolysis. An acquired hypofibrinogenic state in the surgical patient can be a result of pathologic fibrinolysis. This may occur in patients following prostate resection when urokinase is released during surgical manipulation of the prostate or in patients undergoing extracorporeal bypass. The severity of fibrinolytic bleeding is dependent on the concentration of breakdown products in the circulation. Antifibrinolytic agents, such as ε-aminocaproic acid and tranexamic acid, interfere with fibrinolysis by inhibiting plasminogen activation. Myeloproliferative Diseases Polycythemia, or an excess of red blood cells, places surgical patients at risk. Spontaneous thrombosis is a complication of polycythemia vera, a myeloproliferative neoplasm, and can be explained in part by increased blood viscosity, increased platelet count, and an increased tendency toward stasis. Paradoxically, a significant tendency toward spontaneous hemorrhage also is noted in these patients. Thrombocytosis can be reduced by the administration of low-dose aspirin, phlebotomy, and hydroxyurea.27 Coagulopathy of Liver Disease The liver plays a key role in hemostasis because it is responsible for the synthesis of many of the coagulation factors (Table 4-3). Patients with liver disease, therefore, have decreased production of several key non-endothelial cell-derived coagulation factors as well as natural anticoagulant proteins, causing a disturbance in the balance between procoagulant and anticoagulant pathways. This disturbance in coagulation mechanisms causes a complex paradigm of both increased bleeding risk and increased thrombotic risk. The most common coagulation abnormalities Table 4-3 Coagulation factors synthesized by the liver Vitamin K–dependent factors: II (prothrombin factor), VII, IX, X Fibrinogen Factor V Factor VIII Factors XI, XII, XIII Antithrombin III Plasminogen Protein C and protein S VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Coagulopathy of Trauma Traditional teaching regarding trauma-related coagulopathy attributed its development to acidosis, hypothermia, and dilution of coagulation factors. Recent data, however, have shown that over one third of injured patients have evidence of coagulopathy at the time of admission.36 More importantly, patients 2 arriving with coagulopathy are at a significantly higher risk of mortality, especially in the first 24 hours after injury. In light of these findings, a dramatic increase in research focused on the optimal management of the acute coagulopathy of trauma (ACoT) has been observed over the past several years. ACoT is not a simple dilutional coagulopathy but a complex problem with multiple mechanisms.37 Whereas multiple contributing factors exist, the key initiators to the process of ACoT are shock and tissue injury. ACoT is a separate and distinct process from DIC, with its own specific components of hemostatic failure. Brohi et al have demonstrated that only patients in shock arrive coagulopathic and that it is the shock that induces coagulopathy through systemic activation of anticoagulant and fibrinolytic pathways.38 As shown in Fig. 4-5, hypoperfusion causes activation of TM on the surface of endothelial cells. Thrombin-TM complexes induce an anticoagulant state through activation of protein C and enhancement of fibrinolysis. This same complex also limits the availability of thrombin to cleave fibrinogen to fibrin, which may explain why injured patients rarely have low levels of fibrinogen. Acquired Coagulation Inhibitors Among the most common acquired coagulation inhibitors is the antiphospholipid syndrome (APLS), which includes the lupus anticoagulant and anticardiolipin antibodies. These antibodies may be associated with either venous or arterial thrombosis, or both. In fact, patients presenting with recurrent thrombosis should be evaluated for APLS. Antiphospholipid antibodies are very common in patients with systemic lupus but may also be seen in association with rheumatoid arthritis and Sjögren’s syndrome. There are also individuals who will have no autoimmune disorders but develop transient antibodies in response to infections or those who develop drug-induced APLS. The hallmark of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 93 Hemostasis, Surgical Bleeding, and Transfusion mixed following insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Therefore, treatment of thrombocytopenia should not be the primary indication for a TIPS procedure. Decreased production or increased destruction of coagulation factors as well as vitamin K deficiency can all contribute to a prolonged PT and INR in patients with liver disease. As liver dysfunction worsens, so does the liver’s synthetic function, which results in decreased production of coagulation factors. Additionally, laboratory abnormalities may mimic those of DIC. Elevated D-dimers have been reported to increase the risk of variceal bleeding. The absorption of vitamin K is dependent on bile production. Therefore, liver patients with impaired bile production and cholestatic disease may be at risk for vitamin K deficiency. Similar to thrombocytopenia, correction of coagulopathy should be reserved for treatment of active bleeding and prophylaxis for invasive procedures and surgery. Treatment of coagulopathy caused by liver disease is usually done with FFP, but because the coagulopathy is usually not a result of decreased levels of factor V, complete correction is not usually possible. If the fibrinogen is less than 200 mg/dL, administration of cryoprecipitate may be helpful. Cryoprecipitate is also a source of factor VIII for the rare patient with a low factor VIII level. CHAPTER 4 associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolongation of the prothrombin time and international normalized ratio (INR). The etiology of thrombocytopenia in patients with liver disease is typically related to hypersplenism, reduced production of thrombopoietin, and immune-mediated destruction of platelets. The total body platelet mass is often normal in patients with hypersplenism, but a much larger fraction of the platelets is sequestered in the enlarged spleen. Bleeding may be less than anticipated because sequestered platelets can be mobilized to some extent and enter the circulation. Thrombopoietin, the primary stimulus for thrombopoiesis, may be responsible for some cases of thrombocytopenia in cirrhotic patients, although its role is not well delineated. Finally, immune-mediated thrombocytopenia may also occur in cirrhotics, especially those with hepatitis C and primary biliary cirrhosis.28 In addition to thrombocytopenia, these patients also exhibit platelet dysfunction via defective interactions between platelets and the endothelium, and possibly due to uremia and changes in endothelial function in the setting of concomitant renal insufficiency. Hypocoagulopathy is further exacerbated with low platelet counts because platelets help facilitate thrombin generation by assembling coagulation factors on their surfaces. In conditions mimicking intravascular flow, low hematocrit and low platelet counts contributed to decreased adhesion of platelets to endothelial cells, although increased vWF, a common finding in cirrhotic patients, may offset this change in patients with cirrhosis.29 Hypercoagulability of liver disease has recently gained increased attention, with more evidence demonstrating the increased incidence of thromboembolism despite thrombocytopenia and a hypocoagulable state on conventional blood tests.30,31 This is attributed to decreased production of liver-synthesized proteins C and S, antithrombin, and plasminogen levels, as well as elevated levels of endothelial-derived vWF and factor VIII, a potent driver of thrombin generation.32,33 Given the concomitant hypo- and hypercoagulable features seen in patients with liver disease, conventional coagulation tests may be difficult to interpret, and alternative tests such as thromboelastography (TEG) may be more informative of the functional status of clot formation and stability in cirrhotic patients. Several studies imply that TEG provides a better assessment of bleeding risk than standard tests of hemostasis in patients with liver disease; however, no studies have directly tested this, and future prospective trials are needed.34 Before instituting any therapy to ameliorate thrombocytopenia, the actual need for correction should be strongly considered. In general, correction based solely on a low platelet count should be discouraged. Most often, treatment should be withheld for invasive procedures and surgery. Platelet transfusions are the mainstay of therapy; however, the effect typically lasts only several hours. Risks associated with transfusions in general and the development of antiplatelet antibodies in a patient population likely to need recurrent correction should be considered. A potential alternative strategy involves administration of interleukin-11 (IL-11), a cytokine that stimulates proliferation of hematopoietic stem cells and megakaryocyte progenitors.26 Most studies using IL-11 have been in cancer patients, although some evidence exists that it may be beneficial in cirrhotics as well. Significant side effects limit its usefulness.35 A less well-accepted option is splenectomy or splenic embolization to reduce hypersplenism. In addition to the risks associated with these techniques, reduced splenic blood flow can reduce portal vein flow with subsequent portal vein thrombosis. Results are 94 Table 4-4 Central role of thrombomodulin in acute traumatic coagulopathy (ATC) Medications that can alter warfarin dosing Barbiturates, oral contraceptives, ↓ warfarin effect ↑ warfarin requirements estrogen-containing compounds, corticosteroids, adrenocorticotropic hormone Shock PART I Hypoperfusion Thrombin ↑ Thrombomodulin BASIC CONSIDERATIONS Maintains fibrinogen level Thrombomodulin/ Thrombin complex ActivationTAFI Activation of protein C PAI-1 Consumption Fibrinolysis ATC Figure 4-5. Illustration of the pathophysiologic mechanism responsible for the acute coagulopathy of trauma. PAI-1 = plasminogen activator inhibitor 1; TAFI = thrombin-activatable fibrinolysis inhibitor. APLS is a prolonged aPTT in vitro but an increased risk of thrombosis in vivo. Anticoagulation and Bleeding Spontaneous bleeding can be a complication of any anticoagulant therapy whether it is heparin, low molecular weight heparins, warfarin, factor Xa inhibitors, or new direct thrombin inhibitors. The risk of spontaneous bleeding related to heparin is reduced with a continuous infusion technique. Therapeutic anticoagulation is more reliably achieved with a low molecular weight heparin. However, laboratory testing is more challenging with these medications, as they are not detected with conventional coagulation testing. However, their more reliable therapeutic levels (compared to heparin) make them an attractive option for outpatient anticoagulation and more cost-effective for the inpatient setting. If monitoring is required (e.g., in the presence of renal insufficiency or severe obesity), the drug effect should be determined with an assay for anti-Xa activity. Warfarin is used for long-term anticoagulation in various clinical conditions including deep vein thrombosis, pulmonary embolism, valvular heart disease, atrial fibrillation, recurrent systemic emboli, recurrent myocardial infarction, prosthetic heart valves, and prosthetic implants. Due to the interaction of the P450 system, the anticoagulant effect of the warfarin is reduced (e.g., increases dose required) in patients receiving barbiturates as well as in patients with diets low in vitamin K. Increased warfarin requirements may also be needed in patients taking contraceptives or estrogen-containing compounds, corticosteroids, and adrenocorticotropic hormone (ACTH). Medications that can alter warfarin requirements are shown in Table 4-4. Although warfarin use is often associated with a significant increase in morbidity and mortality in acutely injured and emergency surgery patients, with rapid reversal, these complications Phenylbutazone, clofibrate, ↑ warfarin effect ↓ warfarin requirements anabolic steroids, L-thyroxine, glucagons, amiodarone, quinidine, cephalosporins can be dramatically reduced. There are several reversal options that include vitamin K administration, plasma, cryoprecipitate, recombinant factor VIIa, and factor concentrates. Urgent reversal for life-threatening bleeding should include vitamin K and a rapid reversal agent such as plasma or prothrombin complex concentrate. In the elderly or those with intracranial hemorrhage, concentrates are preferred, whereas in situations with hypovolemia from hemorrhage, plasma should be used. Newer anticoagulants like dabigatran and rivaroxaban have no readily available method of detection of the degree of anticoagulation. More concerning is the absence of any 3 available reversal agent. Unlike warfarin, the nonreversible coagulopathy associated with dabigatran and rivaroxaban is of great concern to those providing emergent care to these patients.39 The only possible strategy to reverse the coagulopathy associated with dabigatran may be emergent dialysis. Unfortunately, the ability to rapidly dialyze the hemodynamically unstable bleeding patient or rapidly dialyze the anticoagulated patient with an intracranial bleed is challenging even at large medical centers. Recent data suggest that rivaroxaban, however, may be reversed with the use of prothrombin complex concentrates (four-factor concentrates only: II, VII, IX, and X).40 In less urgent states, these drugs can be held for 36 to 48 hours prior to surgery without increased risk of bleeding in those with normal renal function. Alternatively, activated clotting time (stand alone or with rapid TEG) or ecarin clotting time can be obtained in those on dabigatran, and anti-factor Xa assays can be obtained in those taking rivaroxaban. Bleeding complications in patients on anticoagulants include hematuria, soft tissue bleeding, intracerebral bleeding, skin necrosis, and abdominal bleeding. Bleeding secondary to anticoagulation therapy is also not an uncommon cause of a rectus sheath hematomas. In most of these cases, reversal of anticoagulation is the only treatment that is necessary. Lastly, it is important to remember that symptoms of an underlying tumor may first present with bleeding while on anticoagulation. Surgical intervention may prove necessary in patients receiving anticoagulation therapy. Increasing experience suggests that surgical treatment can be undertaken without full reversal of the anticoagulant, depending on the procedure being performed.41 When the aPTT is less than 1.3 times control in a heparinized patient or when the INR is less than 1.5 in a patient on warfarin, reversal of anticoagulation therapy may not be necessary. However, meticulous surgical technique is mandatory, and the patient must be observed closely throughout the postoperative period. Certain surgical procedures should not be performed in concert with anticoagulation. In particular, cases where even VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Local Hemostasis. Significant surgical bleeding is usually caused by ineffective local hemostasis. The goal is therefore to prevent further blood loss from a disrupted vessel that has been incised or transected. Hemostasis may be accomplished by interrupting the flow of blood to the involved area or by direct closure of the blood vessel wall defect. Mechanical Procedures. The oldest mechanical method of bleeding cessation is application of direct digital pressure, either at the site of bleeding or proximally to permit more definitive action. An extremity tourniquet that occludes a major vessel proximal to the bleeding site or the Pringle maneuver for liver bleeding are good examples. Direct digital pressure is very effective and has the advantage of being less traumatic than hemostatic or even “atraumatic” clamps. When a small vessel is transected, a simple ligature is usually sufficient. However, for larger pulsating arteries, a transfixion suture to prevent slipping is indicated. All sutures represent foreign material, and selection should be based on their intrinsic characteristics and the state of the wound. Direct pressure applied by “packing” a wound with gauze or laparotomy pads affords the best method of controlling diffuse bleeding from large areas, such as in the trauma situation. Packing bone wax on the raw surface to effect pressure can control bleeding from cut bone. Thermal Agents. Heat achieves hemostasis by denaturation of protein that results in coagulation of large areas of tissue. Electrocautery generates heat by induction from an alternating current source, which is then transmitted via conduction from the instrument directly to the tissue. The amplitude setting should be high enough to produce prompt coagulation, but not so high as to set up an arc between the tissue and the cautery tip. This avoids thermal injury outside of the operative field and also prevents exit of current through electrocardiographic leads, other monitoring devices, or permanent pacemakers or defibrillators. A negative grounding plate should be placed beneath the patient to avoid severe skin burns, and caution should be used with certain anesthetic agents (diethyl ether, divinyl ether, ethyl chloride, ethylene, and cyclopropane) because of the hazard of explosion. A direct current also can result in hemostasis. Because the protein moieties and cellular elements of blood have a negative surface charge, they are attracted to a positive pole where a thrombus is formed. Direct currents in the 20- to 100-mA range have successfully controlled diffuse bleeding from raw surfaces, as has argon gas. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 95 Hemostasis, Surgical Bleeding, and Transfusion accepted transfusion thresholds. Platelet concentrates are given for bleeding patients in the immediate postoperative period; however, studies have shown that indiscriminate platelet therapy conferred no therapeutic advantage.46 It is in these patients where rapid coagulation testing is required to assist with directed transfusion therapy.47 Many institutions now use antifibrinolytics, such as ε-aminocaproic acid and tranexamic acid, at the time of anesthesia induction after several studies have shown that such treatment reduced postoperative bleeding and reoperation. Aprotinin, a protease inhibitor that acts as an antifibrinolytic agent, has been shown to reduce transfusion requirements associated with cardiac surgery.48 Desmopressin acetate stimulates release of factor VIII from endothelial cells and may also be effective in reducing blood loss during cardiac surgery. The use of recombinant factor VIIa has also been studied but with conflicting results between improved hemostasis and thrombotic events and mortality, and thus its use is often employed only as a measure of last resort.45,49 CHAPTER 4 minor bleeding can cause great morbidity, such as the central nervous system and the eye, surgery should be avoided. Emergency operations are occasionally necessary in patients who have been heparinized. The first step in these patients is to discontinue heparin. For more rapid reversal, protamine sulfate is effective. However, significant adverse reactions, especially in patients with severe fish allergies, may be encountered when administering protamine.42 Symptoms include hypotension, flushing, bradycardia, nausea, and vomiting. Prolongation of the aPTT after heparin neutralization with protamine may also be a result of the anticoagulant effect of protamine. In the elective surgical patient who is receiving coumarin-derivative therapy sufficient to effect anticoagulation, the drug can be discontinued several days before operation and the prothrombin concentration then checked (a level >50% is considered safe).43 Rapid reversal of anticoagulation can be accomplished with plasma or prothrombin complex concentrates in the emergent situation. Parenteral administration of vitamin K also is indicated in elective surgical treatment of patients with biliary obstruction or malabsorption who may be vitamin K deficient. However, if low levels of factors II, VII, IX, and X (vitamin K–dependent factors) exist as a result of hepatocellular dysfunction, vitamin K administration is ineffective. The perioperative management of patients receiving longterm oral anticoagulation therapy is an increasingly common problem. Definitive evidence-based guidelines regarding 4 which patients require perioperative “bridging” anticoagulation and the most effective way to bridge are lacking. However, the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines do serve as best practice for these situations.44 A few clinical scenarios exist where the patient should be transitioned to intravenous heparin from oral anticoagulants. A heparin infusion should be held for 4 to 6 hours before the procedure and restarted within 12 to 24 hours of the end of its completion. The primary indication for this level of aggressiveness is patients with mechanical heart valves. Other indications include a recent (within 30 days) myocardial infarction, stroke, or pulmonary embolism. Situations such as thromboembolic events greater than 30 days prior, hypercoagulable history, and atrial fibrillation do not require such stringent restarting strategies. Cardiopulmonary Bypass. Under normal conditions, homeostasis of the coagulation system is maintained by complex interactions between the endothelium, platelets, and coagulation factors. In patients undergoing cardiopulmonary bypass (CPB), contact with circuit tubing and membranes results in abnormal platelet and clotting factor activation, as well as activation of inflammatory cascades, that ultimately result in excessive fibrinolysis and a combination of both quantitative and qualitative platelet defects. Platelets undergo reversible alterations in morphology and their ability to aggregate, which causes sequestration in the filter, partially degranulated platelets, and platelet fragments. This multifactorial coagulopathy is compounded by the effects of shear stress in the system, induced hypothermia, hemodilution, and anticoagulation.45 While on pump, activated clotting time measurements are obtained along with blood gas measurements; however, conventional coagulation assays and platelet counts are not normally performed until rewarming and after a standard dose of protamine has been given. TEG may give a better estimate of the extent of coagulopathy and may also be used to anticipate transfusion requirements if bleeding is present.45 Empiric treatment with FFP and cryoprecipitate is often used for bleeding patients; however, there are no universally 96 PART I BASIC CONSIDERATIONS Topical Hemostatic Agents. Topical hemostatic agents can play an important role in helping to facilitate surgical hemostasis. These agents are classified based on their mechanism of action, and many act at specific stages in the coagulation cascade and take advantage of natural physiologic responses to bleeding.50 The ideal topical hemostatic agent has significant hemostatic action, minimal tissue reactivity, nonantigenicity, in vivo biodegradability, ease of sterilization, low cost, and can be tailored to specific needs.51 In 2010, Achneck et al published a comprehensive overview of absorbable, biologic, and synthetic agents.52 Absorbable agents include gelatin foams (Gelfoam), oxidized cellulose (Surgicel), and microfibrillar collagens (Avitene). Both gelatin foam and oxidized cellulose provide a physical matrix for clotting initiation, while microfibrillar collagens facilitate platelet adherence and activation. Biologic agents include topical thrombin, fibrin sealants (FloSeal), and platelet sealants (Vitagel). Human or recombinant thrombin derivatives, which facilitate the formation of fibrin clots and subsequent activation of several clotting factors, take advantage of natural physiologic processes, thereby avoiding foreign body or inflammatory reactions.51 Caution must be taken in judging vessel caliber in the wound because thrombin entry into larger caliber vessels can result in systemic exposure to thrombin with a risk of disseminated intravascular clotting or death. They are particularly effective in controlling capillary bed bleeding when pressure or ligation is insufficient; however, the bovine derivatives should be used with caution due to the potential immunologic response and worsened coagulopathy. Fibrin sealants are prepared from cryoprecipitate (homologous or synthetic) and have the advantage of not promoting inflammation or tissue necrosis.53 Platelet sealants are a mixture of collagen and thrombin combined with plasma-derived fibrinogen and platelets from the patient, which requires the additional need for centrifugation and processing. Topical agents are not a substitute for meticulous surgical technique and only function as adjuncts to help facilitate surgical hemostasis. The advantages and disadvantages of each agent must be considered, and use should be limited to the minimum amount necessary to minimize toxicity, adverse reactions, interference with wound healing, and procedural costs. TRANSFUSION Background Human blood replacement therapy was accepted in the late nineteenth century. This was followed by the introduction of blood grouping by Landsteiner who identified the major A, B, and O groups in 1900, resulting in widespread use of blood products in World War I. Levine and Stetson in 1939 followed with the concept of Rh grouping. These breakthroughs established the foundation from which the field of transfusion medicine has grown. Whole blood was considered the standard in transfusion until the late 1970s when component therapy began to take prominence. This change in practice was made possible by the development of improved collection strategies, infectious disease testing, and advances in preservative solutions and storage. Replacement Therapy Typing and Cross-Matching. Serologic compatibility for A, B, O, and Rh groups is established routinely. Cross-matching between the donors’ red blood cells and the recipients’ sera (the major cross-match) is performed. Rh-negative recipients should be transfused only with Rh-negative blood. However, this group represents only 15% of the population. Therefore, the administration of Rh-positive blood is acceptable if Rh-negative blood is not available. However, Rh-positive blood should not be transfused to Rh-negative females who are of child-bearing age. In emergency situations, type O-negative blood may be transfused to all recipients. O-negative and type-specific red blood cells are equally safe for emergency transfusion. Problems are associated with the administration of four or more units of O-negative blood because there is a significant increase in the risk of hemolysis. In patients with clinically significant cold agglutinins, blood should be administered through a blood warmer. If these antibodies are present in high titer, hypothermia is contraindicated. In patients who have been multiply transfused and who have developed alloantibodies or who have autoimmune hemolytic anemia with pan-red blood cell antibodies, typing and cross-matching is often difficult, and sufficient time should be allotted preoperatively to accumulate blood that might be required during the operation. Cross-matching should always be performed before the administration of dextran because it interferes with the typing procedure. The use of autologous transfusion is growing. Up to 5 units can be collected for subsequent use during elective procedures. Patients can donate and store their own blood if their hemoglobin concentration exceeds 11 g/dL or if the hematocrit is greater than 34%. The first procurement is performed 40 days before the planned operation, and the last one is performed 3 days before the operation. Donations can be scheduled at intervals of 3 to 4 days. Recombinant human erythropoietin (rHuEPO) accelerates generation of red blood cells and allows for more frequent harvesting of blood. Banked Whole Blood. Once the gold standard, whole blood is rarely available in Western countries. With sequential changes in storage solutions, the shelf life of red blood cells is now 42 days. Recent evidence has demonstrated that the age of red cells may play a significant role in the inflammatory response and incidence of multiple organ failure.54 The changes in the red blood cells that occur during storage include reduction of intracellular ADP and 2,3-diphosphoglycerate (2,3DPG), which alters the oxygen dissociation curve of hemoglobin, resulting in a decrease in oxygen transport. Stored RBCs progressively becomes acidodic with elevated levels of lactate, potassium, and ammonia. Red Blood Cells and Frozen Red Blood Cells. Red blood cells are the product of choice for most clinical situations requiring resuscitation. Concentrated suspensions of red blood cells can be prepared by removing most of the supernatant plasma after centrifugation. The preparation reduces but does not eliminate reactions caused by plasma components. Frozen red blood cells are not currently available for use in emergencies, as the thawing and preparation time is measured in hours. They are used for patients who are known to have been previously sensitized. The red blood cell viability is improved, and the ATP and 2,3-DPG concentrations are maintained. Leukocyte-Reduced and Leukocyte-Reduced/Washed Red Blood Cells. These products are prepared by filtration that removes about 99.9% of the white blood cells and most of the platelets (leukocyte-reduced red blood cells) and, if necessary, by additional saline washing (leukocyte-reduced/washed red blood cells). Leukocyte reduction prevents almost all febrile, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fresh Frozen Plasma. Fresh frozen plasma (FFP) prepared from freshly donated blood is the usual source of the vitamin K-dependent factors and is the only source of factor V. FFP carries similar infectious risks as other component therapies. Use of plasma as a primary resuscitation modality in patients who are rapidly bleeding has received attention over the last few years, and ongoing studies are under way to evaluate this concept. FFP can be thawed and stored for up to 5 days, greatly increasing its immediate availability. In an effort to increase the shelf life and avoid the need for refrigeration, lyophilized plasma is being tested. Preliminary animal studies suggest that it preserves the beneficial effects of FFP.59 Concentrates and Recombinant DNA Technology. Technologic advancements have made the majority of clotting factors and albumin readily available as concentrates. These products are readily available and carry none of the inherent infectious risks as other component therapies. Tranexamic Acid. Tranexamic acid (TXA; trade name: Cyklokapron), an antifibrinolytic agent, has been used to decrease bleeding and the need for blood transfusions in coronary artery bypass grafting (CABG), orthotopic liver transplantation, hip and knee arthroplasty, and other surgical settings. The safety and efficacy of using TXA to treat trauma patients was recently evaluated in a large randomized, placebo-controlled clinical trial.60 In this trial, 20,211 adult trauma patients in 274 hospitals in 40 countries with significant hemorrhage (heart rate >110 beats per minute and systolic blood pressure <90 mmHg or both) or judged to be at risk for significant hemorrhage were randomized to either TXA or placebo administered as a loading dose of 1 g over 10 minutes followed by an infusion of 1 g over 8 hours. It is important to understand that the responsible physician did not randomize patients with either a clear indication or a clear contraindication to TXA. The overall mortality rate in the cohort studied was 15.3%, of whom 35.3% died on the day of randomization. A total of 1063 patients died due to Indications for Replacement of Blood and Its Elements Improvement in Oxygen-Carrying Capacity. Oxygencarrying capacity is primarily a function of the red blood cells. Thus, transfusion of red blood cells should augment oxygencarrying capacity. Additionally, hemoglobin is fundamental to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 97 Hemostasis, Surgical Bleeding, and Transfusion Platelet Concentrates. The indications for platelet transfusion include thrombocytopenia caused by massive blood loss and replacement with platelet-poor products, thrombocytopenia caused by inadequate production, and qualitative platelet disorders. The shelf life of platelets is 120 hours from time of donation. One unit of platelet concentrate has a volume of approximately 50 mL. Platelet preparations are capable of transmitting infectious diseases and can account for allergic reactions similar to those caused by red blood cell transfusion. A therapeutic level of platelets is in the range of 50,000 to 100,000/μL but is very dependent on the clinical situation. Recent evidence suggests that earlier use of platelets may improve outcomes in bleeding patients.58 In rare cases, in patients who become alloimmunized through previous transfusion or patients who are refractory from sensitization through prior pregnancies, HLA-matched platelets can be used. hemorrhage, and the majority died on the day of randomization. The authors reported that TXA use resulted in a statistically significant reduction in the relative risk (RR) of all-cause mortality of 9% (14.5 vs. 16.0%, RR 0.91, confidence interval [CI] 0.85–0.97; P = .0035). A recent post hoc analysis of the CRASH-2 data showed that the greatest benefit of TXA administration occurred when patients received the medication soon after injury.61 In this analysis, TXA given between 1 and 3 hours after trauma reduced the risk of death due to bleeding by 21% (147/3037 [4.8%] vs. 184/2996 [6.1%], RR 0.79, CI 0.64–0.97; P = .03). Treatment given after 3 hours increased the risk of death due to bleeding (144/3272 [4.4%] vs. 103/3362 [3.1%], RR 1.44, CI 1.12–1.84; P = .004). Finally, a recent meta-analysis reported that TXA is effective for preventing blood loss in surgery and reducing transfusion and was not associated with increased vascular occlusive events.62 Adverse events associated with TXA use have been reported. These include acute gastrointestinal disturbances (nausea, vomiting, and diarrhea, generally dose-related), visual disturbances (blurry vision and changes in color perception, especially with prolonged use), and occasional thromboembolic events (e.g., deep venous thrombosis and pulmonary embolism, generally observed in the setting of active intravascular clotting). Its use is thus contraindicated in the settings of acquired defective color vision and active intravascular clotting. TXA should be used with caution in the setting of urinary tract bleeding because ureteral obstruction due to clotting has been reported. TXA is contraindicated in patients with aneurysmal subarachnoid hemorrhage; however, there have been no reported complications associated with intra- or extracranial hemorrhage associated with trauma. TXA should not be given with activated prothrombin complex concentrate or factor IX complex concentrates because these may increase the risk of thrombosis. TXA is an antifibrinolytic that inhibits both plasminogen activation and plasmin activity, thus preventing clot breakdown rather than promoting new clot formation. TXA is an inhibitor of plasminogen activation and an inhibitor of plasmin activity. It occupies the lysine binding sites on plasminogen, thus preventing its binding to lysine residues on fibrin. This reduces plasminogen activation to plasmin. Similarly, blockade of lysine-binding sites on circulating plasmin prevents binding to fibrin and thus prevents clot breakdown. TXA is 10 times more potent in vitro than aminocaproic acid. At therapeutically relevant concentrations, TXA does not affect platelet count or aggregation or coagulation parameters. It is excreted largely unchanged in urine and has a half-life of about 2 hours in circulation. While prolonged use requires that dosing be adjusted for renal impairment, use in the acute trauma situation does not appear to require adjustment. No adjustment is needed for hepatic impairment. Based on the CRASH-2 trial, TXA is becoming more widely used in the United States for patients with ongoing bleeding, especially those with documented evidence of fibrinolysis. Careful analysis of recently ongoing trials will further elucidate the safety profile of this powerful drug.63 CHAPTER 4 nonhemolytic transfusion reactions (fever and/or rigors), alloimmunization to HLA class I antigens, and platelet transfusion refractoriness and cytomegalovirus transmission. In most Western nations, it is the standard red blood cell transfusion product. Supporters of universal leukocyte reduction argue that allogenic transfusion of white cells predisposes to postoperative bacterial infection and multiorgan failure. Reviews of randomized trials and meta-analyses have not provided convincing evidence either way,55,56 although a large Canadian retrospective study suggests a decrease in mortality and infections.57 98 PART I arterial oxygen content and thus oxygen delivery. Despite this obvious association, there is little evidence that actually supports the premise that transfusion of red blood cells equates with enhanced cellular delivery and utilization. The reasons for this apparent discrepancy are related to changes that occur with storage of blood. The decrease in 2,3-DPG and P50 impair oxygen offloading, and deformation of the red cells impairs microcirculatory perfusion.64 Treatment of Anemia: Transfusion Triggers. A 1988 BASIC CONSIDERATIONS National Institutes of Health Consensus Report challenged the dictum that a hemoglobin value of less than 10 g/dL or a hematocrit level less than 30% indicates a need for preoperative red blood cell transfusion. This was verified in a prospective randomized controlled trial in critically ill patients that compared a restrictive transfusion threshold to a more liberal strategy and demonstrated that maintaining hemoglobin levels between 7 and 9 g/dL had no adverse effect on mortality. In fact, patients with APACHE II scores of ≤20 or patients age <55 years actually had a lower mortality.65 Despite these results, change in daily clinical practice has been slow. Critically ill patients still frequently receive transfusions, with the pretransfusion hemoglobin approaching 9 g/dL in a recent large observational study.66 This outdated approach unnecessarily exposes patients to increased risk and little benefit. One unresolved issue related to transfusion triggers is the safety of maintaining a hemoglobin of 7 g/dL in a patient with ischemic heart disease. Data on this subject are mixed, and many studies have significant design flaws, including their retrospective nature. However, the majority of the published data favors a restrictive transfusion trigger for patients with non-ST elevation acute coronary syndrome, with many reporting worse outcomes in those patients receiving transfusions.67,68 Volume Replacement The most common indication for blood transfusion in surgical patients is the replenishment of the blood volume; however, a deficit is difficult to evaluate. Measurements of hemoglobin or hematocrit levels are frequently used to assess blood loss. These measurements can be occasionally misleading in the face of acute loss. Both the amount and the rate of bleeding are factors in the development of signs and symptoms of blood loss. Loss of blood in the operating room can be roughly evaluated by estimating the amount of blood in the wound and on the drapes, weighing the sponges, and quantifying blood suctioned from the operative field. In patients with normal preoperative values, blood loss up to 20% of total blood volume can be replaced with crystalloid or colloid solutions. Blood loss above this value may require the addition of a balanced resuscitation including red blood cells, FFP, and platelets (detailed later in this chapter) (Table 4-5). New Concepts in Resuscitation Traditional resuscitation algorithms are sequentially based on crystalloid followed by red blood cells and then plasma and platelet transfusions and have been in widespread use since the 1970s. No quality clinical data supported this concept. Recently the damage control resuscitation (DCR) strategy, aimed at halting and/or preventing rather than treating the lethal triad of coagulopathy, acidosis, and hypothermia, has challenged traditional thinking on early resuscitation strategies.69 Rationale. In civilian trauma systems, nearly half of all deaths happen before a patient reaches the hospital, and many are nonpreventable.70 Patients who survive to an emergency center have a high incidence of truncal hemorrhage, and deaths in this group of patients may be potentially preventable. Truncal hemorrhage patients in shock often present with the early coagulopathy of trauma in the emergency department and are at significant risk of dying.71-73 Many of these patients have suffered substantial bleeding and may receive a significant transfusion, generally defined as the administration of ≥4 to 6 units of red blood cells within 4 to 6 hours of admission. This definition is admittedly arbitrary. Although 25% of all trauma admissions receive a unit of blood early after admission, only a small percentage of patients receive a massive transfusion. In the military setting, the percentage of massive transfusion patients almost doubles.74 Damage Control Resuscitation. Standard advanced trauma life support guidelines start resuscitation with crystalloid, followed by packed red blood cells.75 Only after several liters of crystalloid have been transfused does transfusion of units of plasma or platelets begin. This conventional massive transfusion practice was based on a several small uncontrolled retrospective studies that used blood products containing increased amounts of plasma, which are no longer available.76 Because of the known early coagulopathy of trauma, the current approach to managing the exsanguinating patient involves early implementation of damage control resuscitation 5 (DCR). Although most of the attention to hemorrhagic shock resuscitation has centered on higher ratios of plasma and platelets, DCR is actually composed of three basic components: permissive hypotension, minimizing crystalloid-based resuscitation, and the immediate release and administration of predefined blood products (red blood cells, plasma, and platelets) in ratios similar to those of whole blood. In Iraq and Afghanistan, DCR practices are demonstrating unprecedented success with improved overall survival.77 Civilian data also suggest that a balanced resuscitation approach yields improved outcome in severely injured and bleeding trauma patients.69 To verify military and single-institution civilian data on DCR, a multicenter retrospective study of modern transfusion practice at 17 leading civilian trauma centers was performed.78 It was found that plasma:platelet:red blood cell ratios varied from 1:1:1 to 0.3:0.1:1, with corresponding survival rates ranging from 71% to 41%. A significant center effect was seen, documenting wide variation in both transfusion practice and outcomes between Level 1 trauma centers. This variation correlated with blood product ratios. Increased plasma- and platelet-to-RBC ratios significantly decreased truncal hemorrhagic death and 30-day mortality without a concomitant increase in multiple organ failure as a cause of death. A prospective observational study evaluating current transfusion practice at 10 Level 1 centers was recently published, again documenting the wide variability in practice and improved outcomes with earlier use of increased ratios of plasma and platelets.79 Patients receiving ratios less than 1:2 were four times more likely to die than patients with ratios of 1:1 or higher. Regardless of the optimal ratio, it is essential that the trauma center has an established mechanism to deliver these products quickly and in the correct amounts to these critically injured patients. In fact, several authors have shown that a well-developed massive transfusion protocol is associated with improved outcomes independent of the ratios chosen.80 This aggressive delivery of predefined blood products should begin prior to any laboratory-defined anemia or coagulopathy. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 4-5 Replacement of clotting factors Factor Normal Level Life Span In Vivo (Half-Life) Fate during Coagulation Level Required for Safe Hemostasis Ideal Agent ACD Bank Ideal Agent for Blood (4°C [39.2°F]) Replacing Deficit I (fibrinogen) 200–400 mg/100 mL 72 h Consumed 60–100 mg/100 mL Very stable Bank blood; concentrated fibrinogen II (prothrombin) 20 mg/100 mL (100% of normal level) 72 h Consumed 15%–20% Stable Bank blood; concentrated preparation V (proaccelerin, accelerator globulin, labile factor) 100% of normal level 36 h Consumed 5%–20% Labile (40% of normal level at 1 wk) Fresh frozen plasma; blood under 7 d VII (proconvertin, serum prothrombin conversion accelerator, stable factor) 100% of normal level 5h Survives 5%–30% Stable Bank blood; concentrated preparation VIII (antihemophilic factor, antihemophilic globulin) 100% of normal level (50%–150% of normal level) 6–12 h Consumed 30% Labile (20%–40% of normal level at 1 wk) Fresh frozen plasma; concentrated antihemophilic factor; cryoprecipitate IX (Christmas factor, plasma thromboplastin component) 100% of normal level 24 h Survives 20%–30% Stable Fresh-frozen plasma; bank blood; concentrated preparation X (Stuart-Prower factor) 100% of normal level 40 h Survives 15%–20% Stable Bank blood; concentrated preparation XI (plasma thromboplastin antecedent) 100% of normal level Probably 40–80 h Survives 10% Probably stable Bank blood XII (Hageman factor) 100% of normal level Unknown Survives Deficit produces no bleeding tendency Stable Replacement not required XIII (fibrinase, fibrinstabilizing factor) 100% of normal level 4–7 d Survives Probably <1% Stable Bank blood Platelets 150,000–400,000/μL 8–11 d Consumed 60,000–100,000/μL Very labile (40% of normal level at 20 h; 0 at 48 h) Fresh blood or plasma; fresh platelet concentrate (not frozen plasma) ACD = acid-citrate-dextrose. Source: Reproduced with permission from Salzman EW: Hemorrhagic disorders. In: Kinney JM, Egdahl RH, Zuidema GD, eds. Manual of Preoperative and Postoperative Care. 2nd ed. Philadelphia: WB Saunders; 1971:157. Copyright Elsevier. 99 CHAPTER 4 Hemostasis, Surgical Bleeding, and Transfusion VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 100 Table 4-6 Adult Transfusion Clinical Practice Guideline PART I BASIC CONSIDERATIONS A. Initial Transfusion of Red Blood Cells (RBCs): 1. Notify blood bank immediately of urgent need for RBCs. O negative uncross-matched (available immediately). As soon as possible, switch to O negative for females and O positive for males. Type-specific uncross-matched (available in approximately 5–10 min). Completely cross-matched (available in approximately 40 min). 2. A blood sample must be sent to blood bank for a type and cross. 3. The Emergency Release of Blood form must be completed. If the blood type is not known and blood is needed immediately, O-negative RBCs should be issued. 4. RBCs will be transfused in the standard fashion. All patients must be identified (name and number) prior to transfusion. 5. Patients who are unstable or receive 1–2 RBCs and do not rapidly respond should be considered candidates for the massive transfusion (MT) guideline. B. Adult Massive Transfusion Guideline: 1. The Massive Transfusion Guideline (MTG) should be initiated as soon as it is anticipated that a patient will require massive transfusion (≥10 U RBCs in 24 h). The Blood Bank should strive to deliver plasma, platelets, and RBCs in a 1:1:1 ratio. To be effective and minimize further dilutional coagulopathy, the 1:1:1 ratio must be initiated early, ideally with the first 2 units of transfused RBCs. Crystalloid infusion should be minimized. 2. Once the MTG is activated, the Blood Bank will have 6 RBCs, 6 FFP, and a 6 pack of platelets packed in a cooler available for rapid transport. If 6 units of thawed FFP are not immediately available, the Blood Bank will issue units that are ready and notify appropriate personnel when the remainder is thawed. Every attempt should be made to obtain a 1:1:1 ratio of plasma:platelets:RBCs. 3. Once initiated, the MT will continue until stopped by the attending physician. MT should be terminated once the patient is no longer actively bleeding. 4. No blood components will be issued without a pickup slip with the recipient’s medical record number and name. 5. Basic laboratory tests should be drawn immediately on ED arrival and optimally performed on point-of-care devices, facilitating timely delivery of relevant information to the attending clinicians. These tests should be repeated as clinically indicated (e.g., after each cooler of products has been transfused). Suggested laboratory values are: • CBC • INR, fibrinogen • pH and/or base deficit • TEG, where available CBC = complete blood count; ED = emergency department; FFP = fresh frozen plasma; INR = international normalized ratio; TEG = thromboelastography. An example of an adult massive transfusion clinical guideline specifying the early use of component therapy is shown in Table 4-6. Specific recommendations for the administra6 tion of component therapy during a massive transfusion are shown in Table 4-7. Because only a small percentage of trauma patients require a massive transfusion and because blood products in general are in short supply, the need for early prediction models has been studied and a comparison of results from both civilian and military studies is shown in Table 4-8.81-85 While compelling, none of these algorithms have been prospectively validated. Complications of Transfusion (Table 4-9) Transfusion-related complications are primarily related to blood-induced proinflammatory responses. Transfusion-related events are estimated to occur in approximately 10% of all transfusions, but less than 0.5% are serious in nature. Transfusionrelated deaths, although rare, do occur and are related primarily to transfusion-related acute lung injury (TRALI) (16%–22%), ABO hemolytic transfusion reactions (12%–15%), and bacterial contamination of platelets (11%–18%).86 Nonhemolytic Reactions. Febrile, nonhemolytic reactions are defined as an increase in temperature (>1°C) associated with a transfusion and are fairly common (approximately 1% of all transfusions). Preformed cytokines in donated blood and recipient antibodies reacting with donated antibodies are postulated etiologies. The incidence of febrile reactions can be greatly reduced by the use of leukocyte-reduced blood products. Pretreatment with acetaminophen reduces the severity of the reaction. Bacterial contamination of infused blood is rare. Gramnegative organisms, which are capable of growth at 4°C, are the most common cause. Most cases, however, are associated with the administration of platelets that are stored at 20°C or, even more commonly, with apheresis platelets stored at room temperature. Cases from FFP thawed in contaminated water baths have also been reported.87 Bacterial contamination can result in sepsis and death in up 25% of patients.88 Clinical manifestations includes systemic signs such as fever and chills, tachycardia and hypotension, and gastrointestinal symptoms (abdominal cramps, vomiting, and diarrhea). If the diagnosis is suspected, the transfusion should be discontinued and the blood cultured. Emergency treatment includes oxygen, adrenergic blocking agents, and antibiotics. Allergic Reactions. Allergic reactions are relatively frequent, occurring in about 1% of all transfusions. Reactions are usually mild and consist of rash, urticaria, and flushing. In rare instances, anaphylactic shock develops. Allergic reactions are VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 4-7 As soon as the need for massive transfusion is recognized. For every 6 red blood cells (RBCs), give 6 FFP (1:1 ratio). Platelets For every 6 RBCs and plasma, give one 6 pack of platelets. 6 random-donor platelet packs = 1 apheresis platelet unit. Platelets are in every cooler. Keep platelet counts >100,000. Cryoprecipitate After first 6 RBCs, check fibrinogen level. If ≤200 mg/dL, give 20 units cryoprecipitate (2 g fibrinogen). Repeat as needed, depending on fibrinogen level, and request appropriate amount of cryoprecipitate. caused by the transfusion of antibodies from hypersensitive donors or the transfusion of antigens to which the recipient is hypersensitive. Allergic reactions can occur after the administration of any blood product but are commonly associated with FFP and platelets. Treatment and prophylaxis consist of the administration of antihistamines. In more serious cases, epinephrine or steroids may be indicated. Respiratory Complications. Respiratory compromise may be associated with transfusion-associated circulatory overload (TACO), which is an avoidable complication. It can occur with rapid infusion of blood, plasma expanders, and crystalloids, particularly in older patients with underlying heart disease. Central venous pressure monitoring should be considered whenever large amounts of fluid are administered. Overload is manifest by a rise in venous pressure, dyspnea, and cough. Rales can generally be heard at the lung bases. Treatment consists of diuresis, slowing the rate of blood administration, and minimizing fluids while blood products are being transfused. Table 4-8 Comparison of massive transfusion prediction studies Author Variables ROC AUC Value McLaughlin et al SBP, HR, pH, Hct 0.839 Yücel et al SBP, HR, BD, Hgb, Male, + FAST, long bone/pelvic fracture 0.892 SBP, pH, ISS >25 0.804 Schreiber et al Hgb ≤11, INR >1.5, penetrating injury 0.80 Cotton et al85 HR, SBP, FAST, penetrating injury 0.83-0.90 81 82 Moore et al83 84 AUC = area under the curve; BD = base deficit; FAST = Focused assessment with sonography for trauma; Hct = hematocrit; Hgb = hemoglobin; HR = heart rate; INR = international normalized ratio; ISS = injury severity score; ROC = receiver operating characteristic; SBP = systolic blood pressure. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Hemostasis, Surgical Bleeding, and Transfusion Fresh frozen plasma (FFP) 101 CHAPTER 4 Component therapy administration during massive transfusion The syndrome of TRALI is defined as noncardiogenic pulmonary edema related to transfusion.89 It can occur with the administration of any plasma-containing blood product. Symptoms are similar to circulatory overload with dyspnea and associated hypoxemia. However, TRALI is characterized as noncardiogenic and is often accompanied by fever, rigors, and bilateral pulmonary infiltrates on chest x-ray. It most commonly occurs within 1 to 2 hours after the onset of transfusion but virtually always before 6 hours. Toy et al recently reported a decrease in the incidence of TRALI with the reduction transfusion of plasma from female donors, due to a combination of reduced transfusion of strong cognate HLA class II antibodies and HNA antibodies in patients with risk factors for acute lung injury.90 Treatment of TRALI entails discontinuation of any transfusion, notification of the transfusion service, and pulmonary support, which may vary from supplemental oxygen to mechanical ventilation. Hemolytic Reactions. Hemolytic reactions can be classified as either acute of delayed. Acute hemolytic reactions occur with the administration of ABO-incompatible blood and can be fatal in up to 6% of cases. Contributing factors include errors in the laboratory of a technical or clerical nature or the administration of the wrong blood type. Immediate hemolytic reactions are characterized by intravascular destruction of red blood cells and consequent hemoglobinemia and hemoglobinuria. DIC can be initiated by antibody-antigen complexes activating factor XII and complement, leading to activation of the coagulation cascade. Finally, acute renal insufficiency results from the toxicity associated with free hemoglobin in the plasma, resulting in tubular necrosis and precipitation of hemoglobin within the tubules. Delayed hemolytic transfusion reactions occur 2 to 10 days after transfusion and are characterized by extravascular hemolysis, mild anemia, and indirect (unconjugated) hyperbilirubinemia. They occur when an individual has a low antibody titer at the time of transfusion, but the titer increases after transfusion as a result of an anamnestic response. Reactions to non-ABO antigens involve immunoglobulin G-mediated clearance by the reticuloendothelial system. If the patient is awake, the most common symptoms of acute transfusion reactions are pain at the site of transfusion, facial flushing, and back and chest pain. Associated symptoms include fever, respiratory distress, hypotension, and tachycardia. In anesthetized patients, diffuse bleeding and hypotension are the hallmarks. A high index of suspicion is needed to make the diagnosis. The laboratory criteria for a transfusion reaction are hemoglobinuria and serologic criteria that show incompatibility of the donor and recipient blood. A positive Coombs’ test indicates transfused cells coated with patient antibody and is diagnostic. Delayed hemolytic transfusions may also be manifest by fever and recurrent anemia. Jaundice and decreased haptoglobin usually occur, and low-grade hemoglobinemia and hemoglobinuria may be seen. The Coombs’ test is usually positive, and the blood bank must identify the antigen to prevent subsequent reactions. If an immediate hemolytic transfusion reaction is suspected, the transfusion should be stopped immediately, and a sample of the recipient’s blood drawn and sent along with the suspected unit to the blood bank for comparison with the pretransfusion samples. Urine output should be monitored and adequate hydration maintained to prevent precipitation of hemoglobin within the tubules. Delayed hemolytic transfusion reactions do not usually require specific intervention. 102 Table 4-9 Transfusion-related complications PART I BASIC CONSIDERATIONS Abbreviation Complication Signs and Symptoms Frequency Mechanism Prevention NHTR Febrile, nonhemolytic transfusion reaction Fever 0.5%–1.5% of transfusions Preformed cytokines Host Ab to donor lymphocytes Use leukocytereduced blood Store platelets <5 d Bacterial contamination High fever, chills Hemodynamic changes DIC Emesis, diarrhea Hemoglobinuria <<0.05% of blood Infusion of 0.05% of platelets contaminated blood Allergic reactions Rash, hives Itching 0.1%–0.3% of units TACO Transfusionassociated circulatory overload Pulmonary edema ? 1:200–1:10,00 of Large volume of Increase transfusion transfused blood transfused time patients into an older patient Administer diuretics with CHF Minimize associated fluids TRALI Transfusion-related Acute (<6 h) hypoxemia acute lung injury Bilateral infiltrates ± Tachycardia, hypotension Hemolytic reaction, Fever acute Hypotension DIC Hemoglobinuria Hemoglobinemia Renal insufficiency Soluble transfusion constituents Anti-HLA or anti-HNA Ab in transfused blood attacks circulatory and pulmonary leukocytes Provide antihistamine prophylaxis Limit female donors 1:33,000– Transfusion of ABO- Transfuse 1:1,500,000 units incompatible blood appropriately Preformed IgM Ab to matched blood ABO Ag Hemolytic reaction, Anemia delayed (2–10 d) Indirect hyperbilirubinemia Decreased haptoglobin level Positive result on direct Coombs’ test IgG mediated Identify patient’s Ag to prevent recurrence Ab = antibody; Ag = antigen; CHF = congestive heart failure; DIC = disseminated intravascular coagulation; HLA = human leukocyte antigen; HNA = anti-human neutrophil antigen; IgG = immunoglobulin G; IgM = immunoglobulin M. Transmission of Disease. Malaria, Chagas’ disease, brucellosis, and, very rarely, syphilis are among the diseases that have been transmitted by transfusion. Malaria can be transmitted by all blood components. The species most commonly implicated is Plasmodium malariae. The incubation period ranges from 8 to 100 days; the initial manifestations are shaking chills and spiking fever. Cytomegalovirus (CMV) infection resembling infectious mononucleosis also has occurred. Transmission of hepatitis C and HIV-1 has been dramatically minimized by the introduction of better antibody and nucleic acid screening for these pathogens. The residual risk among allogeneic donations is now estimated to be less than 1 per 1,000,000 donations. The residual risk of hepatitis B is approximately 1 per 300,000 donations.91 Hepatitis A is very rarely transmitted because there is no asymptomatic carrier state. Improved donor selection and testing are responsible for the decreased rates of transmission. Recent concerns about the rare transmission of these and other pathogens, such as West Nile virus, are being addressed by current trials of “pathogen inactivation systems” that reduce infectious levels of all viruses and bacteria known to be transmittable by transfusion. Prion disorders (e.g., Creutzfeldt-Jakob disease) also are transmissible by transfusion, but there is currently no information on inactivation of prions in blood products for transfusion. TESTS OF HEMOSTASIS AND BLOOD COAGULATION The initial approach to assessing hemostatic function is a careful review of the patient’s clinical history (including previous abnormal bleeding or bruising), drug use, and basic laboratory testing. Common screening laboratory testing includes platelet count, PT or INR, and aPTT. Platelet dysfunction can occur VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ The aPTT reagent contains a phospholipid substitute, activator, and calcium, which in the presence of plasma leads to fibrin clot formation. The aPTT measures function of factors I, II, and V of the common pathway and factors VIII, IX, X, and XII of the intrinsic pathway. Heparin therapy is often monitored by following aPTT values with a therapeutic target range of 1.5 to 2.5 times the control value (approximately 50 to 80 seconds). Low molecular weight heparins are selective Xa inhibitors that may mildly elevate the aPTT, but therapeutic monitoring is not routinely recommended. The bleeding time is used to evaluate platelet and vascular dysfunction, although not as frequently as in the past. Several standard methods have been described; however, the Ivy bleeding time is most commonly used. It is conducted by placing a sphygmomanometer on the upper arm and inflating it to 40 mmHg, and then a 5-mm stab incision is made on the flexor surface of the forearm. The time is measured to cessation of bleeding, and the upper limit or normal bleeding time with the Ivy test is 7 minutes. A template aids in administering a uniform test and adds to the reproducibility of the results. An abnormal bleeding time suggests platelet dysfunction (intrinsic or drug-induced), vWD, or certain vascular defects. Many laboratories are replacing the template bleeding time with an in vitro test in which blood is sucked through a capillary and the platelets adhere to the walls of the capillary and aggregate. The closure time in this system appears to be more reproducible than the bleeding time and also correlates with bleeding in vWD, primary platelet function disorders, and patients who are taking aspirin. Fibrinolysis Coagulation Angle R K LY MA Figure 4-6. Illustration of a thromboelastogram (TEG) tracing. K = clot kinetics; LY = lysis; MA = maximal amplitude; R = reaction time. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 103 Hemostasis, Surgical Bleeding, and Transfusion INR = (measured PT/normal PT)ISI Additional medications may significantly impair hemostatic function, such as antiplatelet agents (clopidogrel and GP IIb/IIIa inhibitors), anticoagulant agents (hirudin, chondroitin sulfate, dermatan sulfate), and thrombolytic agents (streptokinase, tPA). If abnormalities in any of the coagulation studies cannot be explained by known medications, congenital abnormalities of coagulation or comorbid disease should be considered. Unfortunately, while these conventional tests (PT, aPTT) capture the classic intrinsic and extrinsic coagulation cascade, they do not reflect the complexity of in vivo coagulation.92 Although they are useful to follow warfarin and heparin therapies, they poorly reflect the status of actively bleeding patients. This is not surprising given that these tests use only plasma and not whole blood to provide their assessment of the patient’s clotting status. To better assess the complex and rapidly changing interactions of an actively bleeding patient, many centers have moved to whole blood-viscoelastic testing such as TEG or rotational thromboelastometry (ROTEM). In addition, some centers have demonstrated that the graphical display options allow for more rapid return of results and that these tests are actually less expensive than standard coagulation panels. TEG was originally described by Hartert in 1948.93 Continuous improvements in this technique have made this test a valuable tool for the medical personnel interested in coagulation. The TEG monitors hemostasis as a dynamic process rather than revealing information of isolated conventional coagulation screens.94 The TEG measures the viscoelastic properties of blood as it is induced to clot under a low-shear environment (resembling sluggish venous flow). The patterns of change in shear-elasticity enable the determination of the kinetics of clot formation and growth as well as the strength and stability of the formed clot. The strength and stability provide information about the ability of the clot to perform the work of hemostasis, while the kinetics determines the adequacy of quantitative factors available for clot formation. A sample of celite-activated whole blood is placed into a prewarmed cuvette, and the clotting process is activated with kaolin with standard TEG and kaolin plus tissue factor with rapid TEG. A suspended piston is then lowered into the cuvette that moves in rotation of a 4.5-degree arc backward and forward. The normal clot goes through acceleration and strengthening phase. The fiber strands that interact with activated platelets attach to the surface of the cuvette and the suspended piston. The clot forming in the cuvette transmits its movement onto the suspended piston. A “weak” clot stretches and therefore delays the arc movement of the piston, which is graphically expressed as a narrow TEG. A strong clot, in contrast, will move the piston simultaneously and proportionally to the cuvette’s movements, creating a thick TEG. The strength of a clot is graphically represented over time as a characteristic cigar-shape figure (Fig. 4-6). CHAPTER 4 at either extreme of platelet count. The normal platelet count ranges from 150,000 to 400,000/μL. Whereas a platelet count greater than 1,000,000/μL may be associated with bleeding or thrombotic complications, increased bleeding complications may be observed with major surgical procedures when the platelets are below 50,000/μL and with minor surgical procedures when counts are below 30,000/μL, and spontaneous hemorrhage can occur when the counts fall below 20,000/μL. Despite a lack of evidence supporting their use, platelet transfusions are still recommended in ophthalmologic and neurosurgical procedures when the platelet count is less than 100,000/μL. The PT and aPTT are variations of plasma recalcification times initiated by the addition of a thromboplastic agent. The PT reagent contains thromboplastin and calcium that, when added to plasma, leads to the formation of a fibrin clot. The PT test measures the function of factors I, II, V, VII, and X. Factor VII is part of the extrinsic pathway, and the remaining factors are part of the common pathway. Factor VII has the shortest half-life of the coagulation factors, and its synthesis is vitamin K dependent. The PT test is best suited to detect abnormal coagulation caused by vitamin K deficiencies and warfarin therapy. Due to variations in thromboplastin activity, it can be difficult to accurately assess the degree of anticoagulation on the basis of PT alone. To account for these variations, the INR is now the method of choice for reporting PT values. The International Sensitivity Index (ISI) is unique to each batch of thromboplastin and is furnished by the manufacturer to the hematology laboratory. Human brain thromboplastin has an ISI of 1, and the optimal reagent has an ISI between 1.3 and 1.5. The INR is a calculated number derived from the following equation: 104 PART I BASIC CONSIDERATIONS Several parameters are generated from the TEG tracing. The r-value (reaction time) represents the time between the start of the assay and initial clot formation. This reflects clotting factor activity and initial fibrin formation and is increased with factor deficiency or severe hemodilution. The k-time (clot kinetics) is the time needed to reach specified clot strength and represents the interactions of clotting factors and platelets. As such, the k-time is prolonged with hypofibrinogenemia and significant factor deficiency. Prolonged r-value and k-time are commonly addressed with plasma transfusions. The alpha or angle (∝) is the slope of the tracing and reflects clot acceleration. The angle reflects the interactions of clotting factors and platelets. The slope is decreased with hypofibrinogenemia and platelet dysfunction. Decreased angles are treated with cryoprecipitate transfusion or fibrinogen administration. The maximal amplitude (mA) is the greatest height of the tracing and represents clot strength. Its height is reduced with dysfunction or deficiencies in platelets or fibrinogen. Decreased mA is addressed with platelet transfusion and, in cases where the angle is also decreased, with cryoprecipitate (or fibrinogen) as well. The G-value is a parametric measure derived from the mA value and reflects overall clot strength or firmness. An increased G-value is associated with hypercoagulability, whereas a decrease is seen with hypocoagulable states. Finally, the LY30 is the amount of lysis occurring in the clot, and the value is the percentage of amplitude reduction at 30 minutes after mA is achieved. The LY30 represents clot stability and when increased fibrinolysis is present. TEG is the only test measuring all dynamic steps of clot formation until eventual clot lysis or retraction. TEG has also been shown to identify on admission those patients likely to develop thromboembolic complications after injury and postoperatively.95-97 Recent trauma data have shown TEG to be useful in predicting early transfusion of red blood cells, plasma, platelets, and cryoprecipitate.98 TEG can also predict the need for lifesaving interventions shortly after arrival and to predict 24-hour and 30-day mortality.99 Lastly, TEG can be useful to guide administration of TXA to injured patients with hyperfibrinolysis.100 Our center now uses TEG rather than PT and a PTT to evaluate injured patients in the emergency room.101 EVALUATION OF EXCESSIVE INTRAOPERATIVE OR POSTOPERATIVE BLEEDING Excessive bleeding during or after a surgical procedure may be the result of ineffective hemostasis, blood transfusion, undetected hemostatic defect, consumptive coagulopathy, and/or fibrinolysis. Excessive bleeding from the operative field unassociated with bleeding from other sites usually suggests inadequate mechanical hemostasis. Massive blood transfusion is a well-known cause of thrombocytopenia. Bleeding following massive transfusion can occur due to hypothermia, dilutional coagulopathy, platelet dysfunction, fibrinolysis, or hypofibrinogenemia. Another cause of hemostatic failure related to the administration of blood is a hemolytic transfusion reaction. The first sign of a transfusion reaction may be diffuse bleeding. The pathogenesis of this bleeding is thought to be related to the release of ADP from hemolyzed red blood cells, resulting in diffuse platelet aggregation, after which the platelet clumps are removed out of the circulation. Transfusion purpura occurs when the donor platelets are of the uncommon PlA1 group. This is an uncommon cause of thrombocytopenia and associated bleeding after transfusion. The platelets sensitize the recipient, who makes antibody to the foreign platelet antigen. The foreign platelet antigen does not completely disappear from the recipient circulation but attaches to the recipient’s own platelets. The antibody then destroys the recipient’s own platelets. The resultant thrombocytopenia and bleeding may continue for several weeks. This uncommon cause of thrombocytopenia should be considered if bleeding follows transfusion by 5 or 6 days. Platelet transfusions are of little help in the management of this syndrome because the new donor platelets usually are subject to the binding of antigen and damage from the antibody. Corticosteroids may be of some help in reducing the bleeding tendency. Posttransfusion purpura is self-limited, and the passage of several weeks inevitably leads to subsidence of the problem. 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Schreiber MA, Perkins J, Kiraly L, et al. Early predictors of massive transfusion in combat casualties. J Am Coll Surg. 2007;205:541. 85. Cotton BA, Dossett LA, Haut ER, et al. Multicenter validation of a simplified score to predict massive transfusion in trauma. J Trauma. 2010;69(Suppl 1):S33-S39. 86. Despotis GJ, Zhang L, Lublin DM. Transfusion risks and transfusion-related pro-inflammatory responses. Hematol Oncol Clin N Am. 2007;21:147. 87. Pandey S, Vyas GN. Adverse-effects of plasma transfusion. Transfusion. 2012;52:65S-79S. 88. Goodnough LT, Brecher ME, Kanter MH: Transfusion medicine: blood transfusion. N Engl J Med. 1999;340:438. 89. Looney MR, Gropper MA, Matthay MA. Transfusion-related acute lung injury. Chest. 2004;126:249. 90. Toy P, Gajic O, Bacchetti P, et al. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012;119(7):1757-1767. 91. Zou S, Stramer SL, Dodd RY. Donor testing and risk: current prevalence, incidence, and residual risk of transfusiontransmissible agents in US allogeneic donations. Transfusion Med Rev. 2012;26(2):119-128. 92. Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21:1-11. 93. Hartert H. Blutgerinnungsstudien mit der thrombelastographie, einem neuen untersuchungsverfahren. Klin Wochenschr. 1948;26:577. 94. Mallet SV, Cox DJA. Thromboelastography: a review article. Br J Anaesth. 1992;69:307. 95. Cotton BA, Radwan ZA, Matijevic N, et al. Admission rapid thromboelastography (rTEG) predicts development of pulmonary embolism in trauma patients. J Trauma. 2012;72(6): 1470-1477. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 100. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis on admission is an uncommon but highly lethal event associated with shock and pre-hospital fluid administration. J Trauma. 2012;72(2):365-370. 101. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thromboelastography (r-TEG) can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012;256(3):476-486. Hemostasis, Surgical Bleeding, and Transfusion VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 107 CHAPTER 4 96. Caprini JA, Arcelus JI, Laubach M, et al. Postoperative hypercoagulability and deep-vein thrombosis after laparoscopic cholecystectomy. Surg Endosc. 1995;9:304-309. 97. Dai Y, Lee A, Critchley LA, et al. Does thromboelastography predict postoperative thromboembolic events? A systematic review of the literature. Anesth Analg. 2009;108:734-742. 98. Cotton BA, Faz G, Hatch Q, et al. Rapid thromboelastography (r-TEG) delivers real-time results that predict transfusion within one hour of admission. J Trauma. 2011;71(2):407-417. 99. Schöchl H, Cotton BA, Inaba K, et al. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care. 2011;15:R265-R271. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 5 chapter Evolution in Understanding Shock Neuroendocrine and Organ-Specific Responses to Hemorrhage / 112 Afferent Signals / 112 Efferent Signals / 113 Brian S. Zuckerbraun, Andrew B. Peitzman, and Timothy R. Billiar 111 Metabolic Effects 114 Cellular Hypoperfusion / 115 Immune and Inflammatory Responses Cytokines/Chemokines / 116 Complement / 118 Neutrophils / 118 Cell Signaling / 118 “Shock is the manifestation of the rude unhinging of the machinery of life.”1 —Samuel V. Gross, 1872 EVOLUTION IN UNDERSTANDING SHOCK Overview Shock, at its most rudimentary definition and regardless of the etiology, is the failure to meet the metabolic needs of the cell and the consequences that ensue. The initial cellular injury 1 that occurs is reversible; however, the injury will become irreversible if tissue perfusion is prolonged or severe enough such that, at the cellular level, compensation is no longer possible. Our evolution in the understanding of shock and the disease processes that result in shock made its most significant advances throughout the twentieth century as our appreciation for the physiology and pathophysiology of shock matured. Most notably, this includes the sympathetic and neuroendocrine stress responses on the cardiovascular system. The clinical manifestations of these physiologic responses are most often what lead practitioners to the diagnosis of shock as well as guide the management of patients in shock. However, hemodynamic parameters such as blood pressure and heart rate are relatively insensitive measures of shock, and additional considerations must be used to help aid in early diagnosis and treatment of patients in shock. The general approach to the management of patients in shock has been empiric: assuring a secure airway with adequate ventilation, control of hemorrhage in the bleeding patient, and restoration of vascular volume and tissue perfusion. Historical Background Forms of Shock Circulatory Homeostasis / 114 109 Overview / 109 Historical Background / 109 Current Definitions and Challenges / 110 Pathophysiology of Shock Shock Integral to our understanding of shock is the appreciation that our bodies attempt to maintain a state of homeostasis. Claude Bernard suggested in the mid-nineteenth century that the 115 119 Hypovolemic/Hemorrhagic / 119 Traumatic Shock / 123 Septic Shock (Vasodilatory Shock) / 124 Cardiogenic Shock / 126 Obstructive Shock / 128 Neurogenic Shock / 129 Endpoints in Resuscitation 130 Assessment of Endpoints in Resuscitation / 130 organism attempts to maintain constancy in the internal environment against external forces that attempt to disrupt the milieu interieur.2 Walter B. Cannon carried Bernard’s observations further and introduced the term homeostasis, emphasizing that an organism’s ability to survive was related to maintenance of homeostasis.3 The failure of physiologic systems to buffer the organism against external forces results in organ and cellular dysfunction, what is clinically recognized as shock. He first described the “fight or flight response,” generated by elevated levels of catecholamines in the bloodstream. Cannon’s observations on the battlefields of World War I led him to propose that the initiation of shock was due to a disturbance of the nervous system that resulted in vasodilation and hypotension. He proposed that secondary shock, with its attendant capillary permeability leak, was caused by a “toxic factor” released from the tissues. In a series of critical experiments, Alfred Blalock documented that the shock state in hemorrhage was associated with reduced cardiac output due to volume loss, not a “toxic factor.”4 In 1934, Blalock proposed four categories of shock: hypovolemic, vasogenic, cardiogenic, and neurogenic. Hypovolemic shock, the most common type, results from loss of circulating blood volume. This may result from loss of whole blood (hemorrhagic shock), plasma, interstitial fluid (bowel obstruction), or a combination. Vasogenic shock results from decreased resistance within capacitance vessels, usually seen in sepsis. Neurogenic shock is a form of vasogenic shock in which spinal cord injury or spinal anesthesia causes vasodilation due to acute loss of sympathetic vascular tone. Cardiogenic shock results from failure of the heart as a pump, as in arrhythmias or acute myocardial infarction (MI). This categorization of shock based on etiology persists today (Table 5-1). In recent clinical practice, further classification has described six types of shock: hypovolemic, septic (vasodilatory), neurogenic, cardiogenic, obstructive, and traumatic shock. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 Shock is defined as a failure to meet the metabolic demands of cells and tissues and the consequences that ensue. A central component of shock is decreased tissue perfusion. This may be a direct consequence of the etiology of shock, such as in hypovolemic/hemorrhagic, cardiogenic, or neurogenic etiologies, or may be secondary to elaborated or released molecules or cellular products that result in endothelial/cellular activation, such as in septic shock or traumatic shock. Physiologic responses to shock are based on a series of afferent (sensing) signals and efferent responses that include neuroendocrine, metabolic, and immune/inflammatory signaling. The mainstay of treatment of hemorrhagic/hypovolemic shock includes volume resuscitation with blood products. In the case Obstructive shock is a form of cardiogenic shock that results from mechanical impediment to circulation leading to depressed cardiac output rather than primary cardiac failure. This includes etiologies such as pulmonary embolism or tension pneumothorax. In traumatic shock, soft tissue and bony injury leads to the activation of inflammatory cells and the release of circulating factors, such as cytokines and intracellular molecules that modulate the immune response. Recent investigations have revealed that the inflammatory mediators released in response to tissue injury (damage-associated molecular patterns [DAMPs]) are recognized by many of the same cellular receptors (pattern recognition receptors [PRRs]) and activate similar signaling pathways as do bacterial products elaborated in sepsis (pathogen-associated molecular patterns), such as lipopolysaccharide.5 These effects of tissue injury are combined with the effects of hemorrhage, creating a more complex and amplified deviation from homeostasis. In the mid to later twentieth century, the further development of experimental models contributed significantly to the understanding of the pathophysiology of shock. In 1947, Wiggers developed a sustainable, irreversible model of hemorrhagic shock based on uptake of shed blood into a reservoir to maintain a set level of hypotension.6 G. Tom Shires added further understanding of hemorrhagic shock with a series of clinical studies demonstrating that a large extracellular fluid deficit, greater than could be attributed to vascular refilling alone, occurred in severe hemorrhagic shock.7,8 The phenomenon of fluid redistribution after major trauma involving blood loss was termed third spacing and described the translocation of intravascular volume Table 5-1 Classification of shock 110 Hypovolemic Cardiogenic Septic (vasogenic) Neurogenic Traumatic Obstructive 5 6 7 of hemorrhagic shock, timely control of bleeding is essential and influences outcome. Prevention of hypothermia, acidemia, and coagulopathy is essential in the management of patients in hemorrhagic shock. The mainstay of treatment of septic shock is fluid resuscitation, initiation of appropriate antibiotic therapy, and control of the source of infection. This includes drainage of infected fluid collections, removal of infected foreign bodies, and débridement of devitalized tissues. A combination of physiologic parameters and markers of organ perfusion/tissue oxygenation are used to determine if patients are in shock and to follow the efficacy of resuscitation. into the peritoneum, bowel, burned tissues, or crush injury sites. These seminal studies form the scientific basis for the current treatment of hemorrhagic shock with red blood cells and lactated Ringer’s solution or isotonic saline. As resuscitation strategies evolved and patients survived the initial consequences of hemorrhage, new challenges of sustained shock became apparent. During the Vietnam War, aggressive fluid resuscitation with red blood cells and crystalloid solution or plasma resulted in survival of patients who previously would have succumbed to hemorrhagic shock. Renal failure became a less frequent clinical problem; however, a new disease process, acute fulminant pulmonary failure, appeared as an early cause of death after seemingly successful surgery to control hemorrhage. Initially called DaNang lung or shock lung, the clinical problem became recognized as acute respiratory distress syndrome (ARDS). This led to new methods of prolonged mechanical ventilation. Our current concept of ARDS is a component in the spectrum of multiple organ system failure. Studies and clinical observations over the past two decades have extended the early observations of Canon, that “restoration of blood pressure prior to control of active bleeding may result in loss of blood that is sorely needed,” and challenged the appropriate endpoints in resuscitation of uncontrolled hemorrhage.9 Core principles in the management of the critically ill or injured patient include: (a) definitive control of the airway must be secured, (b) control of active hemorrhage must occur promptly (delay in control of bleeding increases mortality, and recent battlefield data would suggest that in the young and otherwise healthy population commonly injured in combat, control of bleeding is the paramount priority), (c) volume resuscitation with blood products (red blood cells, plasma, and platelets) with limited volume of crystalloid must occur while operative control of bleeding is achieved, (d) unrecognized or inadequately corrected hypoperfusion increases morbidity and mortality (i.e., inadequate resuscitation results in avoidable early deaths from shock), and (e) excessive fluid resuscitation may exacerbate bleeding (i.e., uncontrolled resuscitation is harmful). Thus both inadequate and uncontrolled volume resuscitation is harmful. Current Definitions and Challenges A modern definition and approach to shock acknowledges that shock consists of inadequate tissue perfusion marked by VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Cellular effect Regardless of etiology, the initial physiologic responses in shock are driven by tissue hypoperfusion and the developing cellular energy deficit.This imbalance between cel3 lular supply and demand leads to neuroendocrine and inflammatory responses, the magnitude of which is usually proportional to the degree and duration of shock. The specific responses will differ based on the etiology of shock, as certain physiologic responses may be limited by the inciting pathology. For example, the cardiovascular response driven by the sympathetic nervous system is markedly blunted in neurogenic or septic shock. Additionally, decreased perfusion may occur as a consequence of cellular activation and dysfunction, such as in septic shock and to a lesser extent traumatic shock (Fig. 5-1). Many of the organ-specific responses are aimed at maintaining Disruption host-microbe equilibrium Trauma Tissue injury Bacterial products (i.e., LPS) Damage associated molecular patterns (i.e., HMGB1, heparan sulfate) Pattern recognition receptor activation (Toll-like receptors, RAGE) Direct effect Acute heart failure Released/elaborated mediators of inflammation Cellular activation Decreased tissue perfusion Neurogenic Cellular hypoxia/ischemia Hemorrhage Shock VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 5-1. Pathways leading to decreased tissue perfusion and shock. Decreased tissue perfusion can result directly from hemorrhage/hypovolemia, cardiac failure, or neurologic injury. Decreased tissue perfusion and cellular injury can then result in immune and inflammatory responses. Alternatively, elaboration of microbial products during infection or release of endogenous cellular products from tissue injury can result in cellular activation to subsequently influence tissue perfusion and the development of shock. HMGB1 = high mobility group box 1; LPS = lipopolysaccharide; RAGE = receptor for advanced glycation end products. 111 Shock PATHOPHYSIOLOGY OF SHOCK perfusion in the cerebral and coronary circulation. These are regulated at multiple levels including (a) stretch receptors and baroreceptors in the heart and vasculature (carotid sinus and aortic arch), (b) chemoreceptors, (c) cerebral ischemia responses, (d) release of endogenous vasoconstrictors, (e) shifting of fluid into the intravascular space, and (f) renal reabsorption and conservation of salt and water. Furthermore, the pathophysiologic responses vary with time and in response to resuscitation. In hemorrhagic shock, the body can compensate for the initial loss of blood volume primarily through the neuroendocrine response to maintain hemodynamics. This represents the compensated phase of shock. With continued hypoperfusion, which may be unrecognized, cellular death and injury are ongoing and the decompensation phase of shock ensues. Microcirculatory dysfunction, parenchymal tissue damage, and inflammatory cell activation can perpetuate hypoperfusion. Ischemia/reperfusion injury will often exacerbate the initial insult. These effects at the cellular level, if untreated, will lead to compromise of function at the organ system level, thus leading to the “vicious cycle” of shock (Fig. 5-2). Persistent hypoperfusion results in further hemodynamic derangements and cardiovascular collapse. This has been termed the irreversible phase of shock and can develop quite insidiously and may only be obvious in retrospect. At this point, there has occurred extensive enough parenchymal and microvascular injury such that volume resuscitation fails to reverse the process, leading to death of the patient. In experimental animal models of hemorrhagic shock (modified Wiggers model), this is represented by the “uptake phase” or “compensation endpoint” when shed blood must be returned to the animal to sustain the hypotension at the set level to prevent further hypotension and death.10 If shed blood volume is slowly returned to maintain the set level of hypotension, eventually the injury progresses to irreversible shock, where further volume will not reverse the process and the animal dies (Fig. 5-3). CHAPTER 5 decreased delivery of required metabolic substrates and inadequate removal of cellular waste products.This involves failure of oxidative metabolism that can involve defects of 2 oxygen (O2) delivery, transport, and/or utilization. Current challenges include moving beyond fluid resuscitation based on endpoints of tissue oxygenation, and using therapeutic strategies at the cellular and molecular level. This approach will help to identify compensated patients or patients early in the course of their disease, initiate appropriate treatment, and allow for continued evaluation for the efficacy of resuscitation and adjuncts. Current investigations focus on determining the cellular events that often occur in parallel to result in organ dysfunction, shock irreversibility, and death. This chapter will review our current understanding of the pathophysiology and cellular responses of shock states. Current and experimental diagnostic and therapeutic modalities for the different categories of shock are reviewed, with a focus on hemorrhagic/hypovolemic shock and septic shock. 112 peripheral perfusion and tissue O2 delivery, and restore homeostasis. The afferent impulses that initiate the body’s intrinsic adaptive responses and converge in the CNS originate from a variety of sources. The initial inciting event usually is loss of circulating blood volume. Other stimuli that can produce the neuroendocrine response include pain, hypoxemia, hypercarbia, acidosis, infection, change in temperature, emotional arousal, or hypoglycemia. The sensation of pain from injured tissue is transmitted via the spinothalamic tracts, resulting in activation of the hypothalamic-pituitary-adrenal axis, as well as activation of the autonomic nervous system (ANS) to induce direct sympathetic stimulation of the adrenal medulla to release catecholamines. Baroreceptors also are an important afferent pathway in initiation of adaptive responses to shock. Volume receptors, sensitive to changes in both chamber pressure and wall stretch, are present within the atria of the heart. They become activated with low volume hemorrhage or mild reductions in right atrial pressure. Receptors in the aortic arch and carotid bodies respond to alterations in pressure or stretch of the arterial wall, responding to larger reductions in intravascular volume or pressure. These receptors normally inhibit induction of the ANS. When activated, these baroreceptors diminish their output, thus disinhibiting the effect of the ANS. The ANS then increases its output, principally via sympathetic activation at the vasomotor centers of the brain stem, producing centrally mediated constriction of peripheral vessels. Chemoreceptors in the aorta and carotid bodies are sensitive to changes in O2 tension, H+ ion concentration, and carbon dioxide (CO2) levels. Stimulation of the chemoreceptors results in vasodilation of the coronary arteries, slowing of the heart rate, and vasoconstriction of the splanchnic and skeletal circulation. In addition, a variety of protein and nonprotein mediators are produced at the site of injury as part of the inflammatory response, and they act as afferent impulses to induce a host response. These mediators include histamine, cytokines, eicosanoids, and endothelins, among others that are discussed in greater detail later in this chapter in the Immune and Inflammatory Responses section. Decreased cardiac output PART I ↓ Venous return Metabolic acidosis Intracellular ↓ Coronary perfusion fluid loss Cellular hypoxia Decreased tissue perfusion Endothelial activation/ microcirculatory damage Cellular aggregation Figure 5-2. The “vicious cycle of shock.” Regardless of the etiology, decreased tissue perfusion and shock results in a feed-forward loop that can exacerbate cellular injury and tissue dysfunction. Neuroendocrine and Organ-Specific Responses to Hemorrhage The goal of the neuroendocrine response to hemorrhage is to maintain perfusion to the heart and the brain, even at the expense of other organ systems. Peripheral vasoconstriction occurs, and fluid excretion is inhibited. The mechanisms include autonomic control of peripheral vascular tone and cardiac contractility, hormonal response to stress and volume depletion, and local microcirculatory mechanisms that are organ specific and regulate regional blood flow. The initial stimulus is loss of circulating blood volume in hemorrhagic shock. The magnitude of the neuroendocrine response is based on both the volume of blood lost and the rate at which it is lost. Afferent Signals Afferent impulses transmitted from the periphery are processed within the central nervous system (CNS) and activate the reflexive effector responses or efferent impulses. These effector responses are designed to expand plasma volume, maintain Rat hemorrhagic shock model 24-hour survival following resuscitation 80 Mean arterial pressure BASIC CONSIDERATIONS Parenchymal cell injury 100% 90% 50% 30% Compensation endpoint 10% 40 0% % Shed blood return 0% 10% 20% 30% B Compensated 40% 50% A Decompensated A B Death Irreversible Transition to acute irreversible shock Transition to subacute lethal shock VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 5-3. Rat model of hemorrhagic shock through the phases of compensation, decompensation, and irreversibility. The percentages shown above the curve represent survival rates. (Adapted with permission from Lippincott Williams & Wilkins/Wolters Kluwer Health: Shah NS, Kelly E, Billiar TR, et al. Utility of clinical parameters of tissue oxygenation in a quantitative model of irreversible hemorrhagic shock. Shock. 1998;10:343346. Copyright © 1998.) Efferent Signals Hormonal Response. The stress response includes activation Hemodynamic responses to different types of shock Type of Shock Cardiac Index SVR Venous Capacitance CVP/PCWP SvO2 Cellular/Metabolic Effects Hypovolemic ↓ ↑ ↓ ↓ ↓ Effect Septic ↑↑ ↓ ↑ ↑↓ ↑↓ Cause Cardiogenic ↓↓ ↑↑ → ↑ ↓ Effect Neurogenic ↑ ↓ → ↓ ↓ Effect The hemodynamic responses are indicated by arrows to show an increase (↑), severe increase (↑↑), decrease (↓), severe decrease (↓↓), varied response (↑↓), or little effect (→). CVP = central venous pressure; PCWP = pulmonary capillary wedge pressure; Svo2 = mixed venous oxygen saturation; SVR = systemic vascular resistance. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Shock Table 5-2 113 CHAPTER 5 Cardiovascular Response. Changes in cardiovascular function are a result of the neuroendocrine response and ANS response to shock, and constitute a prominent feature of both the body’s adaptive response mechanism and the clinical signs and symptoms of the patient in shock. Hemorrhage results in diminished venous return to the heart and decreased cardiac output. This is compensated by increased cardiac heart rate and contractility, as well as venous and arterial vasoconstriction. Stimulation of sympathetic fibers innervating the heart leads to activation of β1-adrenergic receptors that increase heart rate and contractility in this attempt to increase cardiac output. Increased myocardial O2 consumption occurs as a result of the increased workload; thus, myocardial O2 supply must be maintained or myocardial dysfunction will develop. The cardiovascular response in hemorrhage/hypovolemia differs from the responses elicited with the other etiologies of shock. These are compared in Table 5-2. Direct sympathetic stimulation of the peripheral circulation via the activation of α1-adrenergic receptors on arterioles induces vasoconstriction and causes a compensatory increase in systemic vascular resistance and blood pressure. The arterial vasoconstriction is not uniform; marked redistribution of blood flow results. Selective perfusion to tissues occurs due to regional variations in arteriolar resistance, with blood shunted away from less essential organ beds such as the intestine, kidney, and skin. In contrast, the brain and heart have autoregulatory mechanisms that attempt to preserve their blood flow despite a global decrease in cardiac output. Direct sympathetic stimulation also induces constriction of venous vessels, decreasing the capacitance of the circulatory system and accelerating blood return to the central circulation. Increased sympathetic output induces catecholamine release from the adrenal medulla. Catecholamine levels peak within 24 to 48 hours of injury and then return to baseline. Persistent elevation of catecholamine levels beyond this time suggests ongoing noxious afferent stimuli. The majority of the circulating epinephrine is produced by the adrenal medulla, while norepinephrine is derived from synapses of the sympathetic nervous system. Catecholamine effects on peripheral tissues include stimulation of hepatic glycogenolysis and gluconeogenesis to increase circulating glucose availability to peripheral tissues, an increase in skeletal muscle glycogenolysis, suppression of insulin release, and increased glucagon release. of the ANS as discussed earlier in the Afferent Signals section, as well as activation of the hypothalamic-pituitary-adrenal axis. Shock stimulates the hypothalamus to release corticotropinreleasing hormone, which results in the release of adrenocorticotropic hormone (ACTH) by the pituitary. ACTH subsequently stimulates the adrenal cortex to release cortisol. Cortisol acts synergistically with epinephrine and glucagon to induce a catabolic state. Cortisol stimulates gluconeogenesis and insulin resistance, resulting in hyperglycemia as well as muscle cell protein breakdown and lipolysis to provide substrates for hepatic gluconeogenesis. Cortisol causes retention of sodium and water by the nephrons of the kidney. In the setting of severe hypovolemia, ACTH secretion occurs independently of cortisol negative feedback inhibition. The renin-angiotensin system is activated in shock. Decreased renal artery perfusion, β-adrenergic stimulation, and increased renal tubular sodium concentration cause the release of renin from the juxtaglomerular cells. Renin catalyzes the conversion of angiotensinogen (produced by the liver) to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) produced in the lung. While angiotensin I has no significant functional activity, angiotensin II is a potent vasoconstrictor of both splanchnic and peripheral vascular beds, and also stimulates the secretion of aldosterone, ACTH, and antidiuretic hormone (ADH). Aldosterone, a mineralocorticoid, acts on the nephron to promote reabsorption of sodium and, as a consequence, water. Potassium and hydrogen ions are lost in the urine in exchange for sodium. The pituitary also releases vasopressin or ADH in response to hypovolemia, changes in circulating blood volume sensed by baroreceptors and left atrial stretch receptors, and increased plasma osmolality detected by hypothalamic osmoreceptors. Epinephrine, angiotensin II, pain, and hyperglycemia increase production of ADH. ADH levels remain elevated for about 1 week after the initial insult, depending on the severity and persistence of the hemodynamic abnormalities. ADH acts on the distal tubule and collecting duct of the nephron to increase water permeability, decrease water and sodium losses, and preserve intravascular volume. Also known as arginine vasopressin, ADH acts as a potent mesenteric vasoconstrictor, shunting circulating blood away from the splanchnic organs during hypovolemia.11 This may contribute to intestinal ischemia and predispose to intestinal mucosal barrier dysfunction 114 PART I BASIC CONSIDERATIONS in shock states. Vasopressin also increases hepatic gluconeogenesis and increases hepatic glycolysis. In septic states, endotoxin directly stimulates arginine vasopressin secretion independently of blood pressure, osmotic, or intravascular volume changes. Proinflammatory cytokines also contribute to arginine vasopressin release. Interestingly, patients on chronic therapy with ACE inhibitors are more at risk of developing hypotension and vasodilatory shock with open heart surgery. Low plasma levels of arginine vasopressin were confirmed in these patients.12 Circulatory Homeostasis Preload. At rest, the majority of the blood volume is within the venous system. Venous return to the heart generates ventricular end-diastolic wall tension, a major determinant of cardiac output. Gravitational shifts in blood volume distribution are quickly corrected by alterations in venous capacity. With decreased arteriolar inflow, there is active contraction of the venous smooth muscle and passive elastic recoil in the thin-walled systemic veins. This increases venous return to the heart, thus maintaining ventricular filling. Most alterations in cardiac output in the normal heart are related to changes in preload. Increases in sympathetic tone have a minor effect on skeletal muscle beds but produce a dramatic reduction in splanchnic blood volume, which normally holds 20% of the blood volume. The normal circulating blood volume is maintained within narrow limits by the kidney’s ability to manage salt and water balance with external losses via systemic and local hemodynamic changes and hormonal effects of renin, angiotensin, and ADH. These relatively slow responses maintain preload by altering circulating blood volume. Acute responses to intravascular volume include changes in venous tone, systemic vascular resistance, and intrathoracic pressure, with the slower hormonal changes less important in the early response to volume loss. Furthermore, the net effect of preload on cardiac output is influenced by cardiac determinants of ventricular function, which include coordinated atrial activity and tachycardia. Ventricular Contraction. The Frank-Starling curve describes the force of ventricular contraction as a function of its preload. This relationship is based on force of contraction being determined by initial muscle length. Intrinsic cardiac disease will shift the Frank-Starling curve and alter mechanical performance of the heart. In addition, cardiac dysfunction has been demonstrated experimentally in burns and in hemorrhagic, traumatic, and septic shock. Afterload. Afterload is the force that resists myocardial work during contraction. Arterial pressure is the major component of afterload influencing the ejection fraction. This vascular resistance is determined by precapillary smooth muscle sphincters. Blood viscosity also will increase vascular resistance. As afterload increases in the normal heart, stroke volume can be maintained by increases in preload. In shock, with decreased circulating volume and therefore diminished preload, this compensatory mechanism to sustain cardiac output is impeded. The stress response with acute release of catecholamines and sympathetic nerve activity in the heart increases contractility and heart rate. Microcirculation. The microvascular circulation plays an integral role in regulating cellular perfusion and is significantly influenced in response to shock. The microvascular bed is innervated by the sympathetic nervous system and has a profound effect on the larger arterioles. Following hemorrhage, larger arterioles vasoconstrict; however, in the setting of sepsis or neurogenic shock, these vessels vasodilate. Additionally, a host of other vasoactive proteins, including vasopressin, angiotensin II, and endothelin-1, also lead to vasoconstriction to limit organ perfusion to organs such as skin, skeletal muscle, kidneys, and the gastrointestinal (GI) tract to preserve perfusion of the myocardium and CNS. Flow in the capillary bed is heterogeneous in shock states, which likely is secondary to multiple local mechanisms, including endothelial cell swelling, dysfunction, and activation marked by the recruitment of leukocytes and platelets.13 Together, these mechanisms lead to diminished capillary perfusion that may persist after resuscitation. In hemorrhagic shock, correction of hemodynamic parameters and restoration of O2 delivery generally lead to restoration of tissue O2 consumption and tissue O2 levels. In contrast, regional tissue dysoxia often persists in sepsis, despite similar restoration of hemodynamics and O2 delivery. Whether this defect in O2 extraction in sepsis is the result of heterogeneous impairment of the microcirculation (intraparenchymal shunting) or impaired tissue parenchymal cell oxidative phosphorylation and O2 consumption by the mitochondria is not resolved.14 Interesting data suggest that in sepsis the response to limit O2 consumption by the tissue parenchymal cells is an adaptive response to the inflammatory signaling and decreased perfusion.15 An additional pathophysiologic response of the microcirculation to shock is failure of the integrity of the endothelium of the microcirculation and development of capillary leak, intracellular swelling, and the development of an extracellular fluid deficit. Seminal work by Shires helped to define this phenomenon.8,16 There is decreased capillary hydrostatic pressure secondary to changes in blood flow and increased cellular uptake of fluid. The result is a loss of extracellular fluid volume. The cause of intracellular swelling is multifactorial, but dysfunction of energy-dependent mechanisms, such as active transport by the sodium-potassium pump, contributes to loss of membrane integrity. Capillary dysfunction also occurs secondary to activation of endothelial cells by circulating inflammatory mediators generated in septic or traumatic shock. This exacerbates endothelial cell swelling and capillary leak, as well as increases leukocyte adherence. This results in capillary occlusion, which may persist after resuscitation, and is termed no-reflow. Further ischemic injury ensues as well as release of inflammatory cytokines to compound tissue injury. Experimental models have shown that neutrophil depletion in animals subjected to hemorrhagic shock produces fewer capillaries with no-reflow and lower mortality.13 METABOLIC EFFECTS Cellular metabolism is based primarily on the hydrolysis of adenosine triphosphate (ATP). The splitting of the phosphoanhydride bond of the terminal or γ-phosphate from ATP is the source of energy for most processes within the cell under normal conditions. The majority of ATP is generated in our bodies through aerobic metabolism in the process of oxidative phosphorylation in the mitochondria. This process is dependent on the availability of O2 as a final electron acceptor in the electron transport chain. As O2 tension within a cell decreases, there is a decrease in oxidative phosphorylation, and the generation VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Hypoperfused cells and tissues experience what has been termed oxygen debt, a concept first proposed by Crowell in 1961.19 The O2 debt is the deficit in tissue oxygenation over time that occurs during shock. When O2 delivery is limited, O2 consumption can be inadequate to match the metabolic needs of cellular respiration, creating a deficit in O2 requirements at the cellular level. The measurement of O2 deficit uses calculation of the difference between the estimated O2 demand and the actual value obtained for O2 consumption. Under normal circumstances, cells can “repay” the O2 debt during reperfusion. The magnitude of the O2 debt correlates with the severity and duration of hypoperfusion. Surrogate values for measuring O2 debt include base deficit and lactate levels and are discussed later in the Hypovolemic/Hemorrhagic section. In addition to induction of changes in cellular metabolic pathways, shock also induces changes in cellular gene expression. The DNA binding activity of a number of nuclear transcription factors is altered by hypoxia and the production of O2 radicals or nitrogen radicals that are produced at the cellular level by shock. Expression of other gene products such as heat shock proteins, vascular endothelial growth factor, inducible nitric oxide synthase (iNOS), heme oxygenase-1, and cytokines also are clearly increased by shock.20 Many of these shockinduced gene products, such as cytokines, have the ability to IMMUNE AND INFLAMMATORY RESPONSES The inflammatory and immune responses are a complex set of interactions between circulating soluble factors and cells that can arise in response to trauma, infection, ischemia, toxic, or autoimmune stimuli.20 The processes are well regulated and can be conceptualized as an ongoing surveillance and response system that undergoes a coordinated escalation following injury to heal disrupted tissue or restore host-microbe equilibrium, as well as active suppression back to baseline levels. Failure to adequately control the activation, escalation, or suppression of the inflammatory response can lead to systemic inflammatory response syndrome and potentiate multiple organ failure. Both the innate and adaptive branches of the immune system work in concert to rapidly respond in a specific and effective manner to challenges that threaten an organism’s well-being. Each arm of the immune system has its own set of functions, defined primarily by distinct classes of effector cells and their unique cell membrane receptor families. Alterations in the activity of the innate host immune system can be responsible for both the development of shock (i.e., septic shock following severe infection and traumatic shock following tissue injury with hemorrhage) and the pathophysiologic sequelae of shock such as the proinflammatory changes seen following hypoperfusion (see Fig. 5-1). When the predominantly paracrine mediators gain access to the systemic circulation, they can induce a variety of metabolic changes that are collectively referred to as the host inflammatory response. Understanding of the intricate, redundant, and interrelated pathways that comprise the inflammatory response to shock continues to expand. Despite limited understanding of how our current therapeutic interventions impact the host response to illness, inappropriate or excessive inflammation appears to be an essential event in the development of ARDS, multiple organ dysfunction syndrome (MODS), and posttraumatic immunosuppression that can prolong recovery.21 Following direct tissue injury or infection, there are several mechanisms that lead to the activation of the active inflammatory and immune responses. These include release of bioactive peptides by neurons in response to pain and the release of intracellular molecules by broken cells, such as heat shock proteins, mitochondrial products, heparan sulfate, high mobility group box 1, and RNA. Only recently has it been realized that the release of intracellular products from damaged and injured cells can have paracrine and endocrine-like effects on distant tissues to activate the inflammatory and immune responses.22 This hypothesis, which was first proposed by Matzinger, is known as danger signaling. Under this novel paradigm of immune function, endogenous molecules are capable of signaling the presence of danger to surrounding cells and tissues. These molecules that are released from cells are known as damage-associated molecular patterns (DAMPs) (Table 5-3). DAMPs are recognized by cell surface receptors to effect intracellular signaling that primes and amplifies the immune response. These receptors are known as pattern recognition receptors (PRRs) and include the Toll-like receptors (TLRs) and the receptor for advanced glycation end products. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 115 Shock Cellular Hypoperfusion subsequently alter gene expression in specific target cells and tissues. The involvement of multiple pathways emphasizes the complex, integrated, and overlapping nature of the response to shock. CHAPTER 5 of ATP slows. When O2 delivery is so severely impaired such that oxidative phosphorylation cannot be sustained, the state is termed dysoxia.17 When oxidative phosphorylation is insufficient, the cells shift to anaerobic metabolism and glycolysis to generate ATP. This occurs via the breakdown of cellular glycogen stores to pyruvate. Although glycolysis is a rapid process, it is not efficient, allowing for the production of only 2 mol of ATP from 1 mol of glucose. This is compared to complete oxidation of 1 mol of glucose that produces 38 mol of ATP. Additionally, under hypoxic conditions in anaerobic metabolism, pyruvate is converted into lactate, leading to an intracellular metabolic acidosis. There are numerous consequences secondary to these metabolic changes. The depletion of ATP potentially influences all ATP-dependent cellular processes. This includes maintenance of cellular membrane potential, synthesis of enzymes and proteins, cell signaling, and DNA repair mechanisms. Decreased intracellular pH also influences vital cellular functions such as normal enzyme activity, cell membrane ion exchange, and cellular metabolic signaling.18 These changes also will lead to changes in gene expression within the cell. Furthermore, acidosis leads to changes in calcium metabolism and calcium signaling. Compounded, these changes may lead to irreversible cell injury and death. Epinephrine and norepinephrine have a profound impact on cellular metabolism. Hepatic glycogenolysis, gluconeogenesis, ketogenesis, skeletal muscle protein breakdown, and adipose tissue lipolysis are increased by catecholamines. Cortisol, glucagon, and ADH also contribute to the catabolism during shock. Epinephrine induces further release of glucagon, while inhibiting the pancreatic β-cell release of insulin. The result is a catabolic state with glucose mobilization, hyperglycemia, protein breakdown, negative nitrogen balance, lipolysis, and insulin resistance during shock and injury. The relative underuse of glucose by peripheral tissues preserves it for the glucose-dependent organs such as the heart and brain. 116 Table 5-3 Endogenous damage-associated molecular pattern molecules PART I BASIC CONSIDERATIONS Mitochondrial DNA Hyaluronan oligomers Heparan sulfate Extra domain A of fibronectin Heat shock proteins 60, 70, Gp96 Surfactant Protein A β-Defensin 2 Fibrinogen Biglycan High mobility group box 1 Uric acid Interleukin-1α S-100s Nucleolin Cytokines/Chemokines Interestingly, TLRs and PRRs were first recognized for their role in signaling as part of the immune response to the entry of microbes and their secreted products into a normally sterile environment. These bacterial products, including lipopolysaccharide, are known as pathogen-associated molecular patterns. The salutary consequences of PRR activation most likely relate to the initiation of the repair process and the mobilization of antimicrobial defenses at the site of tissue disruption. However, in the setting of excessive tissue damage, the inflammation itself may lead to further tissue damage, amplifying the response both at the local and systemic level.20 PRR activation leads to intracellular signaling and release of cellular products including cytokines (Fig. 5-4). Before the recruitment of leukocytes into sites of injury, tissue-based macrophages or mast cells act as sentinel responders, releasing histamines, eicosanoids, tryptases, and cytokines (Fig. 5-5). Together these signals amplify the immune response Neuropeptides Tissue-based macrophages/ mast cells Trauma DAMPs (HMGB1, heparan sulfate, uric acid) Bacteria and bacterial products Macrophages TNF, Antigen Interferon- by further activation of neurons and mast cells, as well as increasing the expression of adhesion molecules on the endothelium. Furthermore, these mediators cause leukocytes to release platelet-activating factor, further increasing the stickiness of the endothelium. Additionally, the coagulation and kinin cascades impact the interaction of endothelium and leukocytes. Histamines, leukotrienes, chemokines, TNF Complement Degranulation Chemokines, TNF Neutrophils Defensins Lymphocytes Stimulation/activation Production Figure 5-4. A schema of information flow between immune cells in early inflammation following tissue injury and infection. Cells require multiple inputs and stimuli before activation of a full response. DAMPs = damage-associated molecular patterns; HMGB1 = high mobility group box 1; TNF = tumor necrosis factor. The immune response to shock encompasses the elaboration of mediators with both proinflammatory and anti-inflammatory properties (Table 5-4). Furthermore, new mediators, new relationships between mediators, and new functions of known mediators are continually being identified. As new pathways are uncovered, understanding of the immune response to injury and the potential for therapeutic intervention by manipulating the immune response following shock will expand. What seems clear at present, however, is that the innate immune response can help restore homeostasis, or if it is excessive, promote cellular and organ dysfunction. Multiple mediators have been implicated in the host immune response to shock. It is likely that some of the most important mediators have yet to be discovered, and the roles of many known mediators have not been defined. A comprehensive description of all of the mediators and their complex interactions is beyond the scope of this chapter. For a general overview, a brief description of the more extensively studied mediators, and some of the known effects of these substances, see the discussion below. A more comprehensive review can be found in Chap. 2. Tumor necrosis factor alpha (TNF-α) was one of the first cytokines to be described and is one of the earliest cytokines released in response to injurious stimuli. Monocytes, macrophages, and T cells release this potent proinflammatory cytokine. TNF-α levels peak within 90 minutes of stimulation and return frequently to baseline levels within 4 hours. Release of TNF-α may be induced by bacteria or endotoxin and leads to the development of shock and hypoperfusion, most commonly observed in septic shock. Production of TNF-α also may be induced following other insults, such as hemorrhage and ischemia. TNF-α levels correlate with mortality in animal models of hemorrhage.23 In contrast, the increase in serum TNF-α levels reported in trauma patients is far less than that seen in septic patients.24 Once released, TNF-α can produce peripheral vasodilation, activate the release of other cytokines, induce procoagulant activity, and stimulate a wide array of cellular metabolic changes. During the stress response, TNF-α contributes to the muscle protein breakdown and cachexia. Interleukin-1 (IL-1) has actions similar to those of TNF-α. IL-1 has a very short half-life (6 min) and primarily acts in a paracrine fashion to modulate local cellular responses. Systemically, IL-1 produces a febrile response to injury by activating prostaglandins in the posterior hypothalamus, and causes anorexia by activating the satiety center. This cytokine also augments the secretion of ACTH, glucocorticoids, and β-endorphins. In conjunction with TNF-α, IL-1 can stimulate the release of other cytokines such as IL-2, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and interferon-γ. IL-2 is produced by activated T cells in response to a variety of stimuli and activates other lymphocyte subpopulations and natural killer cells. The lack of clarity regarding the role of IL-2 in the response to shock is intimately associated VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ LPS signaling Injury Secretion from stressed cells Necrosis DAMP HMGB-1 ? MD-2 ? LPS HMGB-1 MD-2 TLR 4 m me ? ? Other coreceptors Ce ll m em TLR4 C Activated TLR4 4 ell TLR e n bra MyD88 bra ne TRAM TRIF MAL IRAK 4 MyD88dependent pathway Shock LBP Breakdown of matrix TBK 1 IRAK 1 MyD88independent pathway TRAF 6 IRF 3 TAK 1 NEMO MKK3 IKK 1 MKK 7 IKK 2 Iκ B p 38 p 50 JNK p 65 Nucle ar m p 50 p 65 emb rane IRF 3 NF-κB Figure 5-5. Signaling via the pattern recognition receptor TLR4. LPS signaling via TLR4 requires the cofactors LPS binding protein (LBP), MD-2, and CD14. Endogenous danger signals released from a variety of sources also signal in a TLR4-dependent fashion, although it is as yet unknown what cofactors may be required for this activity. Once TLR4 is activated, an intracellular signaling cascade is initiated that involves both a MyD88-dependent and independent pathway. DAMP = damage-associated molecular pattern; LPS = lipopolysaccharide; MD-2 = myeloid differentiation factor-2; MyD88 = myeloid differentiation primary response gene 88; NF-κB = nuclear factor-κB; TLR4 = Toll-like receptor-4. (Reproduced with permission from Mollen KP, Anand RJ, Tsung A, et al.83 Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock. 2006;26:430–437.) with that of understanding immune function after injury. Some investigators have postulated that increased IL-2 secretion promotes shock-induced tissue injury and the development of shock. Others have demonstrated that depressed IL-2 production is associated with, and perhaps contributes to, the depression in immune function after hemorrhage that may increase the susceptibility of patients who develop shock to suffer infections.25,26 It has been postulated that overly exuberant proinflammatory activation promotes tissue injury, organ dysfunction, and the subsequent immune dysfunction/suppression that may be evident later.21 Emphasizing the importance of temporal changes in the production of mediators, both the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 5 Hemorrhagic shock Ischemia/reperfusion Tissue trauma Toxic exposure CD14 117 Danger signaling 118 Proinflammatory Anti-Inflammatory Interleukin-1α/β Interleukin-4 Interleukin-2 Interleukin-10 Interleukin-6 Interleukin-13 C5a are potent mediators of increased vascular permeability, smooth muscle cell contraction, histamine and arachidonic acid by-product release, and adherence of neutrophils to vascular endothelium. Activated complement acts synergistically with endotoxin to induce the release of TNF-α and IL-1. The development of ARDS and MODS in trauma patients correlates with the intensity of complement activation. 35 Complement and neutrophil activation may correlate with mortality in multiply injured patients. Interleukin-8 Prostaglandin E2 Interferon TGFβ Neutrophils Table 5-4 Inflammatory mediators of shock PART I BASIC CONSIDERATIONS TNF PAF PAF = platelet activating factor; TGFβ = transforming growth factor beta; TNF = tumor necrosis factor. initial excessive production of IL-2 and later depressed IL-2 production are probably important in the progression of shock. IL-6 is elevated in response to hemorrhagic shock, major operative procedures, or trauma. Elevated IL-6 levels correlate with mortality in shock states. IL-6 contributes to lung, liver, and gut injury after hemorrhagic shock.27 Thus, IL-6 may play a role in the development of diffuse alveolar damage and ARDS. IL-6 and IL-1 are mediators of the hepatic acute phase response to injury; enhance the expression and activity of complement, C-reactive protein, fibrinogen, haptoglobin, amyloid A, and α1-antitrypsin; and promote neutrophil activation.28 IL-10 is considered an anti-inflammatory cytokine that may have immunosuppressive properties. Its production is increased after shock and trauma, and it has been associated with depressed immune function clinically, as well as an increased susceptibility to infection.29 IL-10 is secreted by T cells, monocytes, and macrophages, and inhibits proinflammatory cytokine secretion, O2 radical production by phagocytes, adhesion molecule expression, and lymphocyte activation.29,30 Administration of IL-10 depresses cytokine production and improves some aspects of immune function in experimental models of shock and sepsis.31,32 Recent studies point to the importance of chemokines, a specific set of cytokines, that have the ability to induce chemotaxis of leukocytes. Chemokines bind to specific chemokine receptors and transduce chemotactic signals to leukocytes. The significance of this large family of chemoattractant cytokines in immunology is difficult to understate, as almost every facet of the immune system is influenced by chemokines, including immune system development, immune surveillance, immune priming, effector responses, and immune regulation.33 Complement The complement cascade can be activated by injury, shock, and severe infection, and contributes to host defense and proinflammatory activation. Significant complement consumption occurs after hemorrhagic shock.34 In trauma patients, the degree of complement activation is proportional to the magnitude of injury and may serve as a marker for severity of injury. Patients in septic shock also demonstrate activation of the complement pathway, with elevations of the activated complement proteins C3a and C5a. Activation of the complement cascade can contribute to the development of organ dysfunction. Activated complement factors C3a, C4a, and Neutrophil activation is an early event in the upregulation of the inflammatory response; neutrophils are the first cells to be recruited to the site of injury. Polymorphonuclear leukocytes (PMNs) remove infectious agents, foreign substances that have penetrated host barrier defenses, and nonviable tissue through phagocytosis. However, activated PMNs and their products may also produce cell injury and organ dysfunction. Activated PMNs generate and release a number of substances that may induce cell or tissue injury, such as reactive O2 species, lipidperoxidation products, proteolytic enzymes (elastase, cathepsin G), and vasoactive mediators (leukotrienes, eicosanoids, and platelet-activating factor). Oxygen free radicals, such as superoxide anion, hydrogen peroxide, and hydroxyl radical, are released and induce lipid peroxidation, inactivate enzymes, and consume antioxidants (such as glutathione and tocopherol). Ischemia-reperfusion activates PMNs and causes PMN-induced organ injury. In animal models of hemorrhagic shock, activation of PMNs correlates with irreversibility of shock and mortality, and neutrophil depletion prevents the pathophysiologic sequelae of hemorrhagic and septic shock. Human data corroborate the activation of neutrophils in trauma and shock and suggest a role in the development of MODS.36 Plasma markers of PMN activation, such as elastase, correlate with severity of injury in humans. Interactions between endothelial cells and leukocytes are important in the inflammatory process. The vascular endothelium contributes to regulation of blood flow, leukocyte adherence, and the coagulation cascade. Extracellular ligands such as intercellular adhesion molecules, vascular cell adhesion molecules, and the selectins (E-selectin, P-selectin) are expressed on the surface of endothelial cells and are responsible for leukocyte adhesion to the endothelium. This interaction allows activated neutrophils to migrate into the tissues to combat infection, but also can lead to PMN-mediated cytotoxicity and microvascular and tissue injury. Cell Signaling A host of cellular changes occur following shock. Although many of the intracellular and intercellular pathways that are important in shock are being elucidated, undoubtedly there are many more that have yet to be identified. Many of the mediators produced during shock interact with cell surface receptors on target cells to alter target cell metabolism. These signaling pathways may be altered by changes in cellular oxygenation, redox state, high-energy phosphate concentration, gene expression, or intracellular electrolyte concentration induced by shock. Cells communicate with their external environment through the use of cell surface membrane receptors, which, once bound by a ligand, transmit their information to the interior of the cell through a variety of signaling cascades. These signaling pathways may subsequently alter the activity of specific enzymes or the expression or breakdown of important proteins or affect VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Hypovolemic/Hemorrhagic The most common cause of shock in the surgical or trauma patient is loss of circulating volume from hemorrhage. Acute blood loss results in reflexive decreased baroreceptor stimulation from stretch receptors in the large arteries, resulting in decreased inhibition of vasoconstrictor centers in the brain stem, increased chemoreceptor stimulation of vasomotor centers, and diminished output from atrial stretch receptors. These changes increase vasoconstriction and peripheral arterial resistance. Hypovolemia also induces sympathetic stimulation, leading to epinephrine and norepinephrine release, activation of the renin-angiotensin cascade, and increased vasopressin release. Peripheral vasoconstriction Magnitude of response Magnitude of response Complicated outcome Uncomplicated outcome 119 Shock FORMS OF SHOCK Dysregulated innate immune response CHAPTER 5 intracellular energy metabolism. Intracellular calcium (Ca2+) homeostasis and regulation represent one such pathway. Intracellular Ca2+ concentrations regulate many aspects of cellular metabolism; many important enzyme systems require Ca2+ for full activity. Profound changes in intracellular Ca2+ levels and Ca2+ transport are seen in models of shock.37 Alterations in Ca2+ regulation may lead to direct cell injury, changes in transcription factor activation, alterations in the expression of genes important in homeostasis, and the modulation of the activation of cells by other shock-induced hormones or mediators.38,39 A proximal portion of the intracellular signaling cascade consists of a series of kinases that transmit and amplify the signal through the phosphorylation of target proteins. The O2 radicals produced during shock and the intracellular redox state are known to influence the activity of components of this cascade, such as protein tyrosine kinases, mitogen activated kinases, and protein kinase C.40-42 Either through changes in these signaling pathways, changes in the activation of enzyme systems through Ca2+-mediated events, or direct conformational changes to oxygen-sensitive proteins, O2 radicals also regulate the activity of a number of transcription factors that are important in gene expression, such as nuclear factor-κB, APETALA1, and hypoxia-inducible factor 1.43,44 It is therefore becoming increasingly clear that oxidant-mediated direct cell injury is merely one consequence of the production of O2 radicals during shock. The study of the effects of shock on the regulation of gene expression as an important biologic effect was stimulated by the work of Buchman and colleagues.45 The effects of shock on the expression and regulation of numerous genes and gene products has been studied in both experimental animal models and human patients. These studies include investigations into single genes of interest as well as large-scale genomic and proteomic analysis.46-48 Changes in gene expression are critical for adaptive and survival cell signaling. Polymorphisms in gene promoters that lead to a differential level of expression of gene products are also likely to contribute significantly to varied responses to similar insults.49,50 In a recent study, the genetic responses to traumatic injury in humans or endotoxin delivery to healthy human volunteers demonstrated that severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways.51 The similarities in genomic responses between different injuries revealed a fundamental human response to stressors involving dysregulated immune responses (Fig. 5-6). Furthermore, in the traumatic injury patients, complications like nosocomial infections and organ failure were not associated with any genomic evidence of a second hit and differed only in the magnitude and duration of this genomic reprioritization. Dysregulated adaptive immune response Figure 5-6. The concurrent dysregulated innate immune responses that promote inflammation and dysregulated adaptive immune responses that result in immunosuppression occur in patients following traumatic injury. However, these genetic responses can result in complicated outcomes in trauma patients if the magnitude or duration of these responses is pronounced. (Reproduced with permission from Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208:2581– 2590. © 2011 Xiao et al. doi: 10.1084/jem.20111354.) is prominent, while lack of sympathetic effects on cerebral and coronary vessels and local autoregulation promote maintenance of cardiac and CNS blood flow. Diagnosis. Treatment of shock is initially empiric. A secure airway must be confirmed or established and volume infusion initiated while the search for the cause of the hypotension is pursued. Shock in a trauma patient or postoperative patient should be presumed to be due to hemorrhage until proven otherwise. The clinical signs of shock may be evidenced by agitation, cool clammy extremities, tachycardia, weak or absent peripheral pulses, and hypotension. Such apparent clinical shock results from at least 25% to 30% loss of the blood volume. However, substantial volumes of blood may be lost before the classic clinical manifestations of shock are evident. Thus, when a patient is significantly tachycardic or hypotensive, this represents both significant blood loss and physiologic decompensation. The clinical and physiologic response to hemorrhage has been classified according to the magnitude of volume loss. Loss of up to 15% of the circulating volume (700–750 mL for a 70-kg patient) may produce little in terms of obvious symptoms, while loss of up to 30% of the circulating volume (1.5 L) may result in mild tachycardia, tachypnea, and anxiety. Hypotension, marked tachycardia (i.e., pulse greater than 110–120 beats per minute [bpm]), and confusion may not be evident until more than 30% of the blood volume has been lost; loss of 40% of circulating volume (2 L) is immediately life threatening and generally requires operative control of bleeding (Table 5-5). Young healthy patients with vigorous compensatory mechanisms may tolerate larger volumes of blood loss while manifesting fewer clinical signs despite the presence of significant peripheral hypoperfusion. These patients may maintain a near-normal blood pressure until a precipitous cardiovascular collapse occurs. Elderly patients may be taking medications that either promote bleeding (e.g., warfarin or aspirin) or mask the compensatory responses VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 120 Table 5-5 Classification of hemorrhage Parameter I II III IV <750 750–1500 1500–2000 >2000 <15 15–30 30–40 >40 Heart rate (bpm) <100 >100 >120 >140 Blood pressure Normal Orthostatic Hypotension Severe hypotension CNS symptoms Normal Anxious Confused Obtunded bpm = beats per minute; CNS = central nervous system. to bleeding (e.g., β-blockers). In addition, atherosclerotic vascular disease, diminishing cardiac compliance with age, inability to elevate heart rate or cardiac contractility in response to hemorrhage, and overall decline in physiologic reserve decrease the elderly patient’s ability to tolerate hemorrhage. Recent data in trauma patients suggest that a systolic blood pressure (SBP) of less than 110 mmHg is a clinically relevant definition of hypotension and hypoperfusion based on an increasing rate of mortality below this pressure (Fig. 5-7).52 In addressing the sensitivity of vital signs and identifying major thoracoabdominal hemorrhage, a study retrospectively identified patients with injury to the trunk and an abbreviated injury score of 3 or greater who required immediate surgical intervention and transfusion of at least 5 units of blood within the first 24 hours. Ninety-five percent of patients had a heart rate greater than 80 bpm at some point during their postinjury course. However, only 59% of patients achieved a heart rate greater than 120 bpm. Ninety-nine percent of all patients had a recorded blood pressure of less than 120 mmHg at some point. Ninety-three percent of all patients had a recorded SBP of less than 100 mmHg.53 A more recent study corroborated that tachycardia was not a reliable sign of hemorrhage following trauma and was present in only 65% of hypotensive patients.54 Serum lactate and base deficit are measurements that are helpful to both estimate and monitor the extent of bleeding and shock. The amount of lactate that is produced by anaerobic respiration is an indirect marker of tissue hypoperfusion, cellular O2 debt, and the severity of hemorrhagic shock. Several studies have demonstrated that the initial serum lactate and serial lactate levels are reliable predictors of morbidity and mortality with hemorrhage following trauma (Fig. 5-8).55 Similarly, base deficit values derived from arterial blood gas analysis provide clinicians with an indirect estimation of tissue acidosis from hypoperfusion. Davis and colleagues stratified the extent of base deficit into mild (–3 to –5 mmol/L), moderate (–6 to –9 mmol/L), and severe (less than –10 mmol/L), and from this established a correlation between base deficit upon admission and transfusion requirements, the development of multiple organ failure, and death (Fig. 5-9).56 Both base deficit and lactate correlate with the extent of shock and patient outcome, but interestingly do not firmly correlate with each other.57-59 Evaluation of both values may be useful in trauma patients with hemorrhage. Although hematocrit changes may not rapidly reflect the total volume of blood loss, admission hematocrit has been shown to be associated with 24-hour fluid and transfusion requirements and more strongly associated with packed red blood cell transfusion than tachycardia, hypotension, or acidosis.60 It must be noted that lack of a depression in the initial hematocrit does not rule out substantial blood loss or ongoing bleeding. In management of trauma patients, understanding the patterns of injury of the patient in shock will help direct the evaluation and management. Identifying the sources of blood loss in patients with penetrating wounds is relatively simple because potential bleeding sources will be located along the known or suspected path of the wounding object. Patients with penetrating injuries who are in shock usually require operative intervention. Patients who suffer multisystem injuries from blunt trauma have multiple sources of potential hemorrhage. Blood loss sufficient to cause shock is generally of a large volume, and there are a limited number of sites that can harbor sufficient extravascular 30 % Mortality BD 25 12 10 20 8 15 6 10 4 5 2 0 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 Systolic BP in the ED Base deficit BASIC CONSIDERATIONS Blood loss (mL) Blood loss (%) % Mortality PART I Class 0 Figure 5-7. The relationship between systolic blood pressure and mortality in trauma patients with hemorrhage. These data suggest that a systolic blood pressure of less than 110 mmHg is a clinically relevant definition of hypotension and hypoperfusion based on an increasing rate of mortality below this pressure. Base deficit (BD) is also shown on this graph. ED = emergency department. (Reproduced with permission from Eastridge BJ, Salinas J, McManus JG, et al.52 Hypotension begins at 110 mm Hg: redefining “hypotension” with data. J Trauma. 2007;63:291–297.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 20 90 15 60 10 30 5 0 1 2 3 Time (hours) 4 Tissue lactate ( M/gm tissue) 120 5 Figure 5-8. Progressive increases in serum lactate, muscle lactate, and liver lactate in a baboon model of hemorrhagic shock. (From Peitzman et al,7 with permission. Reprinted with permission from the Journal of the American College of Surgeons, formerly Surgery Gynecology & Obstetrics) 100 95 90 85 80 λ 75 % Mortality = e x 100 70 1 + eλ 65 60 55 50 LD50 45 40 35 30 25 Base excess = –11.8 20 15 10 5 0 10 2 –6 –14 –22 Treatment. Control of ongoing hemorrhage is an essential component of the resuscitation of the patient in shock. As mentioned in the earlier Diagnosis section, treatment of hemorrhagic shock is instituted concurrently with diagnostic evaluation to identify a source. Patients who fail to respond to initial resuscitative efforts should be assumed to have ongoing active hemorrhage from large vessels and require prompt 100 –19.2 –23.5 90 80 % Observed death % Mortality blood volume to induce hypotension (e.g., external, intrathoracic, intra-abdominal, retroperitoneal, and long bone fractures). In the nontrauma patient, the GI tract must always be considered as a site for blood loss. Substantial blood loss externally may be suspected from prehospital medical reports documenting a substantial blood loss at the scene of an accident, history of massive blood loss from wounds, visible brisk bleeding, or presence of a large hematoma adjacent to an open wound. Injuries to major arteries or veins with associated open wounds may cause massive blood loss rapidly. Direct pressure must be applied and 60 –11.8 50 –14 –9.7 40 –7.4 30 20 –38 –16.4 70 –4.5 –0.17 10 –0.19 0 10 0 20 30 40 50 60 70 80 90 100 % Predicted death on the basis of linear logistic model from BEAECF Extracellular BEA, mmol/L Figure 5-9. The relationship between base deficit (negative base excess) and mortality in trauma patients. BEA = base excess arterial; ECF = extracellular fluid. (Reproduced with permission from Siegel JH, Rivkind AI, Dalal S, et al. Early physiologic predictors of injury severity and death in blunt multiple trauma. Arch Surg. 1990;125:498. Copyright © 1990 American Medical Association. All rights reserved.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Shock Serum lactate (mg/100 ml) 25 121 CHAPTER 5 Muscle lactate Serum lactate Liver lactate 150 sustained to minimize ongoing blood loss. Persistent bleeding from uncontrolled smaller vessels can, over time, precipitate shock if inadequately treated. When major blood loss is not immediately visible in the setting of trauma, internal (intracavitary) blood loss should be suspected. Each pleural cavity can hold 2 to 3 L of blood and can therefore be a site of significant blood loss. Diagnostic and therapeutic tube thoracostomy may be indicated in unstable patients based on clinical findings and clinical suspicion. In a more stable patient, a chest radiograph may be obtained to look for evidence of hemothorax. Major retroperitoneal hemorrhage typically occurs in association with pelvic fractures, which is confirmed by pelvic radiography in the resuscitation bay. Intraperitoneal hemorrhage is probably the most common source of blood loss inducing shock. The physical exam for detection of substantial blood loss or injury is insensitive and unreliable; large volumes of intraperitoneal blood may be present before physical examination findings are apparent. Findings with intra-abdominal hemorrhage include abdominal distension, abdominal tenderness, or visible abdominal wounds. Hemodynamic abnormalities generally stimulate a search for blood loss before the appearance of obvious abdominal findings. Adjunctive tests are essential in the diagnosis of intraperitoneal bleeding; intraperitoneal blood may be rapidly identified by diagnostic ultrasound or diagnostic peritoneal lavage. Furthermore, patients who have sustained high-energy blunt trauma who are hemodynamically stable or who have normalized their vital signs in response to initial volume resuscitation should undergo computed tomography scans to assess for head, chest, and/or abdominal bleeding. 122 PART I BASIC CONSIDERATIONS operative intervention. Based on trauma literature, patients with ongoing hemorrhage demonstrate increased survival if the elapsed time between the injury and control of bleeding is decreased. Although there are no randomized controlled trials, retrospective studies provide compelling evidence in this regard. To this end, Clarke and colleagues61 demonstrated that trauma patients with major injuries isolated to the abdomen requiring emergency laparotomy had an increased probability of death with increasing length of time in the emergency department for patients who were in the emergency department for 90 minutes or less. This probability increased approximately 1% for each 3 minutes in the emergency department. The appropriate priorities in these patients are (a) secure the airway, (b) control the source of blood loss, and (c) intravenous (IV) volume resuscitation. In trauma, identifying the body cavity harboring active hemorrhage will help focus operative efforts; however, because time is of the essence, rapid treatment is essential and diagnostic laparotomy or thoracotomy may be indicated. The actively bleeding patient cannot be resuscitated until control of ongoing hemorrhage is achieved. Our current understanding has led to the management strategy known as damage control resuscitation.62 This strategy begins in the emergency department and continues into the operating room and into the intensive care unit (ICU). Initial resuscitation is limited to keep SBP around 80 to 90 mmHg. This prevents renewed bleeding from recently clotted vessels. Resuscitation and intravascular volume resuscitation are accomplished with blood products and limited crystalloids, which is addressed 4 further later in this section.Too little volume allowing persistent severe hypotension and hypoperfusion is dangerous, yet too vigorous of a volume resuscitation may be just as deleterious. Control of hemorrhage is achieved in the operating room, and efforts to warm patients and to prevent coagulopathy using multiple blood products and pharmacologic agents are used in both the operating room and ICU. Cannon and colleagues first made the observation that attempts to increase blood pressure in soldiers with uncontrolled sources of hemorrhage is counterproductive, with increased bleeding and higher mortality.3 This work was the foundation for the “hypotensive resuscitation” strategies. Several laboratory studies confirmed the observation that attempts to restore normal blood pressure with fluid infusion or vasopressors were rarely successful and resulted in more bleeding and higher mortality.63 A prospective, randomized clinical study compared delayed fluid resuscitation (upon arrival in the operating room) with standard fluid resuscitation (with arrival by the paramedics) in hypotensive patients with penetrating torso injury.64 The authors reported that delayed fluid resuscitation resulted in lower patient mortality. Further laboratory studies demonstrated that fluid restriction in the setting of profound hypotension resulted in early deaths from severe hypoperfusion. These studies also showed that aggressive crystalloid resuscitation attempting to normalize blood pressure resulted in marked hemodilution, with hematocrits of 5%.63 Reasonable conclusions in the setting of uncontrolled hemorrhage include: Any delay in surgery for control of hemorrhage increases mortality; with uncontrolled hemorrhage attempting to achieve normal blood pressure may increase mortality, particularly with penetrating injuries and short transport times; a goal of SBP of 80 to 90 mmHg may be adequate in the patient with penetrating injury; and profound hemodilution should be avoided by early transfusion of red blood cells. For the patient with blunt injury, where the major cause of death is a closed head injury, the increase in mortality with hypotension in the setting of brain injury must be avoided. In this setting, an SBP of 110 mmHg would seem to be more appropriate. Patients who respond to initial resuscitative effort but then deteriorate hemodynamically frequently have injuries that require operative intervention. The magnitude and duration of their response will dictate whether diagnostic maneuvers can be performed to identify the site of bleeding. However, hemodynamic deterioration generally denotes ongoing bleeding for which some form of intervention (i.e., operation or interventional radiology) is required. Patients who have lost significant intravascular volume, but whose hemorrhage is controlled or has abated, often will respond to resuscitative efforts if the depth and duration of shock have been limited. A subset of patients exists who fail to respond to resuscitative efforts despite adequate control of ongoing hemorrhage. These patients have ongoing fluid requirements despite adequate control of hemorrhage, have persistent hypotension despite restoration of intravascular volume necessitating vasopressor support, and may exhibit a futile cycle of uncor5 rectable hypoperfusion, acidosis, and coagulopathy that cannot be interrupted despite maximum therapy. These patients have deteriorated to decompensated or irreversible shock with peripheral vasodilation and resistance to vasopressor infusion. Mortality is inevitable once the patient manifests shock in its terminal stages. Unfortunately, this is often diagnosed in retrospect. Fluid resuscitation is a major adjunct to physically controlling hemorrhage in patients with shock. The ideal type of fluid to be used continues to be debated; however, crystalloids continue to be the mainstay of fluid choice. Several studies have demonstrated increased risk of death in bleeding trauma patients treated with colloid compared to patients treated with crystalloid.65 In patients with severe hemorrhage, restoration of intravascular volume should be achieved with blood products.66 Ongoing studies continue to evaluate the use of hypertonic saline as a resuscitative adjunct in bleeding patients.67 The benefit of hypertonic saline solutions may be immunomodulatory. Specifically, these effects have been attributed to pharmacologic effects resulting in decreased reperfusion-mediated injury with decreased O2 radical formation, less impairment of immune function compared to standard crystalloid solution, and less brain swelling in the multi-injured patient. The reduction of total volume used for resuscitation makes this approach appealing as a resuscitation agent for combat injuries and may contribute to a decrease in the incidence of ARDS and multiple organ failure. Transfusion of packed red blood cells and other blood products is essential in the treatment of patients in hemorrhagic shock. Current recommendations in stable ICU patients aim for a target hemoglobin of 7 to 9 g/dL68,69; however, no prospective randomized trials have compared restrictive and liberal transfusion regimens in trauma patients with hemorrhagic shock. The current standard in severely injured patients is termed damage control resuscitation and consists of transfusion with red blood cells, fresh frozen plasma (FFP), and platelet units given in equal number.70 Civilian and military trauma data show that the development of coagulopathy of trauma is predictive of mortality.71 Data collected from a U.S. Army combat support hospital helped to propagate this practice, showing in patients who received massive transfusion of packed red blood cells (>10 units in 24 hours) that a high plasma-to-RBC ratio (1:1.4 units) was independently VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 70 1 34% 30 19% 20 10 (Low) 1:8 (Medium) 1:2.5 (High) 1:1.4 Plasma:RBC ratio groups 3 4 5 Shock 0 2 CHAPTER 5 40 Time to treatment (h) 50 Mortality 123 0 65% 60 6 7 Figure 5-10. Increasing ratio of transfusion of fresh frozen plasma to red blood cells improves outcome of trauma patients receiving massive transfusions. RBC = red blood cell. (Reproduced with permission from Borgman MA, Spinella PC, Perkins JG, et al.72 The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63:805-813.) associated with improved survival (Fig. 5-10).72 A number of civilian studies have demonstrated similar results.73 Similarly, platelet transfusion is important. Studies have demonstrated that low platelet counts in trauma patients were associated with increased mortality74 and that increased platelet use appears to improve outcome.75,76 The benefit of platelet transfusion may be most pronounced in trauma patients with brain injury.77 Platelets should be transfused in the bleeding patient to maintain counts above 50 × 109/L. There is a potential role for other coagulation factor-based products, such as fibrinogen concentrates and prothrombin complex concentrates. Use of these agents may be guided by a drop in fibrinogen levels to less than 1 g/L or, less specifically, by thromboelastogram findings to suggest hyperfibrinolysis. Data also support the use of antifibrinolytic agents in bleeding trauma patients, specifically tranexamic acid (a synthetic lysine analogue that acts as a competitive inhibitor of plasmin and plasminogen). The multinational Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH-2) trial suggested that early use of tranexamic acid limits rebleeding and reduces mortality78 (Fig. 5-11). In the past, coagulopathy associated with the bleeding patient was presumed to be due solely to dilution and depletion of clotting factors and platelets. We now understand that an acute coagulopathy of trauma occurs as an immediate consequence of injury, with abnormal admission coagulation as a predictor of high mortality.79 Traditional measurement of platelets, international normalized ratio, and partial thromboplastin time may not reflect the coagulopathy of trauma or response to therapy effectively. Recently, thromboelastography (TEG) has been used as a quicker, more comprehensive determination of coagulopathy and fibrinolysis in the injured patient. Holcomb and colleagues recently reported that TEG predicted patients with substantial bleeding and red cell transfusion better than conventional coagulopathy tests, need for platelet transfusion better than platelet count, and need for plasma transfusion better than fibrinogen levels.80 Additional resuscitative adjuncts in patients with hemorrhagic shock include minimization of heat loss and maintaining normothermia. The development of hypothermia in the bleeding patient is associated with acidosis, hypotension, and coagulopathy. 8 0.5 1.0 1.5 2.0 2.5 OR (95% CI) of tranexamic acid 3.0 Figure 5-11. Early treatment (within 3 hours) of trauma patients with tranexamic acid reduces mortality. However, later treatment exacerbated outcome. OR = odds ratio. (Reprinted from Roberts I, Shakur H, Afolabi A, et al.78 The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRAST-2 randomised controlled trial. The Lancet. 2011;377:10961101. Copyright ©2011 with permission from Elsevier.) Hypothermia in bleeding trauma patients is an independent risk factor for bleeding and death. This likely is secondary to impaired platelet function and impairments in the coagulation cascade. Several studies have investigated the induction of controlled hypothermia in patients with severe shock based on the hypothesis of limiting metabolic activity and energy requirements, creating a state of “suspended animation.” These studies are promising and continue to be evaluated in large trials. Traumatic Shock The systemic response after trauma, combining the effects of soft tissue injury, long bone fractures, and blood loss, is clearly a different physiologic insult than simple hemorrhagic shock. Multiple organ failure, including ARDS, develops relatively often in the blunt trauma patient, but rarely after pure hemorrhagic shock (such as a GI bleed). The hypoperfusion deficit in traumatic shock is magnified by the proinflammatory activation that occurs following the induction of shock. In addition to ischemia or ischemia-reperfusion, accumulating evidence demonstrates that even simple hemorrhage induces proinflammatory activation that results in many of the cellular changes typically ascribed only to septic shock.81,82 At the cellular level, this may be attributable to the release of cellular products termed damage-associated molecular patterns (DAMPs; i.e., riboxynucleic acid, uric acid, and high mobility group box 1) that activate the same set of cell surface receptors as bacterial products, initiating similar cell signaling.5,83 These receptors are termed pattern recognition receptors (PRRs) and include the TLR family of proteins. Examples of traumatic shock include small-volume hemorrhage accompanied by soft tissue injury (femur fracture, crush injury) or any combination of hypovolemic, neurogenic, cardiogenic, and obstructive shock that precipitates rapidly progressive proinflammatory activation. In laboratory models of traumatic shock, the addition of a soft tissue or long bone injury to hemorrhage produces lethality with significantly less blood loss when the animals are stressed by hemorrhage. Treatment of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 124 PART I traumatic shock is focused on correction of the individual elements to diminish the cascade of proinflammatory activation and includes prompt control of hemorrhage, adequate volume resuscitation to correct O2 debt, débridement of nonviable tissue, stabilization of bony injuries, and appropriate treat6 ment of soft tissue injuries. Septic Shock (Vasodilatory Shock) BASIC CONSIDERATIONS In the peripheral circulation, profound vasoconstriction is the typical physiologic response to the decreased arterial pressure and tissue perfusion with hemorrhage, hypovolemia, or acute heart failure. This is not the characteristic response in vasodilatory shock. Vasodilatory shock is the result of dysfunction of the endothelium and vasculature secondary to circulating inflammatory mediators and cells or as a response to prolonged and severe hypoperfusion. Thus, in vasodilatory shock, hypotension results from failure of the vascular smooth muscle to constrict appropriately. Vasodilatory shock is characterized by peripheral vasodilation with resultant hypotension and resistance to treatment with vasopressors. Despite the hypotension, plasma catecholamine levels are elevated, and the renin-angiotensin system is activated in vasodilatory shock. The most frequently encountered form of vasodilatory shock is septic shock. Other causes of vasodilatory shock include hypoxic lactic acidosis, carbon monoxide poisoning, decompensated and irreversible hemorrhagic shock, terminal cardiogenic shock, and postcardiotomy shock (Table 5-6). Thus, vasodilatory shock seems to represent the final common pathway for profound and prolonged shock of any etiology.84 Despite advances in intensive care, the mortality rate for severe sepsis remains at 30% to 50%. In the United States, 750,000 cases of sepsis occur annually, one third of which are fatal.85 Sepsis accounts for 9.3% of deaths in the United States, as many yearly as MI. Septic shock is a by-product of the body’s response to disruption of the host-microbe equilibrium, resulting in invasive or severe localized infection. In the attempt to eradicate the pathogens, the immune and other cell types (e.g., endothelial cells) elaborate soluble mediators that enhance macrophage and neutrophil killing effector mechanisms, increase procoagulant activity and fibroblast activity to localize the invaders, and increase microvascular blood flow to enhance delivery of killing forces to the area of invasion. When this response is overly exuberant or becomes systemic rather than localized, manifestations of sepsis may be evident. Table 5-6 Causes of septic and vasodilatory shock Systemic response to infection Noninfectious systemic inflammation Pancreatitis Burns Anaphylaxis Acute adrenal insufficiency Prolonged, severe hypotension Hemorrhagic shock Cardiogenic shock Cardiopulmonary bypass Metabolic Hypoxic lactic acidosis Carbon monoxide poisoning These findings include enhanced cardiac output, peripheral vasodilation, fever, leukocytosis, hyperglycemia, and tachycardia. In septic shock, the vasodilatory effects are due, in part, to the upregulation of the inducible isoform of nitric oxide synthase (iNOS or NOS 2) in the vessel wall. iNOS produces large quantities of nitric oxide for sustained periods of time. This potent vasodilator suppresses vascular tone and renders the vasculature resistant to the effects of vasoconstricting agents. Diagnosis. Attempts to standardize terminology have led to the establishment of criteria for the diagnosis of sepsis in the hospitalized adult. These criteria include manifestations of the host response to infection in addition to identification of an offending organism. The terms sepsis, severe sepsis, and septic shock are used to quantify the magnitude of the systemic inflammatory reaction. Patients with sepsis have evidence of an infection, as well as systemic signs of inflammation (e.g., fever, leukocytosis, and tachycardia). Hypoperfusion with signs of organ dysfunction is termed severe sepsis. Septic shock requires the presence of the above, associated with more significant evidence of tissue hypoperfusion and systemic hypotension. Beyond the hypotension, maldistribution of blood flow and shunting in the microcirculation further compromise delivery of nutrients to the tissue beds.86,87 Recognizing septic shock begins with defining the patient at risk. The clinical manifestations of septic shock will usually become evident and prompt the initiation of treatment before bacteriologic confirmation of an organism or the source of an organism is identified. In addition to fever, tachycardia, and tachypnea, signs of hypoperfusion such as confusion, malaise, oliguria, or hypotension may be present. These should prompt an aggressive search for infection, including a thorough physical examination, inspection of all wounds, evaluation of intravascular catheters or other foreign bodies, obtaining appropriate cultures, and adjunctive imaging studies, as needed. Treatment. Evaluation of the patient in septic shock begins with an assessment of the adequacy of their airway and ventilation. Severely obtunded patients and patients whose work of breathing is excessive require intubation and ventilation to prevent respiratory collapse. Because vasodilation and decrease in total peripheral resistance may produce hypotension, fluid resuscitation and restoration of circulatory volume with balanced salt solutions is essential. This resuscitation should be at least 30 mL/kg within the first 4 to 6 hours. Incremental fluid boluses should be continued based on the endpoint of resuscitation, including clearance of lactate. Starch-based colloid solutions should be avoided, as recent evidence suggests that these fluids may be deleterious in the setting of sepsis.86,88,89 Empiric antibiotics must be chosen carefully based on the most likely pathogens (gram-negative rods, gram-positive cocci, and anaerobes) because the portal of entry of the offending organism and its identity may not be evident until culture data return or imaging studies are completed. Knowledge of the bacteriologic profile of infections in an individual unit can be obtained from most hospital infection control departments and will suggest potential responsible organisms. Antibiotics should be tailored to cover the responsible organisms once culture data are available, and if appropriate, the spectrum of coverage narrowed. Long-term, empiric, broad-spectrum antibiotic use should be minimized to reduce the development of resistant organisms and to avoid the potential complications of fungal overgrowth and antibioticassociated colitis from overgrowth of Clostridium difficile. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surviving Sepsis Campaign Bundles To be Completed Within 3 Hours: 1) Measure lactate level 2) Obtain blood cultures prior to administration of antibiotics 3) Administer broad spectrum antibiotics 4) Administer 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L To be Completed Within 6 Hours: 5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg 6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L (36 mg/dL): - Measure central venous pressure (CVP)* - Measure central venous oxygen saturation (Scvo2)* 7) Remeasure lactate if initial lactate was elevated* *Targets for quantitative resuscitation included in the guidelines are CVP of ≥ 8 mm Hg, Scvo2 of ≥ 70%, and normalization of lactate. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 5-12. Updated bundles of care from the Surviving Sepsis Campaign 2012. (From Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165228, Figure 1. With kind permission from Springer Science + Business Media.) 125 Shock demand. They found that goal-directed therapy during the first 6 hours of hospital stay (initiated in the emergency department) had significant effects, such as higher mean venous O2 saturation, lower lactate levels, lower base deficit, higher pH, and decreased 28-day mortality (49.2% vs. 33.3%) compared to the standard therapy group. The frequency of sudden cardiovascular collapse was also significantly less in the group managed with goal-directed therapy (21.0% vs. 10.3%). Interestingly, the goaldirected therapy group received more IV fluids during the initial 6 hours, but the standard therapy group required more IV fluids by 72 hours. The authors emphasize that continued cellular and tissue decompensation is subclinical and often irreversible when obvious clinically. Goal-directed therapy allowed identification and treatment of these patients with insidious illness (global tissue hypoxia in the setting of normal vital signs). Hyperglycemia and insulin resistance are typical in critically ill and septic patients, including patients without underlying diabetes mellitus. A recent study reported significant positive impact of tight glucose management on outcome in critically ill patients.91 The two treatment groups in this randomized, prospective study were assigned to receive intensive insulin therapy (maintenance of blood glucose between 80 and 110 mg/dL) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg/dL, with a goal between 180 and 200 mg/dL). The mean morning glucose level was significantly higher in the conventional treatment as compared to the intensive insulin therapy group (153 vs. 103 mg/dL). Mortality in the intensive insulin treatment group (4.6%) was significantly lower than in the conventional treatment group (8.0%), representing a 42% reduction in mortality. This reduction in mortality was most notable in the patients requiring longer than 5 days in the ICU. Furthermore, intensive insulin therapy reduced episodes of septicemia by 46%, reduced duration of antibiotic therapy, and decreased the need for prolonged ventilatory support and renal replacement therapy. Another treatment protocol that has been demonstrated to increase survival in patients with ARDS investigated the use of lower ventilatory tidal volumes compared to traditional tidal volumes.92 The majority of the patients enrolled in this multicenter, randomized trial developed ARDS secondary to pneumonia or sepsis. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 mL/kg of predicted body weight, with ventilation with a lower tidal CHAPTER 5 IV antibiotics will be insufficient to adequately treat the infectious episode in the settings of infected fluid collections, infected foreign bodies, and devitalized tissue. These situations require source control and involve percutaneous drainage and operative management to target a focus of infection. These situations may require multiple operations to ensure proper wound hygiene and healing. After first-line therapy of the septic patient with antibiotics, IV fluids, and intubation if necessary, vasopressors may be necessary to treat patients with septic shock. Catecholamines are the vasopressors used most often, with norepinephrine being the first-line agent followed by epinephrine. Occasionally, patients with septic shock will develop arterial resistance to catecholamines. Arginine vasopressin, a potent vasoconstrictor, is often efficacious in this setting and is often added to norepinephrine. The majority of septic patients have hyperdynamic physiology with supranormal cardiac output and low systemic vascular resistance. On occasion, septic patients may have low cardiac output despite volume resuscitation and even vasopressor support. Dobutamine therapy is recommended for patients with cardiac dysfunction as evidenced by high filling pressures and low cardiac output or clinical signs of hypoperfusion after achievement of restoration of blood pressure following fluid resuscitation. Mortality in this group is high. Despite the increasing incidence of septic shock over the past several decades, the overall mortality rates have changed little. Studies of interventions, including immunotherapy, resuscitation to pulmonary artery endpoints with hemodynamic optimization (cardiac output and O2 delivery, even to supranormal values), and optimization of mixed venous O2 measurements up to 72 hours after admission to the ICU, have not changed mortality. Over the past decade, multiple advances have been made in the treatment of patients with sepsis and septic shock and collaborative groups such as the Surviving Sepsis Campaign continue to evaluate, modify, and put forth recommendations based on data (Fig. 5-12).86 Negative results from previous studies have led to the suggestion that earlier interventions directed at improving global tissue oxygenation may be of benefit. To this end, Rivers and colleagues reported that goal-directed therapy of septic shock and severe sepsis initiated in the emergency department and continued for 6 hours significantly improved outcome.90 This approach involved adjustment of cardiac preload, afterload, and contractility to balance O2 delivery with O2 126 PART I BASIC CONSIDERATIONS volume, which involved an initial tidal volume of 6 mL/kg of predicted body weight. The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0% vs. 39.8%, P = .007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean ± SD, 12 ± 11 vs. 10 ± 11 days; P = .007). The investigators concluded that in patients with acute lung injury and ARDS, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use. Additional strategies in ARDS management include higher levels of positive end expiratory pressure (PEEP), alveolar recruitment maneuvers, and prone positioning. The use of corticosteroids in the treatment of sepsis and septic shock has been controversial for decades. The observation that severe sepsis often is associated with adrenal insufficiency or glucocorticoid receptor resistance has generated renewed interest in therapy for septic shock with corticosteroids. A single IV dose of 50 mg of hydrocortisone improved mean arterial blood pressure response relationships to norepinephrine and phenylephrine in patients with septic shock and was most notable in patients with relative adrenal insufficiency. A more recent study evaluated therapy with hydrocortisone (50 mg IV every 6 hours) and fludrocortisone (50 μg orally once daily) versus placebo for 1 week in patients with septic shock.93 As in earlier studies, the authors performed corticotropin tests on these patients to document and stratify patients by relative adrenal insufficiency. In this study, 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly and safely lowered the risk of death in patients with septic shock and relative adrenal insufficiency. In an international, multicenter, randomized trial of corticosteroids in sepsis (CORTICUS study; 499 analyzable patients), steroids showed no benefit in intentto-treat mortality or shock reversal.94 This study suggested that hydrocortisone therapy cannot be recommended as routine adjuvant therapy for septic shock. However, if SBP remains less than 90 mmHg despite appropriate fluid and vasopressor therapy, hydrocortisone at 200 mg/d for 7 days in four divided doses or by continuous infusion should be considered. Additional adjunctive immune modulation strategies have been developed for the treatment of septic shock. These include the use of antiendotoxin antibodies, anticytokine antibodies, cytokine receptor antagonists, immune enhancers, a non– isoform-specific nitric oxide synthase inhibitor, and O2 radical scavengers. These compounds are each designed to alter some aspect of the host immune response to shock that is hypothesized to play a key role in its pathophysiology. However, most of these strategies have failed to demonstrate efficacy in human patients despite utility in well-controlled animal experiments. It is unclear whether the failure of these compounds is due to poorly designed clinical trials, inadequate understanding of the interactions of the complex host immune response to injury and infection, or animal models of shock that poorly represent the human disease. Cardiogenic Shock Cardiogenic shock is defined clinically as circulatory pump failure leading to diminished forward flow and subsequent tissue hypoxia, in the setting of adequate intravascular volume. Hemodynamic criteria include sustained hypotension (i.e., SBP <90 mmHg for at least 30 minutes), reduced cardiac index (<2.2 L/min per square meter), and elevated pulmonary artery wedge pressure (>15 mmHg).95 Mortality rates for cardiogenic shock are 50% to 80%. Acute, extensive MI is the most common cause of cardiogenic shock; a smaller infarction in a patient with existing left ventricular dysfunction also may precipitate shock. Cardiogenic shock complicates 5% to 10% of acute MIs. Conversely, cardiogenic shock is the most common cause of death in patients hospitalized with acute MI. Although shock may develop early after MI, it typically is not found on admission. Seventy-five percent of patients who have cardiogenic shock complicating acute MIs develop signs of cardiogenic shock within 24 hours after onset of infarction (average 7 hours). Recognition of the patient with occult hypoperfusion is critical to prevent progression to obvious cardiogenic shock with its high mortality rate; early initiation of therapy to maintain blood pressure and cardiac output is vital. Rapid assessment, adequate resuscitation, and reversal of the myocardial ischemia are essential in optimizing outcome in patients with acute MI. Prevention of infarct extension is a critical component. Large segments of nonfunctional but viable myocardium contribute to the development of cardiogenic shock after MI. In the setting of acute MI, expeditious restoration of cardiac output is mandatory to minimize mortality; the extent of myocardial salvage possible decreases exponentially with increased time to restoration of coronary blood flow. The degree of coronary flow after percutaneous transluminal coronary angioplasty correlates with in-hospital mortality (i.e., 33% mortality with complete reperfusion, 50% mortality with incomplete reperfusion, and 85% mortality with absent reperfusion).96 Inadequate cardiac function can be a direct result of cardiac injury, including profound myocardial contusion, blunt cardiac valvular injury, or direct myocardial damage (Table 5-7).95-98 The pathophysiology of cardiogenic shock involves a vicious cycle of myocardial ischemia that causes myocardial dysfunction, which results in more myocardial ischemia. When sufficient mass of the left ventricular wall is necrotic or ischemic and fails to pump, the stroke Table 5-7 Causes of cardiogenic shock Acute myocardial infarction Pump failure Mechanical complications    Acute mitral regurgitation    Acute ventricular septal defect    Free wall rupture   Pericardial tamponade Arrhythmia End-stage cardiomyopathy Myocarditis Severe myocardial contusion Left ventricular outflow obstruction Aortic stenosis Hypertrophic obstructive cardiomyopathy Obstruction to left ventricular filling Mitral stenosis Left atrial myxoma Acute mitral regurgitation Acute aortic insufficiency Metabolic Drug reactions VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ failure and institution of corrective action are essential in preventing the ongoing spiral of decreased cardiac output from injury causing increased myocardial O2 needs that cannot be met, leading to progressive and unremitting cardiac dysfunction. In evaluation of possible cardiogenic shock, other causes of hypotension must be excluded, including hemorrhage, sepsis, pulmonary embolism, and aortic dissection. Signs of circulatory shock include hypotension, cool and mottled skin, depressed mental status, tachycardia, and diminished pulses. Cardiac exam may include dysrhythmia, precordial heave, or distal heart tones. Confirmation of a cardiac source for the shock requires electrocardiogram and urgent echocardiography. Other useful diagnostic tests include chest radiograph, arterial blood gases, electrolytes, complete blood count, and cardiac enzymes. Invasive cardiac monitoring, which generally is not necessary, can be useful to exclude right ventricular infarction, hypovolemia, and possible mechanical complications. Making the diagnosis of cardiogenic shock involves the identification of cardiac dysfunction or acute heart failure in a susceptible patient. In the setting of blunt traumatic injury, hemorrhagic shock from intra-abdominal bleeding, intrathoracic bleeding, and bleeding from fractures must be excluded, before implicating cardiogenic shock from blunt cardiac injury. Relatively few patients with blunt cardiac injury will develop cardiac pump dysfunction. Those who do generally exhibit cardiogenic shock early in their evaluation. Therefore, establishing the diagnosis of blunt cardiac injury is secondary to excluding other etiologies for shock and establishing that cardiac dysfunction is present. Invasive hemodynamic monitoring with a pulmonary artery catheter may uncover evidence of diminished cardiac output and elevated pulmonary artery pressure. Treatment. After ensuring that an adequate airway is present and ventilation is sufficient, attention should be focused on support of the circulation. Intubation and mechanical ventilation often are required, if only to decrease work of breathing and facilitate sedation of the patient. Rapidly excluding hypovolemia VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 127 Shock Diagnosis. Rapid identification of the patient with pump and establishing the presence of cardiac dysfunction are essential. Treatment of cardiac dysfunction includes maintenance of adequate oxygenation to ensure adequate myocardial O2 delivery and judicious fluid administration to avoid fluid overload and development of cardiogenic pulmonary edema. Electrolyte abnormalities, commonly hypokalemia and hypomagnesemia, should be corrected. Pain is treated with IV morphine sulfate or fentanyl. Significant dysrhythmias and heart block must be treated with antiarrhythmic drugs, pacing, or cardioversion, if necessary. Early consultation with cardiology is essential in current management of cardiogenic shock, particularly in the setting of acute MI.95 When profound cardiac dysfunction exists, inotropic support may be indicated to improve cardiac contractility and cardiac output. Dobutamine primarily stimulates cardiac β1 receptors to increase cardiac output but may also vasodilate peripheral vascular beds, lower total peripheral resistance, and lower systemic blood pressure through effects on β2 receptors. Ensuring adequate preload and intravascular volume is therefore essential prior to instituting therapy with dobutamine. Dopamine stimulates receptors (vasoconstriction), β1 receptors (cardiac stimulation), and β2 receptors (vasodilation), with its effects on β receptors predominating at lower doses. Dopamine may be preferable to dobutamine in treatment of cardiac dysfunction in hypotensive patients. Tachycardia and increased peripheral resistance from dopamine infusion may worsen myocardial ischemia. Titration of both dopamine and dobutamine infusions may be required in some patients. Epinephrine stimulates α and β receptors and may increase cardiac contractility and heart rate; however, it also may have intense peripheral vasoconstrictor effects that impair further cardiac performance. Catecholamine infusions must be carefully controlled to maximize coronary perfusion, while minimizing myocardial O2 demand. Balancing the beneficial effects of impaired cardiac performance with the potential side effects of excessive reflex tachycardia and peripheral vasoconstriction requires serial assessment of tissue perfusion using indices such as capillary refill, character of peripheral pulses, adequacy of urine output, or improvement in laboratory parameters of resuscitation such as pH, base deficit, and lactate. Invasive monitoring generally is necessary in these unstable patients. The phosphodiesterase inhibitors amrinone and milrinone may be required on occasion in patients with resistant cardiogenic shock. These agents have long half-lives and induce thrombocytopenia and hypotension, and use is reserved for patients unresponsive to other treatment. Patients whose cardiac dysfunction is refractory to cardiotonics may require mechanical circulatory support with an intraaortic balloon pump.100 Intra-aortic balloon pumping increases cardiac output and improves coronary blood flow by reduction of systolic afterload and augmentation of diastolic perfusion pressure. Unlike vasopressor agents, these beneficial effects occur without an increase in myocardial O2 demand. An intra-aortic balloon pump can be inserted at the bedside in the ICU via the femoral artery through either a cutdown or using the percutaneous approach. Aggressive circulatory support of patients with cardiac dysfunction from intrinsic cardiac disease has led to more widespread application of these devices and more familiarity with their operation by both physicians and critical care nurses. Preservation of existing myocardium and preservation of cardiac function are priorities of therapy for patients who have suffered an acute MI. Ensuring adequate oxygenation and O2 CHAPTER 5 volume decreases. An autopsy series of patients dying from cardiogenic shock has found damage to 40% of the left ventricle.99 Ischemia distant from the infarct zone may contribute to the systolic dysfunction in patients with cardiogenic shock. The majority of these patients have multivessel disease, with limited vasodilator reserve and pressure-dependent coronary flow in multiple areas of the heart. Myocardial diastolic function is impaired in cardiogenic shock as well. Decreased compliance results from myocardial ischemia, and compensatory increases in left ventricular filling pressures progressively occur. Diminished cardiac output or contractility in the face of adequate intravascular volume (preload) may lead to underperfused vascular beds and reflexive sympathetic discharge. Increased sympathetic stimulation of the heart, either through direct neural input or from circulating catecholamines, increases heart rate, myocardial contraction, and myocardial O2 consumption, which may not be relieved by increases in coronary artery blood flow in patients with fixed stenoses of the coronary arteries. Diminished cardiac output may also decrease coronary artery blood flow, resulting in a scenario of increased myocardial O2 demand at a time when myocardial O2 supply may be limited. Acute heart failure may also result in fluid accumulation in the pulmonary microcirculatory bed, decreasing myocardial O2 delivery even further. 128 PART I BASIC CONSIDERATIONS delivery, maintaining adequate preload with judicious volume restoration, minimizing sympathetic discharge through adequate relief of pain, and correcting electrolyte imbalances are all straightforward nonspecific maneuvers that may improve existing cardiac function or prevent future cardiac complications. Anticoagulation and aspirin are given for acute MI. Although thrombolytic therapy reduces mortality in patients with acute MI, its role in cardiogenic shock is less clear. Patients in cardiac failure from an acute MI may benefit from pharmacologic or mechanical circulatory support in a manner similar to that of patients with cardiac failure related to blunt cardiac injury. Additional pharmacologic tools may include the use of β-blockers to control heart rate and myocardial O2 consumption, nitrates to promote coronary blood flow through vasodilation, and ACE inhibitors to reduce ACE-mediated vasoconstrictive effects that increase myocardial workload and myocardial O2 consumption. Current guidelines of the American Heart Association recommend percutaneous transluminal coronary angiography for patients with cardiogenic shock, ST elevation, left bundlebranch block, and age less than 75 years.101,102 Early definition of coronary anatomy and revascularization is the pivotal step in treatment of patients with cardiogenic shock from acute MI.103 When feasible, percutaneous transluminal coronary angioplasty (generally with stent placement) is the treatment of choice. Coronary artery bypass grafting seems to be more appropriate for patients with multiple vessel disease or left main coronary artery disease. Obstructive Shock Although obstructive shock can be caused by a number of different etiologies that result in mechanical obstruction of venous return (Table 5-8), in trauma patients, this is most commonly due to the presence of tension pneumothorax. Cardiac tamponade occurs when sufficient fluid has accumulated in the pericardial sac to obstruct blood flow to the ventricles. The hemodynamic abnormalities in pericardial tamponade are due to elevation of intracardiac pressures with limitation of ventricular filling in diastole with resultant decrease in cardiac output. Acutely, the pericardium does not distend; thus small volumes of blood may produce cardiac tamponade. If the effusion accumulates slowly (e.g., in the setting of uremia, heart failure, or malignant effusion), the quantity of fluid producing cardiac tamponade may reach 2000 mL. The major determinant of the degree of hypotension is the pericardial pressure. With either cardiac tamponade or tension pneumothorax, reduced filling Table 5-8 Causes of obstructive shock Pericardial tamponade Pulmonary embolus Tension pneumothorax IVC obstruction Deep venous thrombosis Gravid uterus on IVC Neoplasm Increased intrathoracic pressure Excess positive end-expiratory pressure Neoplasm IVC = inferior vena cava. of the right side of the heart from either increased intrapleural pressure secondary to air accumulation (tension pneumothorax) or increased intrapericardial pressure precluding atrial filling secondary to blood accumulation (cardiac tamponade) results in decreased cardiac output associated with increased central venous pressure. Diagnosis and Treatment. The diagnosis of tension pneumothorax should be made on clinical examination. The classic findings include respiratory distress (in an awake patient), hypotension, diminished breath sounds over one hemithorax, hyperresonance to percussion, jugular venous distention, and shift of mediastinal structures to the unaffected side with tracheal deviation. In most instances, empiric treatment with pleural decompression is indicated rather than delaying to wait for radiographic confirmation. When a chest tube cannot be immediately inserted, such as in the prehospital setting, the pleural space can be decompressed with a large-caliber needle. Immediate return of air should be encountered with rapid resolution of hypotension. Unfortunately, not all of the clinical manifestations of tension pneumothorax may be evident on physical examination. Hyperresonance may be difficult to appreciate in a noisy resuscitation area. Jugular venous distention may be absent in a hypovolemic patient. Tracheal deviation is a late finding and often is not apparent on clinical examination. Practically, three findings are sufficient to make the diagnosis of tension pneumothorax: respiratory distress or hypotension, decreased lung sounds, and hypertympany to percussion. Chest x-ray findings that may be visualized include deviation of mediastinal structures, depression of the hemidiaphragm, and hypo-opacification with absent lung markings. As discussed earlier, definitive treatment of a tension pneumothorax is immediate tube thoracostomy. The chest tube should be inserted rapidly, but carefully, and should be large enough to evacuate any blood that may be present in the pleural space. Most recommend placement in the fourth intercostal space (nipple level) at the anterior axillary line. Cardiac tamponade results from the accumulation of blood within the pericardial sac, usually from penetrating trauma or chronic medical conditions such as heart failure or uremia. Although precordial wounds are most likely to injure the heart and produce tamponade, any projectile or wounding agent that passes in proximity to the mediastinum can potentially produce tamponade. Blunt cardiac rupture, a rare event in trauma victims who survive long enough to reach the hospital, can produce refractory shock and tamponade in the multiply-injured patient. The manifestations of cardiac tamponade, such as total circulatory collapse and cardiac arrest, may be catastrophic, or they may be more subtle. A high index of suspicion is warranted to make a rapid diagnosis. Patients who present with circulatory arrest from cardiac tamponade require emergency pericardial decompression, usually through a left thoracotomy. The indications for this maneuver are discussed in Chap. 7. Cardiac tamponade also may be associated with dyspnea, orthopnea, cough, peripheral edema, chest pain, tachycardia, muffled heart tones, jugular venous distention, and elevated central venous pressure. Beck’s triad consists of hypotension, muffled heart tones, and neck vein distention. Unfortunately, absence of these clinical findings may not be sufficient to exclude cardiac injury and cardiac tamponade. Muffled heart tones may be difficult to appreciate in a busy trauma center, and jugular venous distention and central venous pressure may be diminished by coexistent bleeding. Therefore, patients at risk for cardiac tamponade VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Neurogenic shock refers to diminished tissue perfusion as a result of loss of vasomotor tone to peripheral arterial beds. Loss of vasoconstrictor impulses results in increased vascular capacitance, decreased venous return, and decreased cardiac output. Neurogenic shock is usually secondary to spinal cord injuries from vertebral body fractures of the cervical or high thoracic region that disrupt sympathetic regulation of peripheral vascular tone (Table 5-9). Rarely, a spinal cord injury without 129 Causes of neurogenic shock Spinal cord trauma Spinal cord neoplasm Spinal/epidural anesthetic bony fracture, such as an epidural hematoma impinging on the spinal cord, can produce neurogenic shock. Sympathetic input to the heart, which normally increases heart rate and cardiac contractility, and input to the adrenal medulla, which increases catecholamine release, may also be disrupted, preventing the typical reflex tachycardia that occurs with hypovolemia. Acute spinal cord injury results in activation of multiple secondary injury mechanisms: (a) vascular compromise to the spinal cord with loss of autoregulation, vasospasm, and thrombosis; (b) loss of cellular membrane integrity and impaired energy metabolism; and (c) neurotransmitter accumulation and release of free radicals. Importantly, hypotension contributes to the worsening of acute spinal cord injury as the result of further reduction in blood flow to the spinal cord. Management of acute spinal cord injury with attention to blood pressure control, oxygenation, and hemodynamics, essentially optimizing perfusion of an already ischemic spinal cord, seems to result in improved neurologic outcome. Patients with hypotension from spinal cord injury are best monitored in an ICU and carefully followed for evidence of cardiac or respiratory dysfunction. Diagnosis. Acute spinal cord injury may result in bradycardia, hypotension, cardiac dysrhythmias, reduced cardiac output, and decreased peripheral vascular resistance. The severity of the spinal cord injury seems to correlate with the magnitude of cardiovascular dysfunction. Patients with complete motor injuries are over five times more likely to require vasopressors for neurogenic shock compared to those with incomplete lesions.104 The classic description of neurogenic shock consists of decreased blood pressure associated with bradycardia (absence of reflexive tachycardia due to disrupted sympathetic discharge), warm extremities (loss of peripheral vasoconstriction), motor and sensory deficits indicative of a spinal cord injury, and radiographic evidence of a vertebral column fracture. Patients with multisystem trauma that includes spinal cord injuries often have head injuries that may make identification of motor and sensory deficits difficult in the initial evaluation. Furthermore, associated injuries may occur that result in hypovolemia, further complicating the clinical presentation. In a subset of patients with spinal cord injuries from penetrating wounds, most of the patients with hypotension had blood loss as the etiology (74%) rather than neurogenic causes, and few (7%) had the classic findings of neurogenic shock.105 In the multiply injured patient, other causes of hypotension, including hemorrhage, tension pneumothorax, and cardiogenic shock, must be sought and excluded. Treatment. After the airway is secured and ventilation is adequate, fluid resuscitation and restoration of intravascular volume often will improve perfusion in neurogenic shock. Most patients with neurogenic shock will respond to restoration of intravascular volume alone, with satisfactory improvement in perfusion and resolution of hypotension. Administration of vasoconstrictors will improve peripheral vascular tone, decrease vascular capacitance, and increase venous return, but should only be considered once hypovolemia is excluded as the cause of the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Shock Neurogenic Shock Table 5-9 CHAPTER 5 whose hemodynamic status permits additional diagnostic tests frequently require additional diagnostic maneuvers to confirm cardiac injury or tamponade. Invasive hemodynamic monitoring may support the diagnosis of cardiac tamponade if elevated central venous pressure, pulsus paradoxus (i.e., decreased systemic arterial pressure with inspiration), or elevated right atrial and right ventricular pressure by pulmonary artery catheter is present. These hemodynamic profiles suffer from lack of specificity, the duration of time required to obtain them in critically injured patients, and their inability to exclude cardiac injury in the absence of tamponade. Chest radiographs may provide information on the possible trajectory of a projectile, but rarely are diagnostic because the acutely filled pericardium distends poorly. Echocardiography has become the preferred test for the diagnosis of cardiac tamponade. Good results in detecting pericardial fluid have been reported, but the yield in detecting pericardial fluid depends on the skill and experience of the ultrasonographer, body habitus of the patient, and absence of wounds that preclude visualization of the pericardium. Standard two-dimensional and transesophageal echocardiography are sensitive techniques to evaluate the pericardium for fluid and are typically performed by examiners skilled at evaluating ventricular function, valvular abnormalities, and integrity of the proximal thoracic aorta. Unfortunately, these skilled examiners are rarely immediately available at all hours of the night, when many trauma patients present; therefore, waiting for this test may result in inordinate delays. In addition, although both ultrasound techniques may demonstrate the presence of fluid or characteristic findings of tamponade (large volume of fluid, right atrial collapse, poor distensibility of the right ventricle), they do not exclude cardiac injury per se. Pericardiocentesis to diagnose pericardial blood and potentially relieve tamponade may be used. Performing pericardiocentesis under ultrasound guidance has made the procedure safer and more reliable. An indwelling catheter may be placed for several days in patients with chronic pericardial effusions. Needle pericardiocentesis may not evacuate clotted blood and has the potential to produce cardiac injury, making it a poor alternative in busy trauma centers. Diagnostic pericardial window represents the most direct method to determine the presence of blood within the pericardium. The procedure is best performed in the operating room under general anesthesia. It can be performed through either the subxiphoid or transdiaphragmatic approach. Adequate equipment and personnel to rapidly decompress the pericardium, explore the injury, and repair the heart should be present. Once the pericardium is opened and tamponade relieved, hemodynamics usually improve dramatically and formal pericardial exploration can ensue. Exposure of the heart can be achieved by extending the incision to a median sternotomy, performing a left anterior thoracotomy, or performing bilateral anterior thoracotomies (“clamshell”). 130 PART I BASIC CONSIDERATIONS hypotension and the diagnosis of neurogenic shock established. If the patient’s blood pressure has not responded to what is felt to be adequate volume resuscitation, dopamine may be used first. A pure α agonist, such as phenylephrine, may be used primarily or in patients unresponsive to dopamine. Specific treatment for the hypotension is often of brief duration, as the need to administer vasoconstrictors typically lasts 24 to 48 hours. On the other hand, life-threatening cardiac dysrhythmias and hypotension may occur up to 14 days after spinal cord injury. The duration of the need for vasopressor support for neurogenic shock may correlate with the overall prognosis or chances of improvement in neurologic function. Appropriate rapid restoration of blood pressure and circulatory perfusion may improve perfusion to the spinal cord, prevent progressive spinal cord ischemia, and minimize secondary cord injury. Restoration of normal blood pressure and adequate tissue perfusion should precede any operative attempts to stabilize the vertebral fracture. ENDPOINTS IN RESUSCITATION Shock is defined as inadequate perfusion to maintain normal organ function. With prolonged anaerobic metabolism, tissue acidosis and O2 debt accumulate. Thus, the goal in the treatment of shock is restoration of adequate organ perfusion and tissue oxygenation. Resuscitation is complete when O debt is 7 repaid, tissue acidosis is corrected, and aerobic 2metabolism is restored. Clinical confirmation of this endpoint remains a challenge. Resuscitation of the patient in shock requires simultaneous evaluation and treatment; the etiology of the shock often is not initially apparent. Hemorrhagic shock, septic shock, and traumatic shock are the most common types of shock encountered on surgical services. To optimize outcome in bleeding patients, early control of the hemorrhage and adequate volume resuscitation, including both red blood cells and crystalloid solutions, are necessary. Expedient operative resuscitation is mandatory to limit the magnitude of activation of multiple mediator systems and to abort the microcirculatory changes, which may evolve insidiously into the cascade that ends in irreversible hemorrhagic shock. Attempts to stabilize an actively bleeding patient anywhere but in the operating room are inappropriate. Any intervention that delays the patient’s arrival in the operating room for control of hemorrhage increases mortality, thus the important concept of operating room resuscitation of the critically injured patient. Recognition by care providers of the patient who is in the compensated phase of shock is equally important, but more difficult based on clinical criteria. Compensated shock exists when inadequate tissue perfusion persists despite normalization of blood pressure and heart rate. Even with normalization of blood pressure, heart rate, and urine output, 80% to 85% of trauma patients have inadequate tissue perfusion, as evidenced by increased lactate or decreased mixed venous O2 saturation.55,106 Persistent, occult hypoperfusion is frequent in the ICU, with a resultant significant increase in infection rate and mortality in major trauma patients. Patients failing to reverse their lactic acidosis within 12 hours of admission (acidosis that was persistent despite normal heart rate, blood pressure, and urine output) developed an infection three times as often as those who normalized their lactate levels within 12 hours of admission. In addition, mortality was fourfold higher in patients who developed infections. Both injury severity score and occult hypotension Table 5-10 Endpoints in resuscitation Systemic/global Lactate Base deficit Cardiac output Oxygen delivery and consumption Tissue specific Gastric tonometry Tissue pH, oxygen, carbon dioxide levels Near infrared spectroscopy Cellular Membrane potential Adenosine triphosphate (lactic acidosis) longer than 12 hours were independent predictors of infection.107 Thus, recognition of subclinical hypoperfusion requires information beyond vital signs and urinary output. Endpoints in resuscitation can be divided into systemic or global parameters, tissue-specific parameters, and cellular parameters. Global endpoints include vital signs, cardiac output, pulmonary artery wedge pressure, O2 delivery and consumption, lactate, and base deficit (Table 5-10). Assessment of Endpoints in Resuscitation Inability to repay O2 debt is a predictor of mortality and organ failure; the probability of death has been directly correlated to the calculated O2 debt in hemorrhagic shock. Direct measurement of the O2 debt in the resuscitation of patients is difficult. The easily obtainable parameters of arterial blood pressure, heart rate, urine output, central venous pressure, and pulmonary artery occlusion pressure are poor indicators of the adequacy of tissue perfusion. Therefore, surrogate parameters have been sought to estimate the O2 debt; serum lactate and base deficit have been shown to correlate with O2 debt. Lactate. Lactate is generated by conversion of pyruvate to lactate by lactate dehydrogenase in the setting of insufficient O2. Lactate is released into the circulation and is predominantly taken up and metabolized by the liver and kidneys. The liver accounts for approximately 50% and the kidney for about 30% of whole body lactate uptake. Elevated serum lactate is an indirect measure of the O2 debt, and therefore an approximation of the magnitude and duration of the severity of shock. The admission lactate level, highest lactate level, and time interval to normalize the serum lactate are important prognostic indicators for survival. For example, in a study of 76 consecutive patients, 100% survival was observed among the patients with normalization of lactate within 24 hours, 78% survival when lactate normalized between 24 and 48 hours, and only 14% survivorship if it took longer than 48 hours to normalize the serum lactate.55 In contrast, individual variability of lactate may be too great to permit accurate prediction of outcome in any individual case. Base deficit and volume of blood transfusion required in the first 24 hours of resuscitation may be better predictors of mortality than the plasma lactate alone. Base Deficit. Base deficit is the amount of base in millimoles that is required to titrate 1 L of whole blood to a pH of 7.40 with the sample fully saturated with O2 at 37°C (98.6°F) and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ tissue acidosis. Several authors have suggested that tissuespecific endpoints, rather than systemic endpoints, are more predictive of outcome and adequate resuscitation in trauma patients. With heterogeneity of blood flow, regional tissue beds may be hypoperfused. Gastric tonometry has been used to assess perfusion of the GI tract. The concentration of CO2 accumulating in the gastric mucosa can be sampled with a specially designed nasogastric tube. With the assumption that gastric bicarbonate is equal to serum levels, gastric intramucosal pH (pHi) is calculated by applying the Henderson-Hasselbalch equation. pHi should be greater than 7.3; pHi will be lower in the setting of decreased O2 delivery to the tissues. pHi is a good prognostic indicator; patients with normal pHi have better outcomes than those patients with pHi less than 7.3.108,109 Goaldirected human studies, with pHi as an endpoint in resuscitation, have shown normalization of pHi to correlate with improved outcome in several studies and with contradictory findings in other studies. Use of pHi as a singular endpoint in the resuscitation of critically ill patients remains controversial.110 Near Infrared Spectroscopy. Near infrared (NIR) spectroscopy can measure tissue oxygenation and redox state of cytochrome a,a3 on a continuous, noninvasive basis. The NIR probe emits multiple wavelengths of light in the NIR spectrum (650 to 1100 nm). Photons are then either absorbed by the tissue or reflected back to the probe. Maximal exercise in laboratory studies Tissue PH, Oxygen, and Carbon Dioxide Concentration. Tissue probes with optical sensors have been used to measure tissue pH and partial pressure of O2 and CO2 in subcutaneous sites, muscle, and the bladder. These probes may use transcutaneous methodology with Clark electrodes or direct percutaneous probes.113,114 The percutaneous probes can be inserted through an 18-gauge catheter and hold promise as continuous monitors of tissue perfusion. Right Ventricular End-Diastolic Volume Index. Right ventricular end-diastolic volume index (RVEDVI) seems to more accurately predict preload for cardiac index than does pulmonary artery wedge pressure.115 Chang and colleagues reported that 50% of trauma patients had persistent splanchnic ischemia that was reversed by increasing RVEDVI. RVEDVI is a parameter that seems to correlate with preload-related increases in cardiac output. More recently, these authors have described left ventricular power output as an endpoint (LVP >320 mmHg⋅L/ min per square meter), which is associated with improved clearance of base deficit and a lower rate of organ dysfunction following injury.116 REFERENCES Entries highlighted in bright blue are key references.   1.  Gross S. A System of Surgery: Pathologic, Diagnostic, Therapeutic and Operative. Philadelphia: Lea and Febiger; 1872.   2. Bernard C. Lecons sur les Phenomenes de la Via Communs aux Animaux et aux Vegetaux. Paris: JB Ballieve; 1879.   3.  Cannon W. Traumatic Shock. New York: Appleton and Co.; 1923.   4. Blalock A. Principles of Surgical Care, Shock and Other Problems. St. Louis: CV Mosby; 1940.    5. Mollen KP, Levy RM, Prince JM, et al. Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells. J Leukoc Biol. 2008;83(1):80-88.   6.  Wiggers C. Experimental Hemorrhagic Shock. 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The mortality of trauma patients can be stratified according to the magnitude of base deficit measured in the first 24 hours after admission.60 In a retrospective study of over 3000 trauma admissions, patients with a base deficit worse than 15 mmol/L had a mortality of 70%. Base deficit can be stratified into mild (3–5 mmol/L), moderate (6–14 mmol/L), and severe (15 mmol/L) categories, with a trend toward higher mortality with worsening base deficit in patients with trauma. Both the magnitude of the perfusion deficit as indicated by the base deficit and the time required to correct it are major factors determining outcome in shock. Indeed, when elevated base deficit persists (or lactic acidosis) in the trauma patient, ongoing bleeding is often the etiology. Trauma patients admitted with a base deficit greater than 15 mmol/L required twice the volume of fluid infusion and six times more blood transfusion in the first 24 hours compared to patients with mild acidosis. 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J Trauma. 2008;64(6):1459-1463; discussion 1463-1465. 80. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012;256(3):476-486. 81. Roumen RM, Redl H, Schlag G, et al. Inflammatory mediators in relation to the development of multiple organ failure in patients after severe blunt trauma. Crit Care Med. 1995;23(3):474-480. 82. Leone M, Boutiere B, Camoin-Jau L, et al. Systemic endothelial activation is greater in septic than in traumatichemorrhagic shock but does not correlate with endothelial activation in skin biopsies. Crit Care Med. 2002;30(4): 808-814. 83. M ollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR. Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock. 2006;26(5): 430-437. 84. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001;345(8):588-595. 85. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310. 86. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228. 87. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1): 296-327. 88. Myburgh JA, Finfer S, Billot L. Hydroxyethyl starch or saline in intensive care. N Engl J Med. 2013;368(8):775. 89. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124-134. 90. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. CHAPTER 5 54. Victorino GP, Battistella FD, Wisner DH. Does tachycardia correlate with hypotension after trauma? J Am Coll Surg. 2003;196(5):679-684. 55. Abramson D, Scalea TM, Hitchcock R, Trooskin SZ, Henry SM, Greenspan J. Lactate clearance and survival following injury. J Trauma. 1993;35(4):584-588; discussion 588-589. 56. Davis JW, Parks SN, Kaups KL, Gladen HE, O’Donnell-Nicol S. Admission base deficit predicts transfusion requirements and risk of complications. J Trauma. 1996;41(5):769-774. 57. Kincaid EH, Miller PR, Meredith JW, Rahman N, Chang MC. Elevated arterial base deficit in trauma patients: a marker of impaired oxygen utilization. J Am Coll Surg. 1998;187(4): 384-392. 58. Rixen D, Raum M, Bouillon B, Lefering R, Neugebauer E. Base deficit development and its prognostic significance in posttrauma critical illness: an analysis by the trauma registry of the Deutsche Gesellschaft fur Unfallchirurgie. Shock. 2001;15(2):83-89. 59. Rutherford EJ, Morris JA Jr., Reed GW, Hall KS. Base deficit stratifies mortality and determines therapy. J Trauma. 1992;33(3):417-423. 60. Thorson CM, Van Haren RM, Ryan ML, et al. Admission hematocrit and transfusion requirements after trauma. J Am Coll Surg. 2013;216(1):65-73. 61. Clarke JR, Trooskin SZ, Doshi PJ, Greenwald L, Mode CJ. Time to laparotomy for intra-abdominal bleeding from trauma does affect survival for delays up to 90 minutes. J Trauma. 2002;52(3):420-425. 62. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-310. 63. Marshall HP Jr., Capone A, Courcoulas AP, et al. Effects of hemodilution on long-term survival in an uncontrolled hemorrhagic shock model in rats. J Trauma. Oct 1997;43(4): 673-679. 64. Bickell WH, Wall MJ Jr., Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994;331(17):1105-1109. 65. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. BMJ. 1998;317(7153):235-240. 66. Mann DV, Robinson MK, Rounds JD, et al. Superiority of blood over saline resuscitation from hemorrhagic shock: a 31P magnetic resonance spectroscopy study. Ann Surg. 1997;226(5):653-661. 67. Vassar MJ, Fischer RP, O’Brien PE, et al. A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride. The effect of added dextran 70. The Multicenter Group for the Study of Hypertonic Saline in Trauma Patients. Arch Surg. 1993;128(9):1003-1011; discussion 1011-1013. 68. Hebert PC, Yetisir E, Martin C, et al. Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? Crit Care Med. 2001;29(2):227-234. 69. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409-417. 70. Holcomb JB, Del Junco DJ, Fox EE, et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. Arch Surg. 2012:1-10. 71. Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma. 2007;62(1):112-119. 72. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63(4):805-813. 134 PART I BASIC CONSIDERATIONS 91. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. 92. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18): 1301-1308. 93. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7): 862-871. 94. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2): 111-124. 95. Hollenberg SM, Kavinsky CJ, Parrillo JE. Cardiogenic shock. Ann Intern Med. 1999;131(1):47-59. 96. Webb JG, Lowe AM, Sanborn TA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol. 2003;42(8):1380-1386. 97. Edens JW, Chung KK, Pamplin JC, et al. Predictors of early acute lung injury at a combat support hospital: a prospective observational study. J Trauma. 2010;69(Suppl 1):S81-86. 98. Aji J, Hollenberg S. Cardiogenic shock: giving the heart a break. Crit Care Med. 2006;34(4):1248-1249. 99. Alonso DR, Scheidt S, Post M, Killip T. Pathophysiology of cardiogenic shock. Quantification of myocardial necrosis, clinical, pathologic, and electrocardiographic correlations. Circulation. 1973;48(3):588-596. 100. Goldstein DJ, Oz MC. Mechanical support for postcardiotomy cardiogenic shock. Semin Thorac Cardiovasc Surg. 2000;12(3):220-228. 101. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012; 60(16):1581-1598. 102. Gibbons RJ, Smith SC Jr., Antman E. American College of Cardiology/American Heart Association clinical practice guidelines: Part II: evolutionary changes in a continuous quality improvement project. Circulation. 2003;107(24):3101-3107. 103. Menon V, Hochman JS. Management of cardiogenic shock complicating acute myocardial infarction. Heart. 2002; 88(5):531-537. 104. Levi L, Wolf A, Belzberg H. Hemodynamic parameters in patients with acute cervical cord trauma: description, intervention, and prediction of outcome. Neurosurgery. 1993;33(6): 1007-1016; discussion 1016-1007. 105. Zipnick RI, Scalea TM, Trooskin SZ, et al. Hemodynamic responses to penetrating spinal cord injuries. J Trauma. 1993; 35(4):578-582; discussion 582-583. 106. Abou-Khalil B, Scalea TM, Trooskin SZ, Henry SM, Hitchcock R. Hemodynamic responses to shock in young trauma patients: need for invasive monitoring. Crit Care Med. 1994; 22(4):633-639. 107. Claridge JA, Crabtree TD, Pelletier SJ, Butler K, Sawyer RG, Young JS. Persistent occult hypoperfusion is associated with a significant increase in infection rate and mortality in major trauma patients. J Trauma. 2000;48(1):8-14; discussion 14-15. 108. Ivatury RR, Simon RJ, Havriliak D, Garcia C, Greenbarg J, Stahl WM. Gastric mucosal pH and oxygen delivery and oxygen consumption indices in the assessment of adequacy of resuscitation after trauma: a prospective, randomized study. J Trauma. 1995;39(1):128-134; discussion 134-126. 109. Maynard N, Beale R, Smithies M, Bihari D. Gastric intramucosal pH in critically ill patients. Lancet. 1992;339(8792): 550-551. 110. Gomersall CD, Joynt GM, Freebairn RC, Hung V, Buckley TA, Oh TE. Resuscitation of critically ill patients based on the results of gastric tonometry: a prospective, randomized, controlled trial. Crit Care Med. 2000;28(3):607-614. 111. Cairns CB, Moore FA, Haenel JB, et al. Evidence for early supply independent mitochondrial dysfunction in patients developing multiple organ failure after trauma. J Trauma. 1997;42(3):532-536. 112. Cohn SM, Crookes BA, Proctor KG. Near-infrared spectroscopy in resuscitation. J Trauma. 2003;54(5 Suppl):S199-202. 113. Knudson MM, Bermudez KM, Doyle CA, Mackersie RC, Hopf HW, Morabito D. Use of tissue oxygen tension measurements during resuscitation from hemorrhagic shock. J Trauma. 1997;42(4):608-614; discussion 614-606. 114. McKinley BA, Marvin RG, Cocanour CS, Moore FA. Tissue hemoglobin O2 saturation during resuscitation of traumatic shock monitored using near infrared spectrometry. J Trauma. 2000;48(4):637-642. 115. Cheatham ML, Nelson LD, Chang MC, Safcsak K. Right ventricular end-diastolic volume index as a predictor of preload status in patients on positive end-expiratory pressure. Crit Care Med. 1998;26(11):1801-1806. 116. Chang MC, Meredith JW, Kincaid EH, Miller PR. Maintaining survivors’ values of left ventricular power output during shock resuscitation: a prospective pilot study. J Trauma. 2000;49(1):26-33; discussion 34-37. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 6 chapter Historical Background Pathogenesis of Infection 135 137 Host Defenses / 137 Definitions / 138 Microbiology of Infectious Agents 139 Bacteria / 139 Fungi / 140 Viruses / 140 Prevention and Treatment of Surgical Infections 141 Surgical Infections Greg J. Beilman and David L. Dunn Postoperative Nosocomial Infections / 152 Sepsis / 154 Blood-Borne Pathogens / 156 General Principles / 141 Source Control / 141 Appropriate Use of Antimicrobial Agents / 142 Infections of Significance in Surgical Patients Surgical Site Infections / 147 Intra-Abdominal Infections / 149 Organ-Specific Infections / 150 Infections of the Skin and Soft Tissue / 151 HISTORICAL BACKGROUND Although treatment of infection has been an integral part of the surgeon’s practice since the dawn of time, the body of knowledge that led to the present field of surgical infectious disease was derived from the evolution of germ theory and antisepsis. Application of the latter to clinical practice, concurrent with the development of anesthesia, was pivotal in allowing surgeons to expand their repertoire to encompass complex procedures that previously were associated with extremely high rates of morbidity and mortality due to postoperative infections. However, until recently the occurrence of infection related to the surgical wound was the rule rather than the exception. In fact, the development of modalities to effectively prevent and treat infection has occurred only within the last several decades. A number of observations by nineteenth-century physicians and investigators were critical to our current understanding of the pathogenesis, prevention, and treatment of surgical infections. In 1846, Ignaz Semmelweis, a Magyar physician, took a post at the Allgemein Krankenhaus in Vienna. He noticed that the mortality from puerperal (“childbed”) fever was much higher in the teaching ward (1:11) than in the ward where patients were delivered by midwives (1:29). He also made the interesting observation that women who delivered prior to arrival on the teaching ward had a negligible mortality rate. The tragic death of a colleague due to overwhelming infection after a knife scratch received during an autopsy of a woman who had died of puerperal fever led Semmelweis to observe that pathologic changes in his friend were identical to those of women dying from this postpartum disease. He then hypothesized that puerperal fever was caused by putrid material transmitted from patients dying of this disease by carriage on the examining fingers of the medical students and physicians who frequently went from the autopsy room to the wards. The low mortality noted in the midwives’ ward, Semmelweis realized, was 147 Biologic Warfare Agents 156 Bacillus anthracis (Anthrax) / 156 Yersinia pestis (Plague) / 157 Smallpox / 157 Francisella tularensis (Tularemia) / 157 because midwives did not participate in autopsies. Fired with the zeal of his revelation, he posted a notice on the door to the ward requiring all caregivers to rinse their hands thoroughly in chlorine water prior to entering the area. This simple intervention reduced mortality from puerperal fever to 1.5%, surpassing the record of the midwives. In 1861, he published his classic work on childbed fever based on records from his practice. Unfortunately, Semmelweis’ ideas were not well accepted by the authorities of the time.1 Increasingly frustrated by the indifference of the medical profession, he began writing open letters to well-known obstetricians in Europe, and was committed to an asylum due to concerns that he was losing his mind. He died shortly thereafter. His achievements were only recognized after Pasteur’s description of the germ theory of disease. Louis Pasteur performed a body of work during the latter part of the nineteenth century that provided the underpinnings of modern microbiology, at the time known as “germ theory.” His work in humans followed experiments identifying infectious agents in silkworms. He was able to elucidate the principle that contagious diseases are caused by specific microbes and that these microbes are foreign to the infected organism. Using this principle he developed techniques of sterilization critical to oenology, and identified several bacteria responsible for human illnesses, including Staphylococcus and Streptococcus pneumoniae (pneumococcus). Joseph Lister, the son of a wine merchant, was appointed professor of surgery at the Glasgow Royal Infirmary in 1859. In his early practice, he noted that over 50% of his patients undergoing amputation died because of postoperative infection. After hearing of Pasteur’s theory, Lister experimented with the use of a solution of carbolic acid, which he knew was being used to treat sewage. He first reported his findings to the British Medical Association in 1867 using dressings saturated with carbolic acid on 12 patients with compound fractures; 10 recovered VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 136 Sepsis is both the presence of infection and the host response to infection (systemic inflammatory response syndrome, SIRS). Sepsis is a clinical spectrum, ranging from sepsis (SIRS plus infection) to severe sepsis (organ dysfunction), to septic shock (hypotension requiring vasopressors). Outcomes in patients with sepsis are improved with an organized approach to therapy that includes rapid resuscitation, antibiotics, and source control. Source control is a key concept in the treatment of most surgically relevant infections. Infected or necrotic material must be drained or removed as part of the treatment plan in this setting. Delays in adequate source control are associated with worsened outcomes. Principles relevant to appropriate antibiotic prophylaxis for surgery: (a) select an agent with activity against organisms commonly found at the site of surgery, (b) the initial dose of the antibiotic should be given within 30 minutes prior to the creation of the incision, (c) the antibiotic should be redosed during long operations based upon the half-life of the agent to ensure adequate tissue levels, and (d) the antibiotic regimen should not be continued for more than 24 hours after surgery for routine prophylaxis. When using antimicrobial agents for therapy of serious infection, several principles should be followed: (a) identify likely sources of infection, (b) select an agent (or agents) that will have efficacy against likely organisms for these sources, (c) without amputation, one survived with amputation, and one died of causes unrelated to the wound. In spite of initial resistance, his methods were quickly adopted throughout Europe. From 1878 until 1880, Robert Koch was the District Medical Officer for Wollstein, which was an area in which anthrax was endemic. Performing experiments in his home, without the benefit of scientific equipment and academic contact, Koch developed techniques for culture of Bacillus anthracis and proved the ability of this organism to cause anthrax in healthy animals. He developed the following four postulates to identify the association of organisms with specific diseases: (a) the suspected pathogenic organism should be present in all cases of the disease and absent from healthy animals, (b) the suspected pathogen should be isolated from a diseased host and grown in a pure culture in vitro, (c) cells from a pure culture of the suspected organism should cause disease in a healthy animal, and (d) the organism should be reisolated from the newly diseased animal and shown to be the same as the original. He used these same techniques to identify the organisms responsible for cholera and tuberculosis. During the next century, Koch’s postulates, as they came to be called, became critical to our understanding of surgical infections and remain so today.2 The first intra-abdominal operation to treat infection via “source control” (i.e., surgical intervention to eliminate the source of infection) was appendectomy. This operation was pioneered by Charles McBurney at the New York College of Physicians and Surgeons, among others.3 McBurney’s classic report on early operative intervention for appendicitis was presented before the New York Surgical Society in 1889. Appendectomy for the treatment of appendicitis, previously an often fatal disease, was popularized after the 1902 coronation of King 5 6 7 inadequate or delayed antibiotic therapy results in increased mortality, so it is important to begin therapy rapidly with broader coverage, (d) when possible, obtain cultures early and use results to refine therapy, (e) if no infection is identified after 3 days, strongly consider discontinuation of antibiotics, based upon the patient’s clinical course, (f) discontinue antibiotics after an appropriate course of therapy. The incidence of surgical site infections can be reduced by appropriate patient preparation, timely perioperative antibiotic administration, maintenance of perioperative normothermia and normoglycemia, and appropriate wound management. The keys to good outcomes in patients with necrotizing soft tissue infection are early recognition and appropriate debridement of infected tissue with repeated debridement until no further signs of infection are present. Transmission of HIV and other infections spread by blood and body fluid from patient to health care worker can be minimized by observation of universal precautions, which include routine use of barriers when anticipating contact with blood or body fluids, washing of hands and other skin surfaces immediately after contact with blood or body fluids, and careful handling and disposal of sharp instruments during and after use. Edward VII of England was delayed due to his need for an appendectomy, which was performed by Sir Frederick Treves. The king desperately needed an appendectomy but strongly opposed going into the hospital, protesting, “I have a coronation on hand.” However, Treves was adamant, stating, “It will be a funeral, if you don’t have the operation.” Treves carried the debate, and the king lived. During the twentieth century the discovery of effective antimicrobials added another tool to the armamentarium of modern surgeons. Sir Alexander Fleming, after serving in the British Army Medical Corps during World War I, continued work on the natural antibacterial action of the blood and antiseptics. In 1928, while studying influenza virus, he noted a zone of inhibition around a mold colony (Penicillium notatum) that serendipitously grew on a plate of Staphylococcus, and he named the active substance penicillin. This first effective antibacterial agent subsequently led to the development of hundreds of potent antimicrobials, set the stage for their use as prophylaxis against postoperative infection, and became a critical component of the armamentarium to treat aggressive, lethal surgical infections. Concurrent with the development of numerous antimicrobial agents were advances in the field of clinical microbiology. Many new microbes were identified, including numerous anaerobes; the autochthonous microflora of the skin, gastrointestinal tract, and other parts of the body that the surgeon encountered in the process of an operation were characterized in great detail. However, it remained unclear whether these organisms, anaerobes in particular, were commensals or pathogens. Subsequently, the initial clinical observations of surgeons such as Frank Meleney, William Altemeier, and others provided the key, when they observed that aerobes and anaerobes could VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Host Defenses The mammalian host possesses several layers of endogenous defense mechanisms that serve to prevent microbial invasion, limit proliferation of microbes within the host, and contain or eradicate invading microbes. These defenses are integrated and redundant so that the various components function as a complex, highly regulated system that is extremely effective in coping with microbial invaders. They include site-specific defenses that function at the tissue level, as well as components that freely circulate throughout the body in both blood and lymph. Systemic host defenses invariably are recruited to a site of infection, a process that begins immediately upon introduction of microbes into a sterile area of the body. Perturbation of one or more components of these defenses (e.g., via immunosuppressants, foreign body, chronic illness, and burns) may have substantial negative impact on resistance to infection. Entry of microbes into the mammalian host is precluded by the presence of a number of barriers that possess either an epithelial (integument) or mucosal (respiratory, gut, and urogenital) surface. Barrier function, however, is not solely limited to physical characteristics. Host barrier cells may secrete substances that limit microbial proliferation or prevent invasion. Also, resident or commensal microbes (endogenous or autochthonous host microflora) adherent to the physical surface and to each other may preclude invasion, particularly of virulent organisms (colonization resistance).9 The most extensive physical barrier is the integument or skin. In addition to the physical barrier posed by the epithelial VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 137 Surgical Infections PATHOGENESIS OF INFECTION surface, the skin harbors its own resident microflora that may block the attachment and invasion of noncommensal microbes. Microbes are also held in check by chemicals that sebaceous glands secrete and by the constant shedding of epithelial cells. The endogenous microflora of the integument primarily comprises gram-positive aerobic microbes belonging to the genera Staphylococcus and Streptococcus, as well as Corynebacterium and Propionibacterium species. These organisms plus Enterococcus faecalis and faecium, Escherichia coli and other Enterobacteriaceae, and yeast such as Candida albicans can be isolated from the infraumbilical regions of the body. Diseases of the skin (e.g., eczema and dermatitis) are associated with overgrowth of skin commensal organisms, and barrier breaches invariably lead to the introduction of these microbes. The respiratory tract possesses several host defense mechanisms that facilitate the maintenance of sterility in the distal bronchi and alveoli under normal circumstances. In the upper respiratory tract, respiratory mucus traps larger particles, including microbes. This mucus is then passed into the upper airways and oropharynx by ciliated epithelial cells, where the mucus is cleared via coughing. Smaller particles arriving in the lower respiratory tract are cleared via phagocytosis by pulmonary alveolar macrophages. Any process that diminishes these host defenses can lead to development of bronchitis or pneumonia. The urogenital, biliary, pancreatic ductal, and distal respiratory tracts do not possess resident microflora in healthy individuals, although microbes may be present if these barriers are affected by disease (e.g., malignancy, inflammation, calculi, or foreign body), or if microorganisms are introduced from an external source (e.g., urinary catheter or pulmonary aspiration). In contrast, significant numbers of microbes are encountered in many portions of the gastrointestinal tract, with vast numbers being found within the oropharynx and distal colon or rectum, although the specific organisms differ. One would suppose that the entire gastrointestinal tract would be populated via those microbes found in the oropharynx, but this is not the case.9 This is because after ingestion these organisms routinely are killed in the highly acidic, lowmotility environment of the stomach during the initial phases of digestion. Thus, small numbers of microbes populate the gastric mucosa ~102 to 103 colony-forming units (CFU)/mL. This population expands in the presence of drugs or disease states that diminish gastric acidity. Microbes that are not destroyed within the stomach enter the small intestine, in which a certain amount of microbial proliferation takes place, such that approximately 105 to 108 CFU/mL are present in the terminal ileum. The relatively low-oxygen, static environment of the colon is accompanied by the exponential growth of microbes that comprise the most extensive host endogenous microflora. Anaerobic microbes outnumber aerobic species approximately 100:1 in the distal colon, and approximately 1011 to 1012 CFU/g are present in feces. Large numbers of facultative and strict anaerobes (Bacteroides fragilis,distasonis, and thetaiotaomicron, Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Lactobacillus, and Peptostreptococcus species) as well as several orders of magnitude fewer aerobic microbes (Escherichia coli and other Enterobacteriaceae, Enterococcus faecalis and faecium, Candida albicans and other Candida spp.) are present. Intriguingly, although colonization resistance on the part of this extensive, well-characterized host microflora effectively prevents invasion of enteric pathogens such as Salmonella, Shigella, Vibrio, and other enteropathogenic bacterial species, these same organisms CHAPTER 6 synergize to cause serious soft tissue and severe intra-abdominal infection.4,5 Thus, the concepts that resident microbes were nonpathogenic until they entered a sterile body cavity at the time of surgery, and that many, if not most, surgical infections were polymicrobial in nature, became critical ideas, and were promulgated by a number of clinician-scientists over the last several decades.6,7 These tenets became firmly established after microbiology laboratories demonstrated the invariable presence of aerobes and anaerobes in peritoneal cultures obtained at the time of surgery for intra-abdominal infection due to a perforated viscus or gangrenous appendicitis. Clinical trials provided ample evidence that optimal therapy for these infections required effective source control, plus the administration of antimicrobial agents directed against both types of pathogens. William Osler, a prolific writer and one of the fathers of American medicine, made an observation in 1904 in his treatise The Evolution of Modern Medicine that was to have profound implications for the future of treatment of infection: “Except on few occasions, the patient appears to die from the body’s response to infection rather than from it.”8 The discovery of the first cytokines began to allow insight into the human organism’s response to infection, and led to an explosion in our understanding of the host inflammatory response. Expanding knowledge of the multiple pathways activated during the response to invasion by infectious organisms has permitted the design of new therapies targeted at modifying the inflammatory response to infection, which seems to cause much of the organ dysfunction and failure. Preventing and treating this process of multiple organ failure during infection is one of the major challenges of modern critical care and surgical infectious disease. 138 PART I BASIC CONSIDERATIONS provide the initial inoculum for infection should perforation of the gastrointestinal tract occur. It is of great interest that only some of these microbial species predominate in established intra-abdominal infections. Once microbes enter a sterile body compartment (e.g., pleural or peritoneal cavity) or tissue, additional host defenses act to limit and/or eliminate these pathogens. Initially, several primitive and relatively nonspecific host defenses act to contain the nidus of infection, which may include microbes as well as debris, devitalized tissue, and foreign bodies, depending on the nature of the injury. These defenses include the physical barrier of the tissue itself, as well as the capacity of proteins, such as lactoferrin and transferrin to sequester the critical microbial growth factor iron, thereby limiting microbial growth. In addition, fibrinogen within the inflammatory fluid has the ability to trap large numbers of microbes during the process in which it polymerizes into fibrin. Within the peritoneal cavity, unique host defenses exist, including a diaphragmatic pumping mechanism whereby particles, including microbes within peritoneal fluid are expunged from the abdominal cavity via specialized structures (stomata) on the undersurface of the diaphragm that lead to thoracic lymphatic channels. Concurrently, containment by the omentum, the socalled “gatekeeper” of the abdomen and intestinal ileus, serves to wall off infections. However, the latter processes and fibrin trapping have a high likelihood of contributing to the formation of an intra-abdominal abscess. Microbes also immediately encounter a series of host defense mechanisms that reside within the vast majority of tissues of the body. These include resident macrophages and low levels of complement (C) proteins and immunoglobulins (e.g., antibodies).10 The response in macrophages is initiated by genome-encoded pattern recognition receptors which respond to invading microbes. With exposure to a foreign organism, these receptors recognize microbial pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are one well-defined example of a PAMP that plays an important role in pathogen signaling.11 Resident macrophages secrete a wide array of substances in response to the above-mentioned processes, some of which appear to regulate the cellular components of the host defense response. This results in recruitment and proliferation of inflammatory cells. Macrophage cytokine synthesis is upregulated. Secretion of tumor necrosis factoralpha (TNF-α), of interleukins (IL)-1β, 6, and 8; and of gamma interferon (IFN-γ) occurs within the tissue milieu, and, depending on the magnitude of the host defense response, the systemic circulation.12 Concurrently, a counterregulatory response is initiated consisting of binding protein (TNF-BP), cytokine receptor antagonists (e.g., IL-1ra), and anti-inflammatory cytokines (IL-4 and IL-10). The interaction of microbes with these first-line host defenses leads to microbial opsonization (C1q, C3bi, and IgFc), phagocytosis, and both extracellular (C5b6-9 membrane attack complex) and intracellular microbial destruction (via cellular ingestion into phagocytic vacuoles). Concurrently, the classical and alternate complement pathways are activated both via direct contact with and via IgM>IgG binding to microbes, leading to the release of a number of different complement protein fragments (C3a, C4a, C5a) that are biologically active, acting to markedly enhance vascular permeability. Bacterial cell wall components and a variety of enzymes that are expelled from leukocyte phagocytic vacuoles during microbial phagocytosis and killing act in this capacity as well. Simultaneously, the release of substances to which polymorphonuclear leukocytes (PMNs) in the bloodstream are attracted takes place. These consist of C5a, microbial cell wall peptides containing N-formyl-methionine, and macrophage secretion of cytokines such as IL-8. This process of host defense recruitment leads to further influx of inflammatory fluid into the area of incipient infection, and is accompanied by diapedesis of large numbers of PMNs, a process that begins within several minutes and may peak within hours or days. The magnitude of the response and eventual outcome generally are related to several factors: (a) the initial number of microbes, (b) the rate of microbial proliferation in relation to containment and killing by host defenses, (c) microbial virulence, and (d) the potency of host defenses. In regard to the latter, drugs or disease states that diminish any or multiple components of host defenses are associated with higher rates and potentially more grave infections. Definitions Several possible outcomes can occur subsequent to microbial invasion and the interaction of microbes with resident and recruited host defenses: (a) eradication, (b) containment, often leading to the presence of purulence—the hallmark of chronic infections (e.g., a furuncle in the skin and soft tissue or abscess within the parenchyma of an organ or potential space), (c) locoregional infection (cellulitis, lymphangitis, and aggressive soft tissue infection) with or without distant spread of infection (metastatic abscess), or (d) systemic infection (bacteremia or fungemia). Obviously, the latter represents the failure of resident and recruited host defenses at the local level, and is associated with significant morbidity and mortality in the clinical setting. In addition, it is not uncommon that disease progression occurs such that serious locoregional infection is associated with concurrent systemic infection. A chronic abscess also may intermittently drain and/or be associated with bacteremia. Infection is defined by the presence of microorganisms in host tissue or the bloodstream. At the site of infection the classic findings of rubor, calor, and dolor in areas such as the skin or subcutaneous tissue are common. Most infections in normal individuals with intact host defenses are associated with these local manifestations, plus systemic manifestations such as elevated temperature, elevated white blood cell (WBC) count, tachycardia, or tachypnea. The systemic manifestations noted previously comprise the systemic inflammatory response syn(SIRS). A documented or suspected infection with 1 drome some of the findings of SIRS define sepsis.13 SIRS can be caused by a variety of disease processes, including pancreatitis, polytrauma, malignancy, transfusion reaction, as well as infection (Fig. 6-1). There are a variety of systemic manifestations of infection, with the classic factors of fever, tachycardia, and tachypnea, broadened to include a variety of other variables (Table 6-1).13 Sepsis (SIRS caused by infection) is mediated by the production of a cascade of proinflammatory mediators produced in response to exposure to microbial products. These products include lipopolysaccharide (endotoxin, LPS) derived from Gram-negative organisms; peptidoglycans and teichoic acids from gram-positive organisms; many different microbial cell wall components, such as mannan from yeast and fungi; and many others. Severe sepsis is characterized as sepsis (defined previously) combined with the presence of new-onset organ failure. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 139 Trauma Infection Severe sepsis Aspiration SIRS Pancreatitis Burn Severe sepsis is the most common cause of death in noncoronary critical care units and the 11th most common cause of death overall in the United States, with a mortality rate of 10.3 cases/100,000 population in 2010.14 A number of organ dysfunction scoring systems have been described.15,16,17 With Table 6-1 Criteria for systemic inflammatory response syndrome (SIRS) General variables Fever (core temp >38.3°C) Hypothermia (core temp <36°C) Heart rate >90 bpm Tachypnea Altered mental status Significant edema or positive fluid balance (>20 mL/kg over 24 h) Hyperglycemia in the absence of diabetes Inflammatory variables Leukocytosis (WBC >12,000) Leukopenia (WBC <4000) Bandemia (>10% band forms) Plasma C-reactive protein >2 s.d. above normal value Plasma procalcitonin >2 s.d. above normal value Hemodynamic variables Arterial hypotension (SBP <90 mm Hg, MAP <70, or SBP decrease >40 mm Hg) Organ dysfunction variables Arterial hypoxemia Acute oliguria Creatinine increase Coagulation abnormalities Ileus Thrombocytopenia Hyperbilirubinemia respect to clinical criteria, a patient with sepsis and the need for ventilatory support, with oliguria unresponsive to aggressive fluid resuscitation, or with hypotension requiring vasopressors should be considered to have developed severe sepsis. Septic shock is a state of acute circulatory failure identified by the presence of persistent arterial hypotension (systolic blood pressure <90 mm Hg) despite adequate fluid resuscitation, without other identifiable causes. Septic shock is the most severe manifestation of infection, occurring in approximately 40% of patients with severe sepsis; it has an attendant mortality rate of 30% to 66%.18,19 While classification of severity of shock has been successful in driving efforts to improve patient outcomes, staging of sepsis by other patient characteristics remains in its infancy. The impetus for development of such a scheme is related to the heterogeneity of the patient population developing sepsis, an example of which would include two patients, both in the intensive care unit (ICU), who develop criteria consistent with septic shock. While both have infection and sepsis-associated hypotension, one might expect a different outcome in a young, healthy patient who develops urosepsis than in an elderly, immunosuppressed lung transplant recipient who develops invasive fungal infection. One schema for providing such a classification is the predisposition, infection, response and organ failure (PIRO) classification.20 This scheme has borrowed from the tumor-node-metastasis staging scheme developed for oncology. The PIRO staging system stratifies patients based on their predisposing conditions (P), the nature and extent of the infection (I), the nature and magnitude of the host response (R), and the degree of concomitant organ dysfunction (O). Clinical trials using this classification system have confirmed the validity of this concept.21, 22 MICROBIOLOGY OF INFECTIOUS AGENTS A partial list of common pathogens that cause infections in surgical patients is provided in Table 6-2. Bacteria Tissue perfusion variables Hyperlactatemia Decreased capillary filling bpm = beats per minute; MAP = mean arterial pressure; SBP = systolic blood pressure; s.d. = standard deviations; Svo2 = venous oxygen saturation; WBC = white blood cell count. Bacteria are responsible for the majority of surgical infections. Specific species are identified using Gram’s stain and growth characteristics on specific media. The Gram’s stain is an important evaluation that allows rapid classification of bacteria by color. This color is related to the staining characteristics of the bacterial cell wall: gram-positive bacteria stain blue and Gramnegative bacteria stain red. Bacteria are classified based upon VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Infections Septic shock Figure 6-1. Relationship between infection and systemic inflammatory response syndrome (SIRS). Sepsis is the presence both of infection and the systemic inflammatory response, shown here as the intersection of these two areas. Other conditions may cause SIRS as well (trauma, aspiration, etc.). Severe sepsis (and septic shock) are both subsets of sepsis. CHAPTER 6 Sepsis 140 Table 6-2 Common Pathogens in Surgical Patients PART I Gram-positive aerobic cocci Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Streptococcus pneumoniae Enterococcus faecium, E. faecalis BASIC CONSIDERATIONS Gram-negative aerobic bacilli Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Proteus mirabilis Enterobacter cloacae, E. aerogenes Serratia marcescens Acinetobacter calcoaceticus Citrobacter freundii Pseudomonas aeruginosa Xanthomonas maltophilia Anaerobes Gram-positive Clostridium difficile Clostridium perfringens, C. tetani, C. septicum Peptostreptococcus spp. Gram-negative Bacteroides fragilis Fusobacterium spp. Other bacteria Mycobacterium avium-intracellulare Mycobacterium tuberculosis Nocardia asteroides Legionella pneumophila Listeria monocytogenes Fungi Aspergillus fumigatus, A. niger, A. terreus, A. flavus Blastomyces dermatitidis Candida albicans Candida glabrata, C. paropsilosis, C. krusei Coccidiodes immitis Cryptococcus neoformans Histoplasma capsulatum Mucor/Rhizopus Viruses Cytomegalovirus Epstein-Barr virus Hepatitis A, B, C viruses Herpes simplex virus Human immunodeficiency virus Varicella zoster virus a number of additional characteristics, including morphology (cocci and bacilli), the pattern of division (e.g., single organisms, groups of organisms in pairs [diplococci], clusters [staphylococci], and chains [streptococci]), and the presence and location of spores. Gram-positive bacteria that frequently cause infections in surgical patients include aerobic skin commensals (Staphylococcus aureus and epidermidis and Streptococcus pyogenes) and enteric organisms such as Enterococcus faecalis and faecium. Aerobic skin commensals cause a large percentage of surgical site infections (SSIs), either alone or in conjunction with other pathogens; enterococci can cause nosocomial infections (urinary tract infections [UTIs] and bacteremia) in immunocompromised or chronically ill patients, but are of relatively low virulence in healthy individuals. There are many pathogenic Gram-negative bacterial species that are capable of causing infection in surgical patients. Most Gram-negative organisms of interest to the surgeon are bacilli belonging to the family Enterobacteriaceae, including Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Enterobacter, Citrobacter, and Acinetobacter spp. Other Gram-negative bacilli of note include Pseudomonas spp., including Pseudomonas aeruginosa and fluorescens and Xanthomonas spp. Anaerobic organisms are unable to grow or divide poorly in air, as most do not possess the enzyme catalase, which allows for metabolism of reactive oxygen species. Anaerobes are the predominant indigenous flora in many areas of the human body, with the particular species being dependent on the site. For example, Propionibacterium acnes and other species are a major component of the skin microflora and cause the infectious manifestation of acne. As noted previously, large numbers of anaerobes contribute to the microflora of the oropharynx and colon. Infection due to Mycobacterium tuberculosis was once one of the most common causes of death in Europe, causing one in four deaths in the seventeenth and eighteenth centuries. In the nineteenth and twentieth centuries, thoracic surgical intervention was often required for severe pulmonary disease, now an increasingly uncommon occurrence in developed countries. This organism and other related organisms (M avium-intracellulare and M leprae) are known as acid-fast bacilli. Other acid-fast bacilli include Nocardia spp. These organisms typically are slowgrowing, sometimes necessitating observation in culture for weeks to months prior to final identification, although deoxyribonucleic acid (DNA)-based analysis is increasingly available to provide a means for preliminary, rapid detection. Fungi Fungi typically are identified by use of special stains (e.g., potassium hydroxide (KOH), India ink, methenamine silver, or Giemsa). Initial identification is assisted by observation of the form of branching and septation in stained specimens or in culture. Final identification is based on growth characteristics in special media, similar to bacteria, as well as on the capacity for growth at a different temperature (25°C vs. 37°C). Fungi of relevance to surgeons include those that cause nosocomial infections in surgical patients as part of polymicrobial infections or fungemia (e.g., Candida albicans and related species), rare causes of aggressive soft tissue infections (e.g., Mucor, Rhizopus, and Absidia spp.), and so-called opportunistic pathogens that cause infection in the immunocompromised host (e.g., Aspergillus fumigatus, niger, terreus, and other spp., Blastomyces dermatitidis, Coccidioides immitis, and Cryptococcus neoformans). Agents currently available for antifungal therapy are described in Table 6-3. Viruses Due to their small size and necessity for growth within cells, viruses are difficult to culture, requiring a longer time than is typically optimal for clinical decision making. Previously, viral VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 141 Table 6-3 Antifungal agents and their characteristics Disadvantages Amphotericin B Broad-spectrum, inexpensive Renal toxicity, premeds, IV only Liposomal Amphotericin B Broad-spectrum Expensive, IV only, renal toxicity Fluconazole IV and PO availability Narrow-spectrum, drug interactions Itraconazole IV and PO availability Narrow spectrum, no CSF penetration Drug interactions, decreased cardiac contractility Posaconazole Broad-spectrum, zygomycete activity PO only Voriconazole IV and PO availability, broadspectrum IV diluent accumulates in renal failure (PO) Visual disturbances Broad-spectrum IV only, poor CNS penetration Azoles Echinocandins Anidulafungin, caspofungin, micafungin infection was identified by indirect means (i.e., the host antibody response). Recent advances in technology have allowed for the identification of the presence of viral DNA or ribonucleic acid (RNA) using methods such as polymerase chain reaction. Similarly to many fungal infections, most clinically relevant viral infections in surgical patients occur in the immunocompromised host, particularly those receiving immunosuppression to prevent rejection of a solid organ allograft. Relevant viruses include adenoviruses, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and varicella-zoster virus. Surgeons must be aware of the manifestations of hepatitis B and C virus, as well as human immunodeficiency virus infections, including their capacity to be transmitted to health care workers (see General Principles section). Prophylactic and therapeutic use of antiviral agents is discussed in Chap. 11. has been shown to diminish the quantity of skin microflora, and although a direct correlation between praxis and reduced infection rates has not been demonstrated, comparison to infection rates prior to the use of antisepsis and sterile technique makes clear their utility and importance. The aforementioned modalities are not capable of sterilizing the hands of the surgeon or the skin or epithelial surfaces of the patient, although the inoculum can be reduced considerably. Thus, entry through the skin, into the soft tissue, and into a body cavity or hollow viscus invariably is associated with the introduction of some degree of microbial contamination. For that reason, patients who undergo procedures that may be associated with the ingress of significant numbers of microbes (e.g., colonic resection) or in whom the consequences of any type of infection due to said process would be dire (e.g., prosthetic vascular graft infection) should receive an antimicrobial agent. PREVENTION AND TREATMENT OF SURGICAL INFECTIONS Source Control General Principles Maneuvers to diminish the presence of exogenous (surgeon and operating room environment) and endogenous (patient) microbes are termed prophylaxis, and consist of the use of mechanical, chemical, and antimicrobial modalities, or a combination of these methods. As described previously, the host resident microflora of the skin (patient and surgeon) and other barrier surfaces represent a potential source of microbes that can invade the body during trauma, thermal injury, or elective or emergent surgical intervention. For this reason, operating room personnel are versed in mild mechanical exfoliation of the skin of the hands and forearms using antibacterial preparations, and the intraoperative aseptic technique is employed. Similarly, application of an antibacterial agent to the skin of the patient at the proposed operative site takes place prior to creating an incision. Also, if necessary, hair removal should take place using a clipper rather than a razor; the latter promotes overgrowth of skin microbes in small nicks and cuts. Dedicated use of these modalities clearly The primary precept of surgical infectious disease therapy consists of drainage of all purulent material, débridement of all infected, devitalized tissue, and debris, and/or removal of foreign bodies at the site of infection, plus remediation of the underlying cause of infection.23 A discrete, walled-off 2 purulent fluid collection (i.e., an abscess) requires drainage via percutaneous drain insertion or an operative approach in which incision and drainage take place. An ongoing source of contamination (e.g., bowel perforation) or the presence of an aggressive, rapidly spreading infection (e.g., necrotizing soft tissue infection) invariably requires expedient, aggressive operative intervention, both to remove contaminated material and infected tissue (e.g., radical débridement or amputation) and to remove the initial cause of infection (e.g., bowel resection). Other treatment modalities such as antimicrobial agents, albeit critical, are of secondary importance to effective surgery with regard to treatment of surgical infections and overall outcome. Rarely, if ever, can an aggressive surgical infection be cured only by the administration of antibiotics, and never in the face of an ongoing source of contamination. Also, it has been repeatedly demonstrated that delay in operative intervention, whether due VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Infections Advantages CHAPTER 6 Antifungal 142 to misdiagnosis or the need for additional diagnostic studies, is associated with increased morbidity and occasional mortality.24 Appropriate Use of Antimicrobial Agents PART I BASIC CONSIDERATIONS A classification of antimicrobial agents, mechanisms of action, and spectrum of activity is shown in Table 6-4. Prophylaxis consists of the administration of an antimicrobial agent or agents prior to initiation of certain specific types of surgical procedures in order to reduce the number of microbes that enter the tissue or body cavity. Agents are selected according to their activity against microbes likely to be present at 3 the surgical site, based on knowledge of host microflora. For example, patients undergoing elective colorectal surgery should receive antimicrobial prophylaxis directed against skin flora, gram negative aerobes, and anaerobic bacteria. There are a wide variety of agents that meet these criteria with recently published guidelines.25 By definition, prophylaxis is limited to the time prior to and during the operative procedure; in the vast majority of cases only a single dose of antibiotic is required, and only for certain types of procedures (see Surgical Site Infections). However, patients who undergo complex, prolonged procedures in which the duration of the operation exceeds the serum drug half-life should receive an additional dose or doses of the antimicrobial agent.25 There is no evidence that administration of postoperative doses of an antimicrobial agent provides additional benefit, and this practice should be discouraged, as it is costly and is associated with increased rates of microbial drug resistance. Guidelines for prophylaxis are provided in Table 6-5. Empiric therapy comprises the use of an antimicrobial agent or agents when the risk of a surgical infection is high, based on the underlying disease process (e.g., ruptured appendicitis), or when significant contamination during surgery has occurred (e.g., inadequate bowel preparation or considerable spillage of colon contents). Obviously, prophylaxis merges into empirical therapy in situations in which the risk of infection increases markedly because of intraoperative findings. Empirical therapy also often is employed in critically ill patients in whom a potential site of infection has been identified and severe sepsis or septic shock occurs. Invariably, empirical therapy should be limited to a short course of drug (3 to 5 days), and should be curtailed as soon as possible based on microbiologic data (i.e., absence of positive cultures) coupled with improvements in the clinical course of the patient. Similarly, empirical therapy merges into therapy of established infection in some patients as well. However, among surgical patients, the manner in which therapy is employed, particularly in relation to the use of microbiologic data (culture and antibiotic sensitivity patterns), differs depending on whether the infection is monomicrobial or polymicrobial. Monomicrobial infections frequently are nosocomial infections occurring in postoperative patients, such as UTIs, pneumonia, or bacteremia. Evidence of systemic inflammatory response syndrome (fever, tachycardia, tachypnea, or elevated leukocyte count) in such individuals, coupled with evidence of local infection (e.g., an infiltrate on chest roentgenogram plus a positive Gram’s stain in bronchoalveolar lavage samples) should lead the surgeon to initiate empirical antibiotic therapy. An appropriate approach to antimicrobial treatment involves de-escalation therapy, where initial antimicrobial selection is broad, with a later narrowing of agents based on patient response and culture results. Initial drug selection must be based on initial evidence (Gram-positive vs. Gram-negative microbes, yeast), coupled with institutional and unit-specific drug sensitivity patterns. It is important to ensure that antimicrobial coverage chosen is adequate, since delay in appropriate antibiotic treatment has been shown to be associated with significant increases in mortality. A critical component of this approach is appropriate collection of culture specimens to allow for thorough analysis, since within 48 to 72 hours, culture and sensitivity reports will allow refinement of the antibiotic regimen to select the most efficacious agent.The clinical 4 course of the patient is monitored closely, and in some cases (e.g., UTI) follow-up studies (urine culture) should be obtained after completion of therapy. Although the primary therapeutic modality to treat polymicrobial surgical infections is source control as delineated previously, antimicrobial agents play an important role as well. Culture results are of lesser importance in managing these types of infections, as it has been repeatedly demonstrated that only a limited cadre of microbes predominate in the established infection, selected from a large number present at the time of initial contamination. Invariably it is difficult to identify all microbes that comprise the initial polymicrobial inoculum. For this reason, the antibiotic regimen should not be modified solely on the basis of culture information, as it is less important than the clinical course of the patient. For example, patients who undergo appendectomy for gangrenous, perforated appendicitis, or bowel resection for intestinal perforation, should receive an antimicrobial agent or agents directed against aerobes and anaerobes for 3 to 5 days, occasionally longer. If the patient regains bowel function during this time, conversion from an intravenous to an oral regimen (e.g., ciprofloxacin plus metronidazole) can occur. This is safe, and may facilitate earlier discharge. A survey of several decades of clinical trials examining the effect of antimicrobial agent selection on the treatment of intra-abdominal infection revealed striking similarities in outcome among regimens that possessed aerobic and anaerobic activity (~10% to 30% failure rates): most failures could not be attributed to antibiotic selection, but rather were due to the inability to achieve effective source control.26 Duration of antibiotic administration should be decided at the time the drug regimen is prescribed. As mentioned previously, prophylaxis is limited to a single dose administered immediately prior to creating the incision. Empiric therapy should be limited to 3 to 5 days or less, and should be curtailed if the presence of a local site or systemic infection is not revealed.27 In fact, prolonged use of empirical antibiotic therapy in culture-negative critically ill patients is associated with increased mortality, highlighting the need to discontinue therapy when there is no proven evidence of infection.28 Therapy for monomicrobial infections follows standard guidelines: 3 to 5 days for UTIs, 7 to 10 days for pneumonia, and 7 to14 days for bacteremia. Longer courses of therapy in this setting do not result in improved care and are associated with increased risk of superinfection by resistant organisms.29,30 There is some evidence that measuring and monitoring serum procalcitonin trends in the setting of infection allows earlier cessation of antibiotics without decrement in the rate of clinical cure.31 Antibiotic therapy for osteomyelitis, endocarditis, or prosthetic infections in which it is hazardous to remove the device consists of prolonged courses of an antibiotic or several agents in combination for 6 to 12 weeks. The specific agents are selected based on analysis of the degree to which the organism is killed in vitro using the minimum inhibitory concentration VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 6-4 Antimicrobial agents Organism Antibiotic Class, Generic Name Trade Name Penicillins Mechanism of Action S. pyogenes MSSA MRSA S. epidermidis Enterococcus VRE E. coli P. aeruginosa Anaerobes 1 0 0 0 +/- 0 0 0 1 Cell wall synthesis inhibitors (bind penicillin-binding protein) Penicillin G Nafcillin Nallpen, Unipen 1 1 0 +/- 0 0 0 0 0 Piperacillin Pipracil 1 0 0 0 +/- 0 1 1 +/- Penicillin/beta lactamase inhibitor combinations Cell wall synthesis inhibitors/beta lactamase inhibitors Ampicillin-sulbactam Unasyn 1 1 0 +/- 1 +/- 1 0 1 Ticarcillin-clavulanate Timentin 1 1 0 +/- +/- 0 1 1 1 Piperacillin-tazobactam Zosyn 1 1 0 1 +/- 0 1 1 1 1 1 0 +/- 0 0 1 0 0 First-generation cephalosporins Cefazolin, cephalexin Cell wall synthesis inhibitors (bind penicillin-binding protein) Ancef, Keflex Second-generation cephalosporins Cell wall synthesis inhibitors (bind penicillin-binding protein) Cefoxitin Mefoxin 1 1 0 +/- 0 0 1 0 1 Cefotetan Cefotan 1 1 0 +/- 0 0 1 0 1 Cefuroxime Ceftin 1 1 0 +/- 0 0 1 0 0 Cell wall synthesis inhibitors (bind penicillin-binding protein) (Continued) 143 Surgical Infections VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 6 Third- and fourth-generation cephalosporins 144 PART I BASIC CONSIDERATIONS Table 6-4 Antimicrobial agents (continued) Organism Antibiotic Class, Generic Name Trade Name Ceftriaxone S. pyogenes MSSA MRSA S. epidermidis Enterococcus VRE Rocephin 1 1 0 +/- 0 Ceftazidime Fortaz 1 +/- 0 +/- Cefepime Maxipime 1 1 0 Cefotaxime Cefotaxime 1 1 ceftaroline Teflaro 1 1 Carbapenems Imipenem-cilastatin Mechanism of Action E. coli P. aeruginosa Anaerobes 0 1 0 0 0 0 1 1 0 +/- 0 0 1 1 0 0 +/- 0 0 1 +/- 0 1 1 1 0 0 1 0 0 1 0 1 +/- 0 1 1 1 Cell wall synthesis inhibitors (bind penicillin-binding protein) Primaxin Meropenem Merrem 1 1 0 1 0 0 1 1 1 Ertapenem Invanz 1 1 0 1 0 0 1 +/- 1 Aztreonam Azactam 0 0 0 0 0 0 1 1 0 Gentamicin 0 1 0 +/- 1 0 1 1 0 Tobramycin, amikacin 0 1 0 +/- 0 0 1 1 0 Aminoglycosides Alteration of cell membrane, binding and inhibition of 30S ribosomal unit Fluoroquinolones Inhibit topoisomerase II and IV (DNA synthesis inhibition) Ciprofloxacin Cipro +/- 1 0 1 0 0 1 1 0 Levofloxacin Levaquin 1 1 0 1 0 0 1 +/- 0 0 0 0 0 Glycopeptides Vancomycin Cell wall synthesis inhibition (peptidoglycan synthesis inhibition) Vancocin 1 1 1 1 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 1 0 0 QuinupristinDalfopristin Synercid Inhibits 2 sites on 50S ribosome (protein synthesis inhibition) 1 1 1 1 1 1 0 0 +/- Linezolid Zyvox Inhibits 50S ribosomal activity (protein synthesis inhibition) 1 1 1 1 1 1 0 0 +/- Daptomycin Cubicin Binds bacterial membrane, results in depolarization, lysis 1 1 1 1 1 1 0 0 0 Inhibits DNA-dependent 1 RNA polymerase 1 1 1 +/- 0 0 0 0 Rifampin Clindamycin Cleocin Inhibits 50S ribosomal activity (protein synthesis inhibition) 1 1 0 0 0 0 0 0 1 Metronidazole Flagyl Production of toxic intermediates (free radical production) 0 0 0 0 0 0 0 0 1 1 +/- 0 +/- 0 0 0 0 0 Macrolides Inhibit 50S ribosomal activity (protein synthesis inhibition) Erythromycin Azithromycin Zithromax 1 1 0 0 0 0 0 0 0 Clarithromycin Biaxin 1 1 0 0 0 0 0 0 0 Trimethoprimsulfamethoxazole Bactrim, Septra 1 0 +/- 0 0 1 0 0 +/- Tetracyclines Inhibits sequential steps +/of folate metabolism Bind 30S ribosomal unit (protein synthesis inhibition) Minocycline Minocin 1 1 0 0 0 0 0 0 Doxycycline Vibromycin 1 +/- 0 0 0 0 1 0 +/- Tigacycline Tygacil 1 1 1 1 1 1 1 0 1 1 E coli = Escherichia coli; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive Staphylococcus aureus; P aeruginosa = Pseudomonas aeruginosa; S epidermidis = Staphylococcus epidermidis; S pyogenes = Streptococcus pyogenes; VRE = vancomycin-resistant enterococcus. 1 = Reliable activity; +/– = variable activity; 0 = no activity. The sensitivities presented are generalizations. The clinician should confirm sensitivity patterns at the locale where the patient is being treated since these patterns may vary widely depending on location. 145 CHAPTER 6 Surgical Infections VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 146 Table 6-5 Prophylactic use of antibiotics (adapted from ref 25) PART I Site Antibiotic Alternative (e.g., penicillin allergic) Cardiovascular surgery Cefazolin, cefuroxime Vancomycin, clindamycin BASIC CONSIDERATIONS Gastroduodenal area; small Cefazolin intestine, nonobstructed Clindamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone Biliary tract: open procedure, laparoscopic high risk Cefazolin, cefoxitin, cefotetan, ceftriaxone, ampicillin-sulbactam, Clindamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone Metronidazole + aminoglycoside or fluoroquinolone Biliary tract: laparoscopic low risk None none Appendectomy, uncomplicated Cefoxitin, cefotetan, cefazolin + metronidazole Clindamycin + aminoglycoside or aztreonam or fluoroquinolone Metronidazole + aminoglycoside or flouroquinolone Colorectal surgery, obstructed small intestine Cefazolin or ceftriaxone plus metronidazole, Ertapenem, cefoxitin, cefotetan, ampicillin-sulbactam Clindamycin + aminoglycoside or aztreonam or fluoroquinolone, metronidazole + aminoglycoside or fluoroquinolone Head and neck; clean contaminated Cefazolin or cefuroxime + metronidazole, ampicillin-sulbactam clindamycin Neurosurgical procedures Cefazolin Clindamycin, Vancomycin Orthopedic surgery Cefazolin, ceftriaxone Clindamycin, Vancomycin Breast, hernia Cefazolin Clindamycin, Vancomycin (MIC) of a standard pure inoculum of 105 CFU/mL of the organism isolated from the site of infection or bloodstream. Sensitivities are reported in relation to the achievable blood level of each antibiotic in a panel of agents. The least toxic, least expensive agent to which the organism is most sensitive should be selected, although the latter parameter is of paramount importance. Serious or recrudescent infection may require therapy with two or more agents, particularly if a multidrug-resistant pathogen is causative, limiting therapeutic options to drugs to which the organism is only moderately sensitive. Commonly an agent may be administered intravenously for 1 to 2 weeks, following which the treatment course is completed with an oral drug. However, this should only be undertaken in patients who demonstrate progressive clinical improvement, and the oral agent should be capable of achieving high serum levels as well (e.g., fluoroquinolones). The majority of studies examining the optimal duration of antibiotic therapy for the treatment of polymicrobial infection have focused on patients who develop peritonitis. CoGeNT data exist to support the contention that satisfactory outcomes are achieved with 12 to 24 hours of therapy for penetrating gastrointestinal trauma in the absence of extensive contamination, 3 to 5 days of therapy for perforated or gangrenous appendicitis, 5 to 7 days of therapy for treatment of peritoneal soilage due to a perforated viscus with moderate degrees of contamination, and 7 to 14 days of therapy to adjunctively treat extensive peritoneal soilage (e.g., feculent peritonitis) or that occurring in the immunosuppressed host.32 It bears repeating that the eventual outcome is more closely linked to the ability of the surgeon to achieve effective source control than to the duration of antibiotic administration. One small randomized trial has reported similar outcomes of 3 day vs. standard duration therapy in secondary microbial peritonitis.33 In the later phases of postoperative antibiotic treatment of serious intra-abdominal infection, the absence of an elevated white blood cell (WBC) count, lack of band forms of PMNs on peripheral smear, and lack of fever (<100.5°F) provide close to complete assurance that infection has been eradicated.34 Under these circumstances, antibiotics can be discontinued with impunity. However, the presence of one or more of these indicators does not mandate continuing antibiotics or altering the antibiotic(s) administered. Rather, a search for an extra-abdominal source of infection or a residual or ongoing source of intra-abdominal infection (e.g., abscess or leaking anastomosis) should be sought, the latter mandating maneuvers to effect source control. Allergy to antimicrobial agents must be considered prior to prescribing them. First, it is important to ascertain whether a patient has had any type of allergic reaction in association with administration of a particular antibiotic. However, one should take care to ensure that the purported reaction consists of true allergic symptoms and signs, such as urticaria, bronchospasm, or other similar manifestations, rather than indigestion or nausea. Penicillin allergy is quite common, the reported incidence ranging from 0.7% to 10%. Although avoiding the use of any beta-lactam drug is appropriate in patients who manifest significant allergic reactions to penicillins, the incidence of cross-reactivity appears low for all related agents, with 1% cross-reactivity for carbapenems,35 5% to 7% cross-reactivity for cephalosporins, and extremely small or nonexistent crossreactivity for monobactams. Severe allergic manifestations to a specific class of agents, such as anaphylaxis, generally preclude the use of any agents in VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Site Infections Surgical site infections (SSIs) are infections of the tissues, organs, or spaces exposed by surgeons during perfor5 mance of an invasive procedure. SSIs are classified into incisional and organ/space infections, and the former are further subclassified into superficial (limited to skin and subcutaneous tissue) and deep incisional categories.38,39 The development of SSIs is related to three factors: (a) the degree of microbial contamination of the wound during surgery, (b) the duration of the procedure, and (c) host factors such as diabetes, malnutrition, obesity, immune suppression, and a number of other underlying disease states. Table 6-6 lists risk factors for development of SSIs. By definition, an incisional SSI has occurred if a surgical wound drains purulent material or if the surgeon judges it to be infected and opens it. Surgical wounds are classified based on the presumed magnitude of the bacterial load at the time of surgery (Table 6-7).40 Clean wounds (class I) include those in which no infection is present; only skin microflora potentially contaminate the wound, and no hollow viscus that contains microbes is entered. Class I D wounds are similar except that a prosthetic device (e.g., mesh or valve) is inserted. Clean/contaminated wounds (class II) include those in which a hollow viscus such as the respiratory, alimentary, or genitourinary tracts with indigenous 147 Risk factors for development of surgical site infections Patient factors Older age Immunosuppression Obesity Diabetes mellitus Chronic inflammatory process Malnutrition Smoking Renal failure Peripheral vascular disease Anemia Radiation Chronic skin disease Carrier state (e.g., chronic Staphylococcus carriage) Recent operation Local factors Open compared to laparoscopic surgery Poor skin preparation Contamination of instruments Inadequate antibiotic prophylaxis Prolonged procedure Local tissue necrosis Blood transfusion Hypoxia, hypothermia Microbial factors Prolonged hospitalization (leading to nosocomial organisms) Toxin secretion Resistance to clearance (e.g., capsule formation) bacterial flora is opened under controlled circumstances without significant spillage of contents. While elective colorectal cases have classically been included as class II cases, a number of studies in the last decade have documented higher SSI rates (9% to 25%).41-43 One study identified two-thirds of infections presenting after discharge from hospital, highlighting the need for careful follow-up of these patients.41 Infection is also more common in cases involving entry into the rectal space.42 In a recent single center quality improvement study using a multidisciplinary approach, one group of clinicians has demonstrated the ability to decrease SSI from 9.8% to 4.0%.43 Contaminated wounds (class III) include open accidental wounds encountered early after injury, those with extensive introduction of bacteria into a normally sterile area of the body due to major breaks in sterile technique (e.g., open cardiac massage), gross spillage of viscus contents such as from the intestine, or incision through inflamed, albeit nonpurulent tissue. Dirty wounds (class IV) include traumatic wounds in which a significant delay in treatment has occurred and in which necrotic tissue is present, those created in the presence of overt infection as evidenced by the presence of purulent material, and those created to access a perforated viscus accompanied by a high degree of contamination. The microbiology of SSIs is reflective of the initial host microflora such that SSIs following creation of a class I wound are invariable, due solely to skin microbes found VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Infections INFECTIONS OF SIGNIFICANCE IN SURGICAL PATIENTS Table 6-6 CHAPTER 6 that class, except under circumstances in which use of a certain drug represents a lifesaving measure. In some centers, patients undergo intradermal testing using a dilute solution of a particular antibiotic to determine whether a severe allergic reaction would be elicited by parenteral administration. A pathway, including such intradermal testing, has been effective in reduction of vancomycin use to 16% in surgical patients with reported allergy to penicillin.36 This type of testing is rarely employed because it is simpler to select an alternative class of agent. Should administration of a specific agent to which the patient is allergic become necessary, desensitization using progressively higher doses of antibiotic can be undertaken, providing the initial testing does not cause severe allergic manifestations. Misuse of antimicrobial agents is rampant in both the inpatient and outpatient setting, and is associated with an enormous financial impact on health care costs, adverse reactions due to drug toxicity and allergy, the occurrence of new infections such as Clostridium difficile colitis, and the development of multiagent drug resistance among nosocomial pathogens. Each of these factors has been directly correlated with overall drug administration. It has been estimated that in the United States, in excess of $20 billion is spent on antibiotics each year, and the appearance of so-called “super bugs”— microbes sensitive to few if any agents—has been sobering.37 The responsible practitioner limits prophylaxis to the period during the operative procedure, does not convert prophylaxis into empirical therapy except under well-defined conditions, sets the duration of antibiotic therapy from the outset, curtails antibiotic administration when clinical and microbiologic evidence does not support the presence of an infection, and limits therapy to a short course in every possible instance. Prolonged treatment associated with drains and tubes has not been shown to be beneficial. 148 Table 6-7 Wound class, representative procedures, and expected infection rates PART I Wound Class Examples of Cases Expected Infection Rates BASIC CONSIDERATIONS Clean (class I) Hernia repair, breast biopsy specimen 1%–2% Clean/contaminated (class II) Cholecystectomy, elective GI surgery (not colon) 2.1%–9.5% Clean/contaminated (class II) Colorectal surgery 4%–14% Contaminated (class III) Penetrating abdominal trauma, large tissue injury, enterotomy during bowel obstruction 3.4%–13.2% Dirty (class IV) Perforated diverticulitis, necrotizing soft tissue infections 3.1%–12.8% on that portion of the body, while SSIs subsequent to a class II wound created for the purpose of elective colon resection may be caused by either skin microbes or colonic microflora, or both. In the United States, hospitals are required to conduct surveillance for the development of SSIs for a period of 30 days after the operative procedure.44 Such surveillance has been associated with greater awareness and a reduction in SSI rates, probably in large part based upon the impact of observation and promotion of adherence to appropriate care standards. Beginning in 2012, all hospitals receiving reimbursement from the Center for Medicare and Medicaid Services are required to report SSIs. A recent refinement of risk indexes has been implemented through the National Healthcare Safety Network, a secure, webbased system of surveillance utilized by the Centers for Disease Control and Prevention for surveillance of health care associated infections. This refinement utilized data reported from 847 hospitals in nearly one million patients over a two- year period to develop procedure-specific risk indices for SSIs.45 SSIs are associated with considerable morbidity and occasional lethality, as well as substantial health care costs and patient inconvenience and dissatisfaction.46 For that reason, surgeons strive to avoid SSIs by using the maneuvers described in the previous section. Also, the use of prophylactic antibiotics may serve to reduce the incidence of SSI rates during certain types of procedures. For example, it is well accepted that a single dose of an antimicrobial agent should be administered immediately prior to commencing surgery for class I D, II, III, and IV types of wounds. It seems reasonable that this practice should be extended to patients in any category with high National Nosocomial Infection Surveillance (NNIS) scores, although this remains to be proven. Thus, the utility of prophylactic antibiotics in reducing the rate of wound infection subsequent to clean surgery remains controversial, and these agents should not be employed under routine circumstances (e.g., in healthy young patients). However, because of the potential dire consequences of a wound infection after clean surgery in which prosthetic material is implanted into tissue, patients who undergo such procedures should receive a single preoperative dose of an antibiotic. A number of health care organizations within the United States have become interested in evaluating performance of hospitals and physicians with respect to implementing processes that support delivery of standard of care. One major process of interest is reduction in SSIs, since the morbidity (and subsequent cost) of this complication is high. Several of these organizations are noted in Table 6-8. Appropriate guidelines in this area incorporating the principles discussed previously have been developed and disseminated.47 However, observers have noted that adherence to these guidelines has been poor.48 Most experts believe that better adherence to evidence-based practice recommendations and implementing systems of care Table 6-8 Quality improvement organizations in the United States of interest to surgeons Abbreviation Organization Website SCIP Surgical Care Improvement Project www.premierinc.com/safety/topics/scip/ NSQIP National Surgical Quality Improvement Program www.acsnsqip.org IHI Institute for Healthcare Improvement www.ihi.org CMS Center for Medicare and Medicaid Services www.cms.gov NCQA National Committee for Quality Assurance www.ncqa.org SIS Surgical Infection Society www.sisna.org CDC Centers for Disease Control and Prevention www.cdc.gov/HAI/ssi/ssi.html VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Intra-Abdominal Infections Microbial contamination of the peritoneal cavity is termed peritonitis or intra-abdominal infection, and is classified according to etiology. Primary microbial peritonitis occurs when microbes invade the normally sterile confines of the peritoneal cavity via hematogenous dissemination from a distant source of infection or Figure 6-2. Negative pressure wound therapy in a patient after amputation for wet gangrene (A), and in a patient with enterocutaneous fistula (B). It is possible to adapt these dressings to fit difficult anatomy and provide appropriate wound care while reducing frequency of dressing change. It is important to evaluate the wound under these dressings if patient demonstrates signs of sepsis with an unidentified source, since typical clues of wound sepsis such as odor and drainage are hidden by the suction apparatus. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 149 Surgical Infections The respective effects of body temperature and the level of inhaled oxygen during surgery on SSI rates also have been studied, and both hypothermia and hypoxia during surgery are associated with a higher rater of SSIs. Although an initial study provided evidence that patients who received high levels of inhaled oxygen during colorectal surgery developed fewer SSIs,54 a recent meta-analysis suggest that the overall benefit is small and may not warrant use.55 Further evaluation via multicenter studies is needed prior to implementation of hyperoxia as standard therapy, but it is clear that intraoperative hypothermia and hypoxia should be prevented. Effective therapy for incisional SSIs consists solely of incision and drainage without the additional use of antibiotics. Antibiotic therapy is reserved for patients in whom evidence of significant cellulitis is present, or who concurrently manifest a systemic inflammatory response syndrome. The open wound often is allowed to heal by secondary intention, with dressings being changed twice a day. The use of topical antibiotics and antiseptics to further wound healing remains unproven, although anecdotal studies indicate their potential utility in complex wounds that do not heal with routine measures.56 Despite a paucity of prospective studies,57 vacuum-assisted closure is increasingly used in management of large, complex open wounds and can be applied to wounds in locations that are difficult to manage with dressings (Fig. 6-2). One also should consider obtaining wound cultures in patients who develop SSIs and whom have been hospitalized or reside in long-term care facilities due to the increasing incidence of infection caused by multidrug resistant organisms. The treatment of organ/space infections is discussed in the following section. CHAPTER 6 with redundant safeguards will result in reduction of surgical complications and better patient outcomes. More important, the Center for Medicare and Medicaid Services, the largest third party insurance payer in the United States, has required reporting by hospitals of many processes related to reduction of surgical infections, including appropriate use of perioperative antibiotics. This information, which is currently reported publicly by hospitals, has led to significant improvement in reported rates of these process measures. However, the effect of this approach on the incidence of SSIs is not known at this time. Surgical management of the wound also is a critical determinant of the propensity to develop a SSI. In healthy individuals, class I and II wounds may be closed primarily, while skin closure of class III and IV wounds is associated with high rates of incisional SSIs (~25% to 50%). The superficial aspects of these latter types of wounds should be packed open and allowed to heal by secondary intention, although selective use of delayed primary closure has been associated with a reduction in incisional SSI rates.49 It remains to be determined whether NNIStype stratification schemes can be employed prospectively in order to target specific subgroups of patients which will benefit from the use of prophylactic antibiotic and/or specific wound management techniques. One clear example based on CoGeNT data from clinical trials is that class III wounds in healthy patients undergoing appendectomy for perforated or gangrenous appendicitis can be primarily closed as long as antibiotic therapy directed against aerobes and anaerobes is administered. This practice leads to SSI rates of approximately 3% to 4%.50 Recent investigations have studied the effect of additional maneuvers in an attempt to further reduce the rate of SSIs. The adverse effects of hyperglycemia on WBC function have been well described.51 A number of recent studies in patients undergoing several different types of surgery describe increased risk of SSI in patients with hyperglycemia.52,53 Although randomized trials have not been performed, it is recommended that clinicians maintain appropriate blood sugar control in patients in the perioperative period to minimize the occurrence of SSI. 150 PART I BASIC CONSIDERATIONS direct inoculation. This process is more common among patients who retain large amounts of peritoneal fluid due to ascites, and among those individuals who are being treated for renal failure via peritoneal dialysis. These infections invariably are monomicrobial and rarely require surgical intervention. The diagnosis is established based on identification of risk factors as noted previously, physical examination that reveals diffuse tenderness and guarding without localized findings, absence of pneumoperitoneum on an imaging study, the presence of more than 100 WBCs/mL, and microbes with a single morphology on Gram’s stain performed on fluid obtained via paracentesis. Subsequent cultures typically will demonstrate the presence of gram positive organisms in patients undergoing peritoneal dialysis. In patients without this risk factor organisms can include E. coli, K. pneumoniae, pneumococci, and others, although many different pathogens can be causative. Treatment consists of administration of an antibiotic to which the organism is sensitive; often 14 to 21 days of therapy are required. Removal of indwelling devices (e.g., a peritoneal dialysis catheter or a peritoneovenous shunt) may be required for effective therapy of recurrent infections. Secondary microbial peritonitis occurs subsequent to contamination of the peritoneal cavity due to perforation or severe inflammation and infection of an intra-abdominal organ. Examples include appendicitis, perforation of any portion of the gastrointestinal tract, or diverticulitis. As noted previously, effective therapy requires source control to resect or repair the diseased organ; débridement of necrotic, infected tissue and debris; and administration of antimicrobial agents directed against aerobes and anaerobes.58 This type of antibiotic regimen should be chosen because in most patients the precise diagnosis cannot be established until exploratory laparotomy is performed, and the most morbid form of this disease process is colonic perforation, due to the large number of microbes present. A combination of agents or single agents with a broad spectrum of activity can be used for this purpose; conversion of a parenteral to an oral regimen when the patient’s ileus resolves provides results similar to those achieved with intravenous antibiotics. Effective source control and antibiotic therapy is associated with low failure rates and a mortality rate of approximately 5% to 6%; inability to control the source of infection is associated with mortality greater than 40%.59 The response rate to effective source control and use of appropriate antibiotics has remained approximately 70% to 90% over the past several decades.60 Patients in whom standard therapy fails typically develop one or more of the following: an intra-abdominal abscess, leakage from a gastrointestinal anastomosis leading to postoperative peritonitis, or tertiary (persistent) peritonitis. The latter is a poorly understood entity that is more common in immunosuppressed patients in whom peritoneal host defenses do not effectively clear or sequester the initial secondary microbial peritoneal infection. Microbes such as Enterococcus faecalis and faecium, Staphylococcus epidermidis, Candida albicans, and Pseudomonas aeruginosa commonly are identified, typically in combination, and their presence may be due to their lack of responsiveness to the initial antibiotic regimen, coupled with diminished activity of host defenses. Unfortunately, even with effective antimicrobial agent therapy, this disease process is associated with mortality rates in excess of 50%.61 Formerly, the presence of an intra-abdominal abscess mandated surgical reexploration and drainage. Today, the vast majority of such abscesses can be effectively diagnosed via abdominal computed tomographic (CT) imaging techniques and drained percutaneously. Surgical intervention is reserved for those individuals who harbor multiple abscesses, those with abscesses in proximity to vital structures such that percutaneous drainage would be hazardous, and those in whom an ongoing source of contamination (e.g., enteric leak) is identified. The necessity of antimicrobial agent therapy and precise guidelines that dictate duration of catheter drainage have not been established. A short course (3 to 7 days) of antibiotics that possess aerobic and anaerobic activity seems reasonable, and most practitioners leave the drainage catheter in situ until it is clear that cavity collapse has occurred, output is less than 10 to 20 mL/d, no evidence of an ongoing source of contamination is present, and the patient’s clinical condition has improved. Organ-Specific Infections Hepatic abscesses are rare, currently accounting for approximately 15 per 100,000 hospital admissions in the United States. Pyogenic abscesses account for approximately 80% of cases, the remaining 20% being equally divided among parasitic and fungal forms.62 Formerly, pyogenic liver abscesses mainly were caused by pylephlebitis due to neglected appendicitis or diverticulitis. Today, manipulation of the biliary tract to treat a variety of diseases has become a more common cause, although in nearly 50% of patients no cause is identified. The most common aerobic bacteria identified in recent series include E coli, K pneumoniae, and other enteric bacilli, enterococci, and Pseudomonas spp., while the most common anaerobic bacteria are Bacteroides spp., anaerobic streptococci, and Fusobacterium spp. Candida albicans and other related yeast cause the majority of fungal hepatic abscesses. Small (<1 cm), multiple abscesses should be sampled and treated with a 4 to 6 week course of antibiotics. Larger abscesses invariably are amenable to percutaneous drainage, with parameters for antibiotic therapy and drain removal similar to those mentioned previously. Splenic abscesses are extremely rare and are treated in a similar fashion. Recurrent hepatic or splenic abscesses may require operative intervention—unroofing and marsupialization or splenectomy, respectively. Secondary pancreatic infections (e.g., infected pancreatic necrosis or pancreatic abscess) occur in approximately 10% to 15% of patients who develop severe pancreatitis with necrosis. The surgical treatment of this disorder was pioneered by Bradley and Allen, who noted significant improvements in outcome for patients undergoing repeated pancreatic débridement of infected pancreatic necrosis.63 Current care of patients with severe acute pancreatitis includes staging with dynamic, contrast materialenhanced helical CT scan to evaluate the extent of pancreatitis (unless significant renal dysfunction exists in which case one should forego the use of contrast material) coupled with the use of one of several prognostic scoring systems. Patients who exhibit clinical signs of instability (e.g., oliguria, hypoxemia, large-volume fluid resuscitation) should be carefully monitored in the ICU and undergo follow-up contrast enhanced CT examination when renal function has stabilized to evaluate for development of local pancreatic complications (Fig. 6-3). A recent change in practice has been the elimination of the routine use of prophylactic antibiotics for prevention of infected pancreatic necrosis. Enteral feedings initiated early, using nasojejunal feeding tubes placed past the ligament of Treitz, have been associated with decreased development of infected pancreatic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Infections of the Skin and Soft Tissue These infections can be classified according to whether or not surgical intervention is required. For example, superficial skin and skin structure infections such as cellulitis, erysipelas, and lymphangitis invariably are effectively treated with antibiotics alone, although a search for a local underlying source of infection should be undertaken. Generally, drugs that possess activity against the causative gram-positive skin microflora are selected. Furuncles or boils may drain spontaneously or require surgical incision and drainage. Antibiotics are prescribed if significant cellulitis is present or if cellulitis does not rapidly resolve after surgical drainage. Community-acquired methicillin resistant Staphylococcus aureus (MRSA) infection should be suspected if infection persists after treatment with adequate drainage and administration of first line antibiotics. These infections may require more aggressive drainage and altered antimicrobial therapy.72 Aggressive soft tissue infections are rare, difficult to diagnose, and require immediate surgical intervention plus administration of antimicrobial agents. Failure to do so results in an extremely high mortality rate (~80%–100%), and even with rapid recognition and intervention, current mortality rates are high (16%–24%).73 Eponyms and classification in the past have been a hodgepodge of terminology, such as Meleney’s synergist gangrene, rapidly spreading cellulitis, gas gangrene, and necrotizing fasciitis, among others. Today it seems best to delineate these serious infections based on the soft tissue layer(s) of involvement (e.g., skin and superficial soft tissue, deep soft tissue, and muscle) and the pathogen(s) that cause them. Patients at risk for these types of infections include those who are elderly, immunosuppressed, or diabetic; those who suffer from peripheral vascular disease; or those with a combination of these factors. The common thread among these host factors appears to be compromise of the fascial blood supply to some degree, and if this is coupled with the introduction of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Infections necrosis, possibly due to a decrease in gut translocation of bacteria. These topics have been recently reviewed.64,65 The presence of secondary pancreatic infection should be suspected in patients whose systemic inflammatory response (fever, elevated WBC count, or organ dysfunction) fails to resolve, or in those individuals who initially recuperate, only to develop sepsis syndrome 2 to 3 weeks later. CT-guided aspiration of fluid from the pancreatic bed for performance of Gram’s stain and culture analysis can be useful. A positive Gram’s stain or culture from CT-guided aspiration, or identification of gas within the pancreas on CT scan, mandate surgical intervention. The approach of open necrosectomy with repeated debridements, although life saving, is associated with significant morbidity and prolonged hospitalization. Efforts to reduce the amount of surgical injury, while still preserving the improved outcomes associated with debridement of the infected sequestrum have led to a variety of less invasive approaches.66 These include endoscopic approaches, laparoscopic approaches and other minimally invasive approaches. There are a limited number of randomized trials reporting the use of these new techniques currently. An important concept common to all of these approaches, however, is the attempt to delay surgical intervention, since a number of trials have identified increased mortality when intervention occurs during the first two weeks of illness. Data supporting the use of endoscopic approaches to this problem include nearly a dozen case series and a randomized trial.67,68 The reported mortality rate was 5%, with a 30% complication rate. Most authors noted the common requirement for multiple endoscopic debridements (similar to the open approach), with a median of 4 endoscopic sessions required. Fewer series report experience with the laparoscopic approach, either transgastric or transperitoneal, entering the necrosis through the transverse mesocolon or gastrocolic ligament. The laparoscopic technique is carefully described in a recent publication.69 Laparoscopic intervention is limited by the difficulty in achieving multiple debridements and the technical expertise required to achieve an adequate debridement. Mortality in 65 patients in 9 case series reported was 6% overall. Debridement of necrosis through a lumbar approach has been advocated by a number of authors. This approach, developed with experience in a large number of patients,70 has been recently subjected to a single center randomized prospective 151 CHAPTER 6 Figure 6-3. Contrast-enhanced CT scan of pancreas 1½ weeks after presentation showing large central peripancreatic fluid collection. trial.71 This approach includes delay of intervention when possible until 4 weeks after the onset of disease. Patients receive transgastric or preferably retroperitoneal drainage of the sequestrum. If patients do not improve over 72 hours, they are treated with video-assisted retroperitoneal drainage (VARD), consisting of dilation of the retroperitoneal drain tract, placement of and irrigation, and debridement of the pancreatic bed (Fig. 6-4). Repeat debridements are performed as clinically indicated, 6 with most patients requiring multiple debridements. In the trial reported, patients randomized to VARD (n=43) compared to those randomized to the standard open necrosectomy (n=45) had a decreased incidence of the composite endpoint of complications and death (40% vs. 69%), with comparable mortality rate, hospital, and ICU lengths of stay. Patients randomized to VARD had fewer incisional hernias, new-onset diabetes, and need for pancreatic enzyme supplementation. It is apparent that patients with infected pancreatic necrosis can safely undergo procedures that are more minimal than the gold-standard open necrosectomy with good outcomes. However, to obtain good outcomes these approaches require an experienced multidisciplinary team consisting of interventional radiologists, gastroenterologists, surgeons, and others. Important concepts for successful management include careful preoperative planning, delay (if possible) to allow maturation of the fluid collection, and the willingness to repeat procedures as necessary till the majority if not all nonviable tissue has been removed. exogenous microbes, the result can be devastating. However, it is of note that over the last decade, extremely aggressive necrotizing soft tissue infections among healthy individuals due to streptococci have been described as well. Initially, the diagnosis is established solely upon a constellation of clinical findings, not all of which are present in every patient. Not surprisingly, patients often develop sepsis syndrome or septic shock without an obvious cause. The extremities, perineum, trunk, and torso are most commonly affected, in that order. Careful examination should be undertaken for an entry site such as a small break or sinus in the skin from which grayish, turbid semipurulent material (“dishwater pus”) can be expressed, as well as for the presence of skin changes (bronze hue or brawny induration), blebs, or crepitus. The patient often develops pain at the site of infection that appears to be out of proportion to any of the physical manifestations. Any of these findings mandates immediate surgical intervention, which should consist of exposure and direct visualization of potentially infected tissue (including deep soft tissue, fascia, and underlying muscle) and radical resection of affected areas. Radiologic studies should not be undertaken in patients in whom the diagnosis seriously is considered, as they delay surgical intervention and frequently provide confusing information. Unfortunately, surgical extirpation of infected tissue frequently entails amputation and/or disfiguring procedures; however, incomplete procedures are associated with higher rates of morbidity and mortality (Fig. 6-5). During the procedure a Gram’s stain should be performed on tissue fluid. Antimicrobial agents directed against Grampositive and Gram-negative aerobes and anaerobes (e.g., vancomycin plus a carbapenem), as well as high-dose aqueous penicillin G (16,000,000 to 20,000,000 U/d), the latter to treat clostridial pathogens, should be administered. Approximately 50% of such infections are polymicrobial, the remainder being caused by a single organism such as Streptococcus pyogenes, Pseudomonas aeruginosa, or Clostridium perfringens. The microbiology of these polymicrobial infections is similar to that of secondary microbial peritonitis, with the exception that Gram-positive cocci are more commonly encountered. Most patients should be returned to the operating room on a scheduled basis to determine if disease progression has occurred. If so, additional resection of infected tissue and debridement should take place. Antibiotic therapy can be refined based on culture and sensitivity results, particularly in the case of monomicrobial soft tissue infections. Hyperbaric oxygen therapy may be of use in patients with infection caused by gasforming organisms (e.g., Clostridium perfringens), although the evidence to support efficacy is limited to underpowered studies and case reports.In the absence of such infection, hyperbaric oxygen therapy has not shown to be effective.74 152 PART I BASIC CONSIDERATIONS B Postoperative Nosocomial Infections C Figure 6-4. Infected pancreatic necrosis. (A) Open necrosectomy specimen with pancreatic stent in situ. It is important to gently debride only necrotic pancreatic tissue, relying on repeated operation to ensure complete removal. (B) For video-assisted retroperitoneal debridement (VARD), retroperitoneal access is gained through radiologic placement of a drain, followed by dilation 2-3 days later. (C) Retroperitoneal cavity seen through endoscope during VARD. Surgical patients are prone to develop a wide variety of nosocomial infections during the postoperative period, which include SSIs, UTIs, pneumonia, and bacteremia. SSIs are discussed earlier, and the latter types of nosocomial infections are related to prolonged use of indwelling tubes and catheters for the purpose of urinary drainage, ventilation, and venous and arterial access, respectively. The presence of a postoperative UTI should be considered based on urinalysis demonstrating WBCs or bacteria, a positive test for leukocyte esterase, or a combination of these elements. The diagnosis is established after >104 CFU/mL of microbes are identified by culture techniques in symptomatic patients, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 153 CHAPTER 6 Surgical Infections Figure 6-5 Necrotizing soft tissue infection. (A) This patient presented with hypotension due to severe late necrotizing fasciitis and myositis due to beta-hemolytic streptococcal infection. The patient succumbed to his disease after 16 hours despite aggressive debridement. (B) This patient presented with spreading cellulites and pain on motion of his right hip 2 weeks after total colectomy. Cellulitis on right anterior thigh is outlined. (C) Classic dishwater edema of tissues with necrotic fascia. (D) Right lower extremity after debridement of fascia to viable muscle. or >105 CFU/mL in asymptomatic individuals. Treatment for 3 to 5 days with a single antibiotic directed against the most common organisms (e.g., E. Coli, K. pneumonia) that achieves high levels in the urine is appropriate. Initial therapy is directed by Gram’s stain results and is refined as culture results become available. Postoperative surgical patients should have indwelling urinary catheters removed as quickly as possible, typically within 1 to 2 days, as long as they are mobile, to avoid the development of a UTI. Prolonged mechanical ventilation is associated with nosocomial pneumonia. These patients present with more severe disease, are more likely to be infected with drug-resistant pathogens, and suffer increased mortality compared to patients who develop community-acquired pneumonia. The diagnosis of pneumonia is established by presence of a purulent sputum, elevated leukocyte count, fever, and new chest X-ray abnormalities, such as consolidation. The presence of two of the clinical findings, plus chest X-ray findings, significantly increases VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 154 PART I BASIC CONSIDERATIONS the likelihood of pneumonia.75 Consideration should be given to performing bronchoalveolar lavage to obtain samples for Gram’s stain and culture. Some authors advocate quantitative cultures as a means to identify a threshold for diagnosis.76 Surgical patients should be weaned from mechanical ventilation as soon as feasible, based on oxygenation and inspiratory effort, as prolonged mechanical ventilation increases the risk of nosocomial pneumonia. Infection associated with indwelling intravascular catheters has become a common problem among hospitalized patients. Because of the complexity of many surgical procedures, these devices are increasingly used for physiologic monitoring, vascular access, drug delivery, and hyperalimentation. Among the several million catheters inserted each year in the United States, approximately 25% will become colonized, and approximately 5% will be associated with bacteremia. Duration of catheterization, insertion or manipulation under emergency or nonsterile conditions, use for hyperalimentation, and the use of multilumen catheters increase the risk of infection. Use of a central line insertion protocol that includes full barrier precautions and chlorhexidine skin prep has been shown to decrease the incidence of infection.77 Although no randomized trials have been performed, peripherally inserted central venous catheters have a catheter-related infection rate similar to those inserted in the subclavian or jugular veins.78 Many patients who develop intravascular catheter infections are asymptomatic, often exhibiting solely an elevation in the blood WBC count. Blood cultures obtained from a peripheral site and drawn through the catheter that reveal the presence of the same organism increase the index of suspicion for the presence of a catheter infection. Obvious purulence at the exit site of the skin tunnel, severe sepsis syndrome due to any type of organism when other potential causes have been excluded, or bacteremia due to Gram-negative aerobes or fungi should lead to catheter removal. Selected catheter infections due to low-virulence microbes such as Staphylococcus epidermidis can be effectively treated in approximately 50% to 60% of patients with a 14- to 21-day course of an antibiotic, which should be considered when no other vascular access site exists.79 The use of antibiotic-bonded catheters and chlorhexidine sponges at the insertion site have been associated with lower rates of colonization.77 Use of ethanol or antimicrobial catheter “locks” have shown promise in reducing incidence of infection in dialysis catheters.80 The surgeon should carefully consider the need for any type of vascular access device, rigorously attend to their maintenance to prevent infection, and remove them as quickly as possible. Use of systemic antibacterial or antifungal agents to prevent catheter infection is of no utility and is contraindicated. Sepsis Severe sepsis is increasing in incidence, with over 1.1 million cases estimated per year in the United States with an annual cost of 24 billion dollars. This rate is expected to increase as the population of aged in the United States increases. One third of sepsis cases occur in surgical populations and sepsis is a major cause of morbidity and mortality.81 The treatment of sepsis has improved dramatically over the last decade, with mortality rates dropping to under 30%. Factors contributing to this improvement in mortality relate both to recent randomized prospective trials demonstrating improved outcomes with new therapies, and to improvements in the process of care delivery to the sepsis patient. The “Surviving Sepsis Campaign,” a multidisciplinary group that worked to develop treatment recommendations has published guidelines incorporating evidence-based treatment strategies most recently in 2013.13 These guidelines are summarized in Table 6-9. Patients presenting with severe sepsis should receive resuscitation fluids to achieve a central venous pressure target of 8-12 mm Hg, with a goal of mean arterial pressure of ≥ 65 mHg and urine output of ≥ 0.5 mL/kg/h. Delaying this resuscitative step for as little as 3 hours until arrival in the ICU has been shown to result in poor outcome.82 Typically this goal necessitates early placement of central venous catheter. A number of studies have demonstrated the importance of early empirical antibiotic therapy in patients who develop sepsis or nosocomial infection. This therapy should be initiated as soon as possible with broad spectrum antibiotics directed against most likely organisms, since early appropriate antibiotic therapy has been associated with significant reductions in mortality, and delays in appropriate antibiotic administration are associated with increased mortality. Use of institutional and unit specific sensitivity patterns are critical in selecting an appropriate agent for patients with nosocomial infection. It is key, however, to obtain cultures of appropriate areas without delaying initiating antibiotics so that appropriate adjustment of antibiotic therapy can take place when culture results return. Additionally, early identification and treatment of septic sources is key for improved outcomes in patients with sepsis. Although there are no randomized trials demonstrating this concept, repeated evidence in studies of patients who develop intraabdominal infection, necrotizing soft tissue infection, and other types of infections demonstrate increased mortality with delayed treatment. As discussed earlier, one exception is that of infected pancreatic necrosis. Multiple recent trials have evaluated the use of vasopressors and inotropes for treatment of septic shock. The current first-line agent for treatment of hypotension is norepinephrine. It is important to titrate therapy based on other parameters such as mixed venous oxygen saturation and plasma lactate levels as well as mean arterial pressure to reduce the risk of vasopressorinduced perfusion deficits. Several recent randomized trials have failed to demonstrate benefit with use of pulmonary arterial catheterization, leading to a significant decrease in its use. A number of other adjunctive therapies are useful in treatment of the patient with severe sepsis and septic shock. Lowdose corticosteroids (hydrocortisone at ≤300 mg/day) can be used in patients with septic shock who are not responsive to fluids and vasopressors. However, a recent randomized trial failed to show survival benefit. Patients with acute lung injury associated with sepsis should receive mechanical ventilation with tidal volumes of 6 mL/kg and pulmonary airway plateau pressures of ≤30 cm H2O. Finally, red blood cell transfusion should be reserved for patients with hemoglobin of <7 grams/ dL, with a more liberal transfusion strategy reserved for those patients with severe coronary artery disease, ongoing blood loss, or severe hypoxemia. Resistant Organisms: In the 1940s, penicillin was first produced for widespread clinical use. Within a year of its introduction, the first resistant strains of Staphylococcus aureus were identified. There are two major components that are responsible for antibiotic resistance. First, there may be a genetic component innate to the organism that prevents an effect of a particular antibiotic. For instance, if an organism does not have a target receptor specific to the mechanism of action of a particular antibiotic, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 155 Table 6-9 Summary of Surviving Sepsis Campaign guidelines Target resuscitation to normalize lactate in patients with elevated lactate levels. Antibiotic therapy: Begin IV antibiotic therapy as early as possible: should be within the first hour after recognition of severe sepsis/septic shock. Use broad spectrum antibiotic regimen with penetration into presumed source, reassess regimen daily with deescalation as appropriate. Discontinue antibiotics in 7–10 d for most infections, stop antibiotics for noninfectious issues. Source control: Establish anatomic site of infection as rapidly as possible, implement source control measures immediately after initial resuscitation. Remove intravascular access devices if potentially infected. Infection prevention: Selective oral and digestive tract decontamination. Hemodynamic Support and Adjunctive Therapy Fluid therapy: Fluid resuscitate using crystalloid, using fluid volumes of 1000 mL (crystalloid), target CVP of 8 to12 mm Hg. Vasopressors/Inotropic Therapy: Maintain MAP of ≥65 mm Hg, centrally-administered norepinephrine is first-line choice. Dopamine should not be used for “renal protection,” insert arterial catheters for patients requiring vasopressors. Phenylephrine is not recommended in treatment of septic shock. Dobutamine infusion can be used in setting of myocardial dysfunction. Do not use strategy of targeting supranormal cardiac index. Steroids: Consider intravenous hydrocortisone (dose ≤300 mg/d) for adult septic shock when hypotension responds poorly to fluids and vasopressors. Other Supportive Therapy Blood product administration: Transfuse red blood cells when hemoglobin decreases to <7.0 g/dL. Mechanical ventilation: Target an initial tidal volume of 6 mL/kg body weight and plateau pressure of ≤30 cm H2O in patients with acute lung injury. Use positive end-expiratory pressure to avoid lung collapse. Use a weaning protocol to evaluate the potential for discontinuing mechanical ventilation. Pulmonary artery catheter is not indicated for routine monitoring. Sedation: Minimize sedation using specific titration endpoints. Glucose control: Use protocolized approach to blood glucose management targeting upper blood glucose target of 180 mg/dL. Prophylaxis: Use stress ulcer (proton pump inhibitor or H2 blocker) and deep venous thrombosis (low-dose unfractionated or fractionated heparin) prophylaxis. Limitation of support: Discuss advance care planning with patients and families and set realistic expectations. Adapted from Dellinger et. al13 the antibiotic will not be effective against this organism. A good example is penicillin and Gram-negative organisms, as these microbes lack penicillin-binding proteins. The second component driving resistance is that related to antibiotic selection. Over generations of exposure to a particular antibiotic, selection pressure will drive proliferation of more organisms resistant to that antibiotic. It is this mechanism that leads to antibiotic resistance in the world today, given that there are millions of kilograms of antibiotics used annually in people, in agriculture, and for animal use. This has led to antibiotic resistance described in all classes of antibiotics in common use today. Antibiotic resistance comes at a high cost, with a significant increase in mortality associated with infection from resistant organisms, and an economic cost of billions of dollars per year. Resistance mechanisms are varied, and include one of three routes. Resistance can be intrinsic to the organism (natural resistance), can be mutational and mediated by changes in the chromosomal makeup of the organism, and finally can be mediated by extrachromosomal transfer of genetic material via transposons or plasmids. Resistance due to mutation includes mechanisms mediated by target site modification, reduced permeability/uptake, metabolic bypass, or derepression of multidrug efflux systems. Genes transferred via plasmid or transposon include those that cause drug inactivation, increases in antibiotic efflux systems, target site modification, and metabolic bypass. There are several drug resistant organisms of interest to the surgeon. MRSA occurs as a hospital-associated infection more common in chronically ill patients receiving multiple courses of antibiotics. However, recent strains of MRSA have emerged in the community among patients without preexisting risk factors for disease.72 These strains, which produce a toxin known as Panton-Valentin leukocidin, make up an increasingly high percentage of surgical site infections since they are resistant to commonly employed prophylactic antimicrobial agents.83 Extended spectrum β-lactamase (ESBL)-producing strains of Enterobacteraceae, originally geographically localized and infrequent, have become much more widespread and common in the last decade.84 These strains, typically Klebsiella or E coli VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Infections Diagnosis: Obtain appropriate cultures prior to antibiotics but do not delay antibiotic therapy. Use rapid antigen assays in patients with suspected fungal infection. Imaging studies should be performed promptly to confirm a source of infection. CHAPTER 6 Initial Evaluation and Infection Issues Initial resuscitation: Begin resuscitation immediately in patients with hypotension or elevated serum lactate with resuscitation goal of central venous pressure (CVP) 8 to 12 mm Hg, mean arterial pressure of ≥65 mm Hg, urine output of ≥0.5 mL/kg/h, and mixed venous oxygen saturation of 65%. 156 PART I BASIC CONSIDERATIONS species, produce a plasmid-mediated inducible β-lactamase. Commonly encountered plasmids also confer resistance to many other antibiotic classes (multidrug resistance). A common laboratory finding with ESBL is sensitivity to first-, second-, or third- generation cephalosporins with resistance to others. Unfortunately, use of this seemingly active agent leads to rapid induction of resistance and failure of antibiotic therapy. The appropriate antibiotic choice in this setting is a carbepenem. While Enterococcus used to be considered a low virulence organism in the past, infections caused by E faecium and faecalis have been found to be increasingly virulent, especially in the immunocompromised host. The last decade has seen increased isolation of a vancomycin-resistant strain of Enterococcus.85 This resistance is transposon-mediated via the vanA gene and is typically seen in E faecium strains. A real concern in this setting is transfer of genetic material to S aureus in a host coinfected with both organisms. This is thought to be the mechanism behind the half dozen recently described cases of vancomycin resistance in S aureus. Blood-Borne Pathogens While alarming to contemplate, the risk of human immunodeficiency virus (HIV) transmission from patient to surgeon is low. As of May 2011, there had been six cases of surgeons with HIV seroconversion from a possible occupational exposure, with no new cases reported since 1999. Of the numbers of health care workers with likely occupationally acquired HIV infection (n = 200), surgeons were one of the lower risk groups (compared to nurses at 60 cases and nonsurgeon physicians at 19 cases).86 The estimated risk of transmission from a needlestick from a source with HIV-infected blood is estimated at 0.3%. Transmission of HIV (and other infections spread by blood and body fluid) from patient to health care worker can be minimized by observation of universal precautions, which include the following: (a) routine use of barriers (such as gloves and/or goggles) when anticipating contact with blood or body fluids, (b) washing of hands and other skin surfaces immediately after contact with blood or body fluids, and (c) careful handling and disposal of sharp 7 instruments during and after use. Postexposure prophylaxis for HIV has significantly decreased the risk of seroconversion for health care workers with occupational exposure to HIV. Steps to initiate postexposure prophylaxis should be initiated within hours rather than days for the most effective preventive therapy. Postexposure prophylaxis with a two- or three-drug regimen should be initiated for health care workers with significant exposure to patients with an HIV-positive status. If a patient’s HIV status is unknown, it may be advisable to begin postexposure prophylaxis while testing is carried out, particularly if the patient is at high risk for infection due to HIV (e.g., intravenous narcotic use). Generally, postexposure prophylaxis is not warranted for exposure to sources with unknown status, such as deceased persons or needles from a sharps container. The risks for surgeons of acquiring HIV infection have recently been evaluated by Goldberg and coauthors.87 They noted that the risks are related to the prevalence of HIV infection in the population being cared for, the probability of transmission from a percutaneous injury suffered while caring for an infected patient, the number of such injuries sustained, and the use of postexposure prophylaxis. Annual calculated risks in Glasgow, Scotland, ranged from one in 200,000 for general surgeons not utilizing postexposure prophylaxis to as low as one in 10,000,000 with use of routine postexposure prophylaxis after significant exposures. Hepatitis B virus (HBV) is a DNA virus that affects only humans. Primary infection with HBV generally is self-limited, but can cause fulminant hepatitis or progress to a chronic carrier state. Death from chronic liver disease or hepatocellular cancer occurs in roughly 30% of chronically infected persons. Surgeons and other health care workers are at high risk for this blood-borne infection and should receive the HBV vaccine; children are routinely vaccinated in the United States.88 This vaccine has contributed to a significant decline in the number of new cases of HBV per year in the United States, from approximately 250,000 annually in the 1980s to 3,350 in 2010.89,90 This is truly one of the unsung victories in vaccination strategy in the last 20 years. Hepatitis C virus (HCV), previously known as non-A, non-B hepatitis, is a RNA flavivirus first identified specifically in the late 1980s. This virus is confined to humans and chimpanzees. A chronic carrier state develops in 75% to 80% of patients with the infection, with chronic liver disease occurring in three-fourths of patients who develop chronic infection. The number of new infections per year has declined since the 1980s due to routine testing of blood donors for this virus. Fortunately, HCV is not transmitted efficiently through occupational exposures to blood, with the seroconversion rate after accidental needlestick approximately 1.8%.91 To date, a vaccine to prevent HCV infection has not been developed. Experimental studies in chimpanzees with HCV immunoglobulin using a model of needlestick injury have failed to demonstrate a protective effect, and no effective antiviral agents for postexposure prophylaxis are available. Treatment of patients who develop HCV infection includes ribavirin and pegylated gamma interferon.92 BIOLOGIC WARFARE AGENTS Several infectious organisms have been studied by the United States and the former Soviet Union and presumably other entities for potential use as biologic weapons. Programs involving biologic agents in the United States were halted by presidential decree in 1971. However, concern remains that these agents could be used by rogue states or terrorist organizations as weapons of mass destruction, as they are relatively inexpensive to make in terms of infrastructure development. A related issue is the recent controversy regarding publication of genetic sequences and synthesis of virulent viruses, such as the 1918 influenza strain, responsible for death of an estimated 3% of the world population. Given these concerns, physicians, including surgeons should familiarize themselves with the manifestations of infection due to these pathogens. The typical agent is selected for the ability to be spread via the inhalational route, as this is the most efficient mode of mass exposure. Several potential agents are discussed in the following sections. Bacillus anthracis (Anthrax) Anthrax is a zoonotic disease occurring in domesticated and wild herbivores. The first identification of inhalational anthrax as a disease occurred among woolsorters in England in the late 1800s. The largest recent epidemic of inhalational anthrax occurred in Sverdlovsk, Russia, in 1979 after accidental release of anthrax spores from a military facility. Inhalational anthrax develops after a 1- to 6-day incubation period, with VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Yersinia pestis (Plague) 1. Nuland SB. The Doctors’ Plague: Germs, Childbed Fever, and the Strange Story of Ignaz Semmelweis. New York: WW Norton & Co.: 2003:1. 2. Wangensteen OH, Wangensteen SD. Germ theory of infection and disease. In: Wangensteen OH, Wangensteen SD: The Rise of Surgery: From Empiric Craft to Scientific Discipline. Minneapolis: University of Minnesota Press: 1978:387. 3. Rutkow E. Appendicitis: The quintessential American surgical disease. Arch Surg. 1998; 133:1024. 4. Meleney F. Bacterial synergism in disease processes with confirmation of synergistic bacterial etiology of certain types of progressive gangrene of the abdominal wall. Ann Surg. 1931;94:961-981. 5. Altemeier WA. Manual of Control of Infection in Surgical Patients. Chicago: American College of Surgeons Press: 1976:1. 6. Bartlett JG. Intra-abdominal sepsis. Med Clin North Am. 1995;79:599-617. 7. Dunn DL, Simmons RL. The role of anaerobic bacteria in intraabdominal infections. Rev Infect Dis. 1984;6:S139-S146. 8. Osler W. The Evolution of Modern Medicine. New Haven, CT: Yale University Press: 1913:1. 9. Dunn DL. Autochthonous microflora of the gastrointestinal tract. Perspect Colon Rectal Surg. 1990;2:105-119. 10. van Till JW, van Veen SQ, van Ruler O, et al. The innate immune response to secondary peritonitis. Shock. 2007 Nov; 28(5):504-517. 11. Zeytun A, Chaudhary A, Pardington P, et al. Induction of cytokines and chemokines by Toll-like receptor signaling: strategies for control of inflammation. Crit Rev Immunol. 2010;30(1): 53-67. 12. Aziz M, Jacob A, Yang WL, et al. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 2013;(3)320-342. 13. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013; 41: 580-637. 14. Murphy SL, Xu Jiaquan, Kochanek KD. Deaths: preliminary data for 2010. National Vital Statistics Reports. 2012;60(4): 1-52. 15. Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638-1652. 16. Ferreira FL, Bota DP, Bross A, et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2002;286:1754-1758. 17. Sauaia A, Moore FA, Moore EE, Lezotte DC. Early risk factors for postinjury multiple organ failure. World J Surg. 1996;20:392-400. Plague is caused by the Gram-negative organism Yersinia pestis. The naturally occurring disease in humans is transmitted via flea bites from rodents. It was the first biologic warfare agent, and was used in the Crimean city of Caffa by the Tartar army, whose soldiers catapulted bodies of plague victims at the Genoese. When plague is used as a biologic warfare agent, clinical manifestations include epidemic pneumonia with blood-tinged sputum if aerosolized bacteria are used, or bubonic plague if fleas are used as carriers. Individuals who develop a painful enlarged lymph node lesion termed a “bubo” associated with fever, severe malaise, and exposure to fleas should be suspected to have plague. Diagnosis is confirmed via aspirate of the bubo and a direct antibody stain to detect plague bacillus. Typical morphology for this organism is that of a bipolar safety-pin– shaped Gram-negative organism. Postexposure prophylaxis for patients exposed to plague consists of doxycycline. Treatment of the pneumonic or bubonic/septicemic form includes administration of either streptomycin, an aminoglycoside, doxycycline, ciprofloxacin, levofloxacin, or chloramphenicol.94 Smallpox Variola, the causative agent of smallpox, was a major cause of infectious morbidity and mortality until its eradication in the late 1970s. During the European colonization of North America, British commanders may have used it against native inhabitants and the colonists by distribution of blankets from smallpox victims. Even in the absence of laboratory-preserved virus, the prolonged viability of variola virus has been demonstrated in scabs up to 13 years after collection; the potential for reverse genetic engineering using the known sequence of smallpox also makes it a potential biologic weapon. This has resulted in the United States undertaking a vaccination program for key health care workers.95 Variola virus is highly infectious in the aerosolized form; after an incubation period of 10 to 12 days, clinical manifestations of malaise, fever, vomiting, and headache appear, followed by development of a characteristic centripetal rash (which is found to predominate on the face and extremities). The fatality rate may reach 30%. Postexposure prophylaxis with smallpox vaccine has been noted to be effective for up to 4 days postexposure. Cidofovir, an acyclic nucleoside phosphonate analogue, has demonstrated activity in animal models of poxvirus infections and may offer promise for the treatment of smallpox.96 The principal reservoir of this Gram-negative aerobic organism is the tick. After inoculation, this organism proliferates within macrophages. This organism has been considered a potential bioterrorist threat due to a very high infectivity rate after aerosolization. Patients with tularemia pneumonia develop a cough and demonstrate pneumonia on chest roentgenogram. Enlarged lymph nodes occur in approximately 85% of patients. The organism can be cultured from tissue samples, but this is difficult, and the diagnosis is based on acute-phase agglutination tests. Treatment of inhalational tularemia consists of administration of an aminoglycoside or second-line agents such as doxycycline and ciprofloxacin. REFERENCES Entries highlighted in bright blue are key references. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 157 Surgical Infections Francisella tularensis (Tularemia) CHAPTER 6 nonspecific symptoms, including malaise, myalgia, and fever. Over a short period of time, these symptoms worsen, with development of respiratory distress, chest pain, and diaphoresis. Characteristic chest roentgenographic findings include a widened mediastinum and pleural effusions. A key aspect in establishing the diagnosis is eliciting an exposure history. Rapid antigen tests are currently under development for identification of this gram-positive rod. Postexposure prophylaxis consists of administration of either ciprofloxacin or doxycycline.93 If an isolate is demonstrated to be penicillin-sensitive, the patient should be switched to amoxicillin. Inhalational exposure followed by the development of symptoms is associated with a high mortality rate. Treatment options include combination therapy with ciprofloxacin, clindamycin, and rifampin; clindamycin added to block production of toxin, while rifampin penetrates into the central nervous system and intracellular locations. 158 PART I BASIC CONSIDERATIONS 18. Zahar JR, Timsit JF, Garrouste-Orgeas M, et al. Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Crit Care Med. 2011;39(8):1886-1895. 19. Dreiher J, Almog Y, Sprung CL, et al. 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JAMA. 2002;287:2236-2252. 94. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon; medical and public health management. Working group on civilian biodefense. JAMA 2000;283:2281-2290. 95. Russell PK, Gronvall GK. U.S. medical countermeasure development since 2001: a long way yet to go. Biosecur Bioterror. 2012;10(1):66-76. 96. DeClercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res 2002;55:1-13 CHAPTER 6 57. Roberts DJ, Zygun DA, Grendar J, et al. Negative-pressure wound therapy for critically ill adults with open abdominal wounds: a systematic review. J Trauma Acute Care Surg. 2012;73(3):629-639. 58. Solomkin JS, Mazuski JE, Baron EJ, et al. Infectious Diseases Society of America: Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37:997-1005. 59. Solomkin JS, Dellinger EP, Christou NV, et al. Results of a multicenter trial comparing imipenem/cilastatin to tobramycin/clindamycin for intra-abdominal infections. Ann Surg. 1990;212:581-591. 60. Solomkin JS, Yellin AE, Rotstein OD, et al. Protocol 017 Study Group. Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial. Ann Surg. 2003;237:235-245. 61. Chromik AM, Meiser A, Hölling J, et al. Identification of patients at risk for development of tertiary peritonitis on a surgical intensive care unit. J Gastrointest Surg. 2009;13(7): 1358-1367. 62. Pang TC, Fung T, Samra J, et al. Pyogenic liver abscess: an audit of 10 years’ experience. World J Gastroenterol. 2011; 17(12):1622-1630. 63. Bradley EL III, Allen K. A prospective longitudinal study of observation versus surgical intervention in the management of necrotizing pancreatitis. Am J Surg. 1991;161:19. 64. Charbonney E, Nathens AB. Severe acute pancreatitis: a review. Surg Infect (Larchmt). 2008;9(6):573-578. 65. Freeman ML, Werner J, van Santvoort HC, et al. Interventions for necrotizing pancreatitis: summary of a multidisciplinary consensus conference. Pancreas. 2012;41(8):1176-1194. 66. Wysocki AP, McKay CJ, Carter CR. Infected pancreatic necrosis: minimizing the cut. ANZ J Surg. 2010;80(1-2):58-70. 67. Haghshenasskashani A, Laurence JM, Kwan V, et al. Endoscopic necrosectomy of pancreatic necrosis: a systematic review. Surg Endosc. 2011; 25(12):3724-3730. 68. Bakker OJ, van Santvoort HC, van Brunschot S, et al. Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis: a randomized trial. JAMA. 2012;307(10): 1053-1061. 69. Fink D, Soares R, Matthews JB, Alverdy JC. History, goals, and technique of laparoscopic pancreatic necrosectomy. J Gastrointest Surg. 2011;15(7):1092-1097. 70. van Santvoort HC, Bakker OJ, Bollen TL, et al. A Conservative and Minimally Invasive Approach to Necrotizing Pancreatitis Improves Outcome. Gastroenterology. 2011;141(4): 1254-1263. 71. van Santvoort HC, Besselink MG, Bakker OJ, et al. A stepup approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010;362(16):1491-1502. 72. Beilman GJ, Sandifer G, Skarda D, et al. Emerging infections with community-associated methicillin-resistant Staphylococcus aureus in outpatients at an Army Community Hospital. Surg Infect (Larchmt). 2005;6(1):87-92. 73. Kao LS, Lew DF, Arab SN, et al. Local variations in the epidemiology, microbiology, and outcome of necrotizing softtissue infections: a multicenter study. Am J Surg. 2011; 202(2): 139-145. 74. George ME, Rueth NM, Skarda DE, et al. Hyperbaric oxygen does not improve outcome in patients with necrotizing soft tissue infection. Surg Infect (Larchmt). 2009;10(1):21-28. 75. Klompas M. Does this patient have ventilator-associated pneumonia? JAMA. 2007 11;297(14):1583-1593. 76. Riaz OJ, Malhotra AK, Aboutanos MB, et al. Bronchoalveolar lavage in the diagnosis of ventilator-associated pneumonia: to quantitate or not, that is the question. Am Surg. 2011;77(3): 297-303. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 7 chapter Introduction 161 Initial Evaluation and Resuscitation of the Injured Patient 161 Primary Survey / 161 Secondary Survey / 173 Mechanisms and Patterns of Injury / 173 Regional Assessment and Special Diagnostic Tests / 174 General Principles of Management 183 Trauma Clay Cothren Burlew and Ernest E. Moore Transfusion Practices / 184 Prophylactic Measures / 185 Operative Approaches and Exposure / 187 Damage Control Surgery / 192 Treatment of Specific Injuries Head Injuries / 195 Cervical Injuries / 197 Chest Injuries / 200 Abdominal Injuries / 203 Pelvic Fracture Hemorrhage Control / 212 INTRODUCTION Trauma, or injury, is defined as cellular disruption caused by an exchange with environmental energy that is beyond the body’s resilience which is compounded by cell death due to ischemia/reperfusion. Trauma remains the most common cause of death for all individuals between the ages of 1 and 44 years and is the third most common cause of death regardless of 1 age.1 It is also the leading cause of years of productive life lost. Unintentional injuries account for over 110,000 deaths per year, with motor vehicle collisions accounting for over 40%. Homicides, suicides, and other causes are responsible for another 50,000 deaths each year. However, death rate underestimates the magnitude of the societal toll. For example, in 2004 there were approximately 167,000 injury-related deaths, but 29.6 million injured patients treated in emergency departments (EDs). Injury-related medical expenditures are estimated to be $117 billion each year in the United States.2 The aggregate lifetime cost for all injured patients is estimated to be in excess of $260 trillion. For these reasons, trauma must be considered a major public health issue. The American College of Surgeons Committee on Trauma addresses this issue by assisting in the development of trauma centers and systems. The organization of trauma systems has had a significant favorable impact on patient outcomes.3–5 INITIAL EVALUATION AND RESUSCITATION OF THE INJURED PATIENT Primary Survey 195 The Advanced Trauma Life Support (ATLS) course of the American College of Surgeons Committee on Trauma was developed in the late 1970s, based on the premise that appropriate and timely care can significantly improve the outcome for the injured patient.6 ATLS provides a structured approach to Extremity Vascular Injuries, Fractures, and Compartment Syndromes / 214 Surgical Intensive Care Management 215 Postinjury Resuscitation / 215 Abdominal Compartment Syndrome / 217 Special Populations 218 Pregnant Patients / 218 Geriatric Patients / 221 Pediatric Patients / 222 the trauma patient with standard algorithms of care; it emphasizes the “golden hour” concept that timely, prioritized interventions are necessary to prevent death and disability. The ATLS format and basic tenets are followed throughout this chapter, with some modifications. The initial management of seriously injured patients consists of phases that include the primary survey/ concurrent resuscitation, the secondary survey/diagnostic evaluation, definitive care, and the tertiary survey. The first step in patient management is performing the primary survey, the goal of which is to identify and treat conditions that constitute an immediate threat to life. The ATLS course refers to the primary survey as assessment of the “ABCs” (Airway with cervical spine protection, Breathing, and Circulation). Although 2 the concepts within the primary survey are presented in a sequential fashion, in reality they are pursued simultaneously in coordinated team resuscitation. Life-threatening injuries must be identified (Table 7-1) and treated before being distracted by the secondary survey. Airway Management with Cervical Spine Protection Ensuring a patent airway is the first priority in the primary survey. This is essential, because efforts to restore cardiovascular integrity will be futile unless the oxygen content of the blood is adequate. Simultaneously, all patients with blunt trauma require cervical spine immobilization until injury is excluded. This is typically accomplished by applying a hard collar or placing sandbags on both sides of the head with the patient’s forehead taped across the bags to the backboard. Soft collars do not effectively immobilize the cervical spine. For penetrating neck wounds, however, cervical collars are not believed useful because they provide no benefit, but may interfere with assessment and treatment. 7,8 In general, patients who are conscious, without tachypnea, and have a normal voice are unlikely to require early airway intervention. Exceptions are penetrating injuries to the neck with an expanding hematoma; evidence of chemical or thermal VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 5  Trauma remains the most common cause of death for all individuals between the ages of 1 and 44 years and is the third most common cause of death regardless of age.  The initial management of seriously injured patients consists of performing the primary survey (the “ABCs”—Airway with cervical spine protection, Breathing, and Circulation); the goals of the primary survey are to identify and treat conditions that constitute an immediate threat to life.  All patients with blunt injury should be assumed to have unstable cervical spine injuries until proven otherwise; one must maintain cervical spine precautions and in-line stabilization.  Patients with ongoing hemodynamic instability, whether “nonresponders” or “transient responders,” require prompt intervention; one must consider the four categories of shock that may represent the underlying pathophysiology: hemorrhagic, cardiogenic, neurogenic, and septic.  Indications for immediate operative intervention for penetrating cervical injury include hemodynamic instability and significant external arterial hemorrhage; the management algorithm for hemodynamically stable patients is based on the presenting symptoms and anatomic location of injury, with the neck being divided into three distinct zones. injury to the mouth, nares, or hypopharynx; extensive subcutaneous air in the neck; complex maxillofacial trauma; or airway bleeding. Although these patients may initially have an adequate airway, it may become obstructed if soft tissue swelling, hematoma formation, or edema progresses. In these cases, preemptive intubation should be performed before airway access becomes challenging. Table 7-1 Immediately life-threatening injuries to be identified during the primary survey Airway Airway obstruction Airway injury Breathing Tension pneumothorax Open pneumothorax Massive air leak Flail chest with underlying pulmonary contusion Circulation Hemorrhagic shock Massive hemothorax Massive hemoperitoneum Mechanically unstable pelvis fracture with bleeding Extremity blood loss Cardiogenic shock Cardiac tamponade Neurogenic shock 162 Disability Intracranial hemorrhage/mass lesion Cervical spine injury 6 7 8 9 10  The gold standard for determining if there is a blunt descending torn aorta injury is CT scanning; indications are primarily based on injury mechanisms.  The abdomen is a diagnostic black box. However, physical examination and ultrasound can rapidly identify patients requiring emergent laparotomy. Computed tomographic (CT) scanning is the mainstay of evaluation in the remaining patients to more precisely identify the site and magnitude of injury.  Manifestation of the “bloody vicious cycle” (the lethal combination of coagulopathy, hypothermia, and metabolic acidosis) is the most common indication for damage control surgery. The primary objectives of damage control laparotomy are to control bleeding and limit GI spillage.  Blunt injuries to the carotid and vertebral arteries are usually managed with systemic antithrombotic therapy.  The abdominal compartment syndrome may be primary (i.e., due to the injury of abdominal organs, bleeding, and packing) or secondary (i.e., due to reperfusion visceral edema, retroperitoneal edema, and ascites). Patients who have an abnormal voice, abnormal breathing sounds, tachypnea, or altered mental status require further airway evaluation. Blood, vomit, the tongue, foreign objects, and soft tissue swelling can cause airway obstruction; suctioning affords immediate relief in many patients. In the comatose patient, the tongue may fall backward and obstruct the hypopharynx; this can be relieved by either a chin lift or jaw thrust. An oral airway or a nasal trumpet is also helpful in maintaining airway patency, although the former is not usually tolerated by an awake patient. Establishing a definitive airway (i.e., endotracheal intubation) is indicated in patients with apnea; inability to protect the airway due to altered mental status; impending airway compromise due to inhalation injury, hematoma, facial bleeding, soft tissue swelling, or aspiration; and inability to maintain oxygenation. Altered mental status is the most common indication for intubation. Agitation or obtundation, often attributed to intoxication or drug use, may actually be due to hypoxia. Options for endotracheal intubation include nasotracheal, orotracheal, or operative routes. Nasotracheal intubation can be accomplished only in patients who are breathing spontaneously. Although nasotracheal intubation is frequently used by prehospital providers, the application for this technique in the ED is limited to those patients requiring emergent airway support in whom chemical paralysis cannot be used. Orotracheal intubation is the preferred technique used to establish a definitive airway. Because all patients are presumed to have cervical spine injuries, manual in-line cervical immobilization is essential.6 Correct endotracheal placement is verified with 3 direct laryngoscopy, capnography, audible bilateral breath sounds, and finally a chest film. The GlideScope, a video laryngoscope that uses fiber optics to visualize the vocal cords, is being employed more frequently.9 Advantages of orotracheal intubation include the direct visualization of the vocal cords, ability to use larger-diameter endotracheal tubes, and applicability to apneic patients. The disadvantage of orotracheal VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 163 CHAPTER 7 Trauma A Figure 7-2. A “clothesline” injury can partially or completely transect the anterior neck structures, including the trachea. With complete tracheal transection, the endotracheal tube is placed directly into the distal aperture, with care taken not to push the trachea into the mediastinum. B Figure 7-1. Cricothyroidotomy is recommended for emergent surgical establishment of a patent airway. A vertical skin incision avoids injury to the anterior jugular veins, which are located just lateral to the midline. Hemorrhage from these vessels obscures vision and prolongs the procedure. When a transverse incision is made in the cricothyroid membrane, the blade of the knife should be angled inferiorly to avoid injury to the vocal cords. A. Use of a tracheostomy hook stabilizes the thyroid cartilage and facilitates tube insertion. B. A 6.0 endotracheal tube is inserted after digital confirmation of airway access. intubation is that conscious patients usually require neuromuscular blockade, which may result in inability to intubate, aspiration, or medication complications. Those who attempt rapid-sequence induction must be thoroughly familiar with the procedure (see Chap. 13). Patients in whom attempts at intubation have failed or who are precluded from intubation due to extensive facial injuries require operative establishment of an airway. Cricothyroidotomy (Fig. 7-1) is performed through a generous vertical incision, with sharp division of the subcutaneous tissues. Visualization may be improved by having an assistant retract laterally on the neck incision using army-navy retractors. The cricothyroid membrane is verified by digital palpation and opened in a horizontal direction. The airway may be stabilized before incision of the membrane using a tracheostomy hook; the hook should be placed under the thyroid cartilage to elevate the airway. A 6.0 endotracheal tube (maximum diameter in adults) is then advanced through the cricothyroid opening and sutured into place. In patients under the age of 11, cricothyroidotomy is relatively contraindicated due to the risk of subglottic stenosis, and tracheostomy should be performed. Emergent tracheostomy is indicated in patients with laryngotracheal separation or laryngeal fractures, in whom cricothyroidotomy may cause further damage or result in complete loss of the airway. This procedure is best performed in the OR where there is optimal lighting and availability of more equipment (e.g., sternal saw). In these cases, often after a “clothesline” injury, direct visualization and instrumentation of the trachea usually is done through the traumatic anterior neck defect or after a generous collar skin incision (Fig. 7-2). If the trachea is completely transected, a nonpenetrating clamp should be placed on the distal aspect to prevent tracheal retraction into the mediastinum; this is particularly important before placement of the endotracheal tube. Breathing and Ventilation Once a secure airway is obtained, adequate oxygenation and ventilation must be ensured. All injured patients should receive supplemental oxygen and be monitored by pulse oximetry. The following conditions constitute an immediate threat to life due to inadequate ventilation and should be recognized during the primary survey: tension pneumothorax, open pneumothorax, flail chest with underlying pulmonary contusion, and massive air leak. All of these diagnoses should be made during the initial physical examination. The diagnosis of tension pneumothorax is presumed in any patient manifesting respiratory distress and hypotension in combination with any of the following physical signs: tracheal deviation away from the affected side, lack of or decreased breath sounds on the affected side, and subcutaneous emphysema on the affected side. Patients may have distended neck veins due to impedance of venous return, but the neck veins may be flat due to concurrent systemic hypovolemia. Tension pneumothorax and simple pneumothorax have similar signs, symptoms, and examination findings, but hypotension qualifies the pneumothorax as a tension pneumothorax. Although immediate needle thoracostomy decompression with a 14-gauge angiocatheter in the second intercostal space in the midclavicular line may be indicated in the field, tube thoracostomy should be performed immediately in the ED before a chest radiograph is obtained (Fig. 7-3). Recent studies suggest the preferred location for needle decompression may be the 5th intercostal space in the anterior axillary line due to body habitus.10 In cases of tension pneumothorax, the parenchymal tear in the lung acts as a one-way valve, with each inhalation allowing additional air to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 164 PART I BASIC CONSIDERATIONS Figure 7-3. A. Tube thoracostomy is performed in the midaxillary line at the fourth or fifth intercostal space (inframammary crease) to avoid iatrogenic injury to the liver or spleen. B. Heavy scissors are used to cut through the intercostal muscle into the pleural space. This is done on top of the rib to avoid injury to the intercostal bundle located just beneath the rib. C. The incision is digitally explored to confirm intrathoracic location and identify pleural adhesions. D. A 28F chest tube is directed superiorly and posteriorly with the aid of a large clamp. accumulate in the pleural space. The normally negative intrapleural pressure becomes positive, which depresses the ipsilateral hemidiaphragm and shifts the mediastinal structures into the contralateral chest. Subsequently, the contralateral lung is compressed and the heart rotates about the superior and inferior vena cava; this decreases venous return and ultimately cardiac output, which culminates in cardiovascular collapse. An open pneumothorax or “sucking chest wound” occurs with full-thickness loss of the chest wall, permitting free communication between the pleural space and the atmosphere (Fig. 7-4). This compromises ventilation due to equilibration of atmospheric and pleural pressures, which prevents lung inflation and alveolar ventilation, and results in hypoxia and hypercarbia. Complete occlusion of the chest wall defect without a tube thoracostomy may convert an open pneumothorax to a tension pneumothorax. Temporary management of this injury includes covering the wound with an occlusive dressing that is taped on three sides. This acts as a flutter valve, permitting effective ventilation on inspiration while allowing accumulated air to escape from the pleural space on the untaped side, so that a tension pneumothorax is prevented. Definitive treatment requires closure of the chest wall defect and tube thoracostomy remote from the wound. Flail chest occurs when three or more contiguous ribs are fractured in at least two locations. Paradoxical movement of this free-floating segment of chest wall is usually evident in patients with spontaneous ventilation, due to the negative intrapleural pressure of inspiration. However, the additional work of breathing Figure 7-4. A. Full-thickness loss of the chest wall results in an open pneumothorax. B. The defect is temporarily managed with an occlusive dressing that is taped on three sides, which allows accumulated air to escape from the pleural space and thus prevents a tension pneumothorax. Repair of the chest wall defect and tube thoracostomy remote from the wound is definitive treatment. and chest wall pain caused by the flail segment is rarely sufficient to compromise ventilation. Instead, it is the decreased compliance and increased shunt fraction caused by the associated pulmonary contusion that is the source of acute respiratory failure. Pulmonary contusion often progresses during the first 12 hours. Resultant hypoventilation and hypoxemia may require intubation and mechanical ventilation. The patient’s initial chest radiograph often underestimates the extent of the pulmonary parenchymal damage (Fig. 7-5); close monitoring and frequent clinical re-evaluation are warranted. Massive air leak occurs from major tracheobronchial injuries. Type I injuries are those occurring within 2 cm of the carina.11,12 These are often not associated with a pneumothorax due to the envelopment in the mediastinal pleura. Type II injuries are more distal injuries within the tracheobronchial tree and manifest with pneumothorax. Bronchoscopy confirms diagnosis and directs management. Circulation with Hemorrhage Control With a secure airway and adequate ventilation established, circulatory status is the next priority. An initial approximation of the patient’s cardiovascular VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 165 CHAPTER 7 Trauma Figure 7-6. Intraosseous infusions are indicated for children <6 years of age in whom one or two attempts at IV access have failed. A. The proximal tibia is the preferred location. Alternatively, the distal femur can be used if the tibia is fractured. B. The needle should be directed away from the epiphyseal plate to avoid injury. The position is satisfactory if bone marrow can be aspirated and saline can be easily infused without evidence of extravasation. Figure 7-5. A. Admission chest film may not show the full extent of the patient’s pulmonary parenchymal injury. B. This patient’s left pulmonary contusion blossomed 12 hours later, and its associated opacity is noted on repeat chest radiograph. status can be obtained by palpating peripheral pulses. In general, systolic blood pressure (SBP) must be 60 mm Hg for the carotid pulse to be palpable, 70 mm Hg for the femoral pulse, and 80 mm Hg for the radial pulse. Any episode of hypotension (defined as a SBP <90 mm Hg) is assumed to be caused by hemorrhage until proven otherwise. Patients with acute massive blood loss may have paradoxical bradycardia.13 Blood pressure and pulse should be measured at least every 5 minutes in patients with significant blood loss until normal vital sign values are restored. High energy auto-pedestrian victims should have their pelvis wrapped with a sheet until radiography can be done. IV access for fluid resuscitation is obtained with two peripheral catheters, 16-gauge or larger in adults. For patients in whom peripheral angiocatheter access is difficult, intraosseous (IO) needles can be rapidly placed in the proximal tibia of the lower extremity (Fig. 7-6).14,15 All medications administered IV may be administered in a similar dosage intraosseously. Although safe for emergent use, the needle should be removed once alternative access is established to prevent osteomyelitis. Blood should be drawn simultaneously for a bedside hemoglobin level and routine trauma laboratory tests. In the seriously injured patient arriving in shock, an arterial blood gas, cross-matching for possible red blood cell (RBC) transfusion, and a coagulation panel should be obtained. In these patients, secondary large bore cannulae should be obtained via the femoral or subclavian veins, or saphenous vein cutdown; Cordis introducer catheters are preferred over triple-lumen catheters. In general, initial access in trauma patients is best secured in the groin or ankle, so that the catheter will not interfere with the performance of other diagnostic and therapeutic thoracic procedures. Saphenous vein cutdowns at the ankle provide excellent access (Fig. 7-7). The saphenous vein is reliably found 1 cm anterior and 1 cm superior to the medial malleolus. Standard 14-gauge catheters can be quickly placed, even in an exsanguinating patient with Figure 7-7. Saphenous vein cutdowns are excellent sites for fluid resuscitation access. A. The vein is consistently found 1 cm anterior and 1 cm superior to the medial malleolus. B. Proximal and distal traction sutures are placed with the distal suture ligated. C. A 14-gauge IV catheter is introduced and secured with sutures and tape to prevent dislodgment. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 166 PART I BASIC CONSIDERATIONS collapsed veins. If IV access cannot be achieved readily, the IO route is very useful, particularly for drug administration.14,15 Additional venous access often is obtained through the femoral or subclavian veins with Cordis introducer catheters. A rule of thumb to consider for secondary access is placement of femoral access for thoracic trauma and jugular or subclavian access for abdominal trauma. However, jugular or subclavian catheters provide a more reliable measurement of central venous pressure (CVP), which may be helpful in determining the volume status of the patient and in excluding cardiac tamponade. In severely injured children < 6 years of age, the preferred venous access is peripheral intravenous catheters followed by an IO needle. Central venous catheter placement or saphenous vein cutdown may be considered as the third choice of access based upon provider experience. Inadvertent femoral artery cannulation, however, may result in limb-threatening distal arterial spasm. External control of any visible hemorrhage should be achieved promptly while circulating volume is restored. Manual compression of open wounds with ongoing bleeding should be done with a single 4 × 4 gauze and a gloved hand. Covering the wound with excessive dressings may permit ongoing unrecognized blood loss that is hidden underneath the dressing. Blind clamping of bleeding vessels should be avoided because of the risk to adjacent structures, including nerves. This is particularly true for penetrating injuries of the neck, thoracic outlet, and groin, where bleeding may be torrential and arising deep within the wound. In these situations, a gloved finger is placed through the wound directly onto the bleeding vessel and enough pressure is applied to control active bleeding. The surgeon performing this maneuver must then walk with the patient to the OR for definitive treatment. For bleeding of the extremities it is tempting to apply tourniquets for hemorrhage control, but digital occlusion will usually control the bleeding, and complete vascular occlusion risks permanent neuromuscular impairment. Patients in shock have a lower tolerance to warm ischemia, and an occluded extremity is prone to small vessel thrombosis. For patients with open fractures, fracture reduction with stabilization via splints will limit bleeding both externally and into the subcutaneous tissues. Scalp lacerations through the galea aponeurotica tend to bleed profusely; these can be temporarily controlled with skin staples, Raney clips, or a large full-thickness continuous running nylon stitch. During the circulation section of the primary survey, four life-threatening injuries must be identified promptly: (a) massive hemothorax, (b) cardiac tamponade, (c) massive hemoperitoneum, and (d) mechanically unstable pelvic fractures with bleeding. Massive hemoperitoneum and mechanically unstable pelvic fractures are discussed in “Emergent Abdominal Exploration” and “Pelvic Fractures and Emergent Hemorrhage Control,” respectively. Three critical tools used to differentiate these in the multisystem trauma patient are chest radiograph, pelvis radiograph, and focused abdominal sonography for trauma (FAST) (see “Regional Assessment and Special Diagnostic Tests”). A massive hemothorax (life-threatening injury number one) is defined as >1500 mL of blood or, in the pediatric population, >25% of the patient’s blood volume in the pleural space (Fig. 7-8). Although it may be estimated on chest radiograph, tube thoracostomy is the only reliable means to quantify the amount of hemothorax. After blunt trauma, a major hemothorax usually is due to multiple rib fractures with severed intercostal arteries, but occasionally bleeding is from lacerated lung parenchyma which is usually associated with an air leak. After penetrating trauma, a great vessel or pulmonary hilar vessel injury should be presumed. In either scenario, a massive hemothorax is an indication for operative intervention, but tube thoracostomy is critical to facilitate lung re-expansion, which may improve oxygenation and cardiac performance as well as tamponade venous bleeding. Cardiac tamponade (life-threatening injury number two) occurs most commonly after penetrating thoracic wounds, although occasionally blunt rupture of the heart, particularly the atrial appendage, is seen. Acutely, <100 mL of pericardial Figure 7-8. More than 1500 mL of blood in the pleural space is considered a massive hemothorax. Chest film findings reflect the positioning of the patient. A. In the supine position, blood tracks along the entire posterior section of the chest and is most notable pushing the lung away from the chest wall. B. In the upright position, blood is visible dependently in the right pleural space. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 7-2 blood may cause pericardial tamponade.16 The classic Beck’s triad—dilated neck veins, muffled heart tones, and a decline in arterial pressure—is usually not appreciated in the trauma bay because of the noisy environment and associated hypovolemia. Because the pericardium is not acutely distensible, the pressure in the pericardial sac will rise to match that of the injured chamber. When this pressure exceeds that of the right atrium, right atrial filling is impaired and right ventricular preload is reduced. This ultimately leads to decreased right ventricular output. Additionally, increased intrapericardial pressure impedes myocardial blood flow, which leads to subendocardial ischemia and a further reduction in cardiac output. Diagnosis of hemopericardium is best achieved by bedside ultrasound of the pericardium (Fig. 7-9). Early in the course of tamponade, blood pressure and cardiac output will transiently improve with fluid administration due to increased central venous pressure. In patients with any hemodynamic disturbance, a pericardial drain is placed using ultrasound guidance (Fig. 7-10). Removing as little as 15 to 20 mL of blood will often temporarily stabilize the patient’s hemodynamic status, Contraindications  Penetrating trauma: CPR >15 min and no signs of life (pupillary response, respiratory effort, motor activity)  Blunt trauma: CPR >10 min and no signs of life or asystole without associated tamponade CPR = cardiopulmonary resuscitation; SBP = systolic blood pressure. and alleviate subendocardial ischemia with associated lethal arrhythmias, and allow safe transport to the OR for sternotomy. Pericardiocentesis is successful in decompressing tamponade in approximately 80% of cases; the majority of failures are due to the presence of clotted blood within the pericardium. Patients with a SBP <60 mm Hg warrant resuscitative thoracotomy (RT) with opening of the pericardium for rapid decompression and to address the injury. The utility of RT has been debated for decades. Current indications are based on 30 years of prospective data, supported by a recent multicenter prospective study (Table 7-2).17,18 RT Figure 7-10. Pericardiocentesis is indicated for patients with evidence of pericardial tamponade. A. Access to the pericardium is obtained through a subxiphoid approach, with the needle angled 45 degrees up from the chest wall and toward the left shoulder. B. Seldinger technique is used to place a pigtail catheter. Blood can be repeatedly aspirated with a syringe or the tubing may be attached to a gravity drain. Evacuation of unclotted pericardial blood prevents subendocardial ischemia and stabilizes the patient for transport to the operating room for sternotomy. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Trauma Figure 7-9. Subxiphoid pericardial ultrasound reveals a large pericardial fluid collection. Indications Salvageable postinjury cardiac arrest:  Patients sustaining witnessed penetrating trauma to the torso with <15 min of prehospital CPR  Patients sustaining witnessed blunt trauma with <10 min of prehospital CPR  Patients sustaining witnessed penetrating trauma to the neck or extremities with <5 min of prehospital CPR  Persistent severe postinjury hypotension (SBP ≤60 mm Hg) due to: Cardiac tamponade  Hemorrhage—intrathoracic, intra-abdominal, extremity, cervical Air embolism CHAPTER 7 Current indications and contraindications for emergency department thoracotomy 167 168 PART I BASIC CONSIDERATIONS is associated with the highest survival rate after isolated cardiac injury; 35% of patients presenting in shock and 20% without vital signs (i.e., no pulse or obtainable blood pressure) are salvaged after isolated penetrating injury to the heart. For all penetrating wounds, survival rate is 15%. Conversely, patient outcome is poor when RT is done for blunt trauma, with 2% survival among patients in shock and <1% survival among those with no vital signs. Thus, patients undergoing cardiopulmonary resuscitation upon arrival to the ED should undergo RT selectively based on injury and transport time (Fig. 7-11). RT is best accomplished using a generous left anterolateral thoracotomy, with the skin incision started to the right of the sternum (Fig. 7-12). A longitudinal pericardiotomy anterior to the phrenic nerve is used to release cardiac tamponade and permits access to the heart for cardiac repair and open cardiac massage. Cross-clamping of the aorta improves central circulation, augments cerebral and coronary blood flow, and limits further abdominal blood loss (Fig. 7-13). The patient must sustain a SBP of 70 mm Hg after RT and associated interventions to be considered resuscitatable, and hence transported to the OR.17,18 Disability and Exposure The Glasgow coma scale (GCS) score should be determined for all injured patients (Table 7-3). It is calculated by adding the scores of the best motor response, best verbal response, and the best eye response. Scores range from 3 (the lowest) to 15 (normal). Scores of 13 to 15 indicate mild head injury, 9 to 12 moderate injury, and ≤8 severe injury. The GCS is a quantifiable determination of neurologic function that is useful for triage, treatment, and prognosis. Neurologic evaluation is critical before administration of neuromuscular blockade for intubation. Subtle changes in mental status can be caused by hypoxia, hypercarbia, or hypovolemia, or may be an early sign of increasing intracranial pressure. An abnormal mental status should prompt an immediate reevaluation of the ABCs and consideration of central nervous system injury. Deterioration in mental status may be subtle and may not progress in a predictable fashion. For example, previously calm, cooperative patients may become anxious and combative as they become hypoxic. However, a patient who is agitated and combative from drugs or alcohol may become somnolent if hypovolemic shock develops. Patients with neurogenic shock are typified by hypotension with relative bradycardia, and are often first recognized due to paralysis, decreased rectal tone or priapism. Patients with high spinal cord disruption are at greatest risk for neurogenic shock due to physiologic disruption of sympathetic fibers; treatment consists of volume loading and a dopamine infusion which is both inotropic and chronotropic. Seriously injured patients must have all of their clothing removed to avoid overlooking limb- or life-threatening injuries. Shock Classification and Initial Fluid Resuscitation Classic signs and symptoms of shock are tachycardia, hypotension, tachypnea, altered mental status, diaphoresis, and pallor (Table 7-4). In general, the quantity of acute blood loss correlates Blunt Trauma CPR < 10 min Patient Undergoing CPR ---------Penetrating Torso Trauma – CPR < 15 min No Signs of Life* Penetrating Non-Torso Trauma No Dead ---------CPR < 5 min Yes Profound Refractory Shock Resuscitative Thoracotomy Cardiac Activity? Yes Tamponade Thoracic Hemorrhage No Tamponade? No Yes Repair Heart SBP < 70, Control apply Aortic X-clamp Air Emboli *no respiratory or motor effort, electrical activity, or pupillary activity Assess Viability Hilar X-clamp Extrathoracic OR Hemorrhage Figure 7-11. Algorithm directing the use of resuscitative thoracotomy (RT) in the injured patient undergoing cardiopulmonary resuscitation (CPR). ECG = electrocardiogram; OR = operating room; SBP = systolic blood pressure. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 169 CHAPTER 7 Trauma Figure 7-12. A. Resuscitative thoracotomy (RT) is performed through the fifth intercostal space using the anterolateral approach. B and C. The pericardium is opened anterior to the phrenic nerve, and the heart is rotated out for evaluation. D. Open cardiac massage should be performed with a hinged, clapping motion of the hands, with sequential closing from palms to fingers. The two-handed technique is strongly recommended because the one-handed massage technique poses the risk of myocardial perforation with the thumb. with physiologic abnormalities. For example, patients in class II shock are tachycardic but they do not exhibit a reduction in blood pressure until over 1500 mL of blood loss, or class III shock. Physical findings should be used as an aid in the evaluation of the patient’s response to treatment. The goal of fluid resuscitation is to re-establish tissue perfusion. Fluid resuscitation begins with a 2 L (adult) or 20 mL/kg (child) IV bolus of isotonic crystalloid, typically Ringer’s lactate. For persistent hypotension (SBP <90 mm Hg in an adult), the current trend is to activate a massive transfusion protocol (MTP) in which red blood cells (RBC) and fresh-frozen plasma (FFP) are administered early. The details of a MTP are discussed later. Patients who have a good response to fluid infusion (i.e., normalization of vital signs, clearing of the sensorium) and evidence of good Figure 7-13. Aortic cross-clamp is applied with the left lung retracted superiorly, below the inferior pulmonary ligament, just above the diaphragm. The flaccid aorta is identified as the first structure encountered on top of the spine when approached from the left chest. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 170 Table 7-3 Glasgow coma scalea PART I Eye opening BASIC CONSIDERATIONS Verbal Motor response 4 Adults Infants/Children Spontaneous Spontaneous 3 To voice To voice 2 To pain To pain 1 None None 5 Oriented Alert, normal vocalization 4 Confused Cries, but consolable 3 Inappropriate words Persistently irritable 2 Incomprehensible words Restless, agitated, moaning 1 None None 6 Obeys commands Spontaneous, purposeful 5 Localizes pain Localizes pain 4 Withdraws Withdraws 3 Abnormal flexion Abnormal flexion 2 Abnormal extension Abnormal extension 1 None None Score is calculated by adding the scores of the best motor response, best verbal response, and eye opening. Scores range from 3 (the lowest) to 15 (normal). a peripheral perfusion (warm fingers and toes with normal capillary refill) are presumed to have adequate overall perfusion. Urine output is a quantitative, reliable indicator of organ perfusion. Adequate urine output is 0.5 mL/kg per hour in an adult, 1 mL/kg per hour in a child, and 2 mL/kg per hour in an infant <1 year of age. Because measurement of this resuscitationrelated variable is time dependent, it is generally more useful in the OR and intensive care unit (ICU) setting, than in initial evaluation in the trauma bay. There are several caveats to be considered when evaluating the injured patient for shock. Tachycardia is often the earliest sign of ongoing blood loss, but the critical issue is change over time. Furthermore, individuals in good physical condition with a resting pulse rate in the fifties may manifest a relative tachycardia in the nineties; although clinically significant, this does not meet the standard definition of tachycardia. Conversely, patients receiving cardiac medications such as beta blockers may not be capable of increasing their heart rate to compensate for hypovolemia. Bradycardia can occur with rapid severe blood loss13; this is an ominous sign, often heralding impending cardiovascular collapse. Other physiologic stresses, aside from hypovolemia, may produce tachycardia, such as hypoxia, pain, anxiety, and stimulant drugs (cocaine, amphetamines). As noted previously, decreased SBP is not a reliable early sign of hypovolemia, because blood loss must exceed 30% before hypotension occurs. Additionally, younger patients may maintain their SBP due to sympathetic tone despite severe intravascular deficits until they are on the verge of cardiac arrest. Pregnant patients have a progressive increase in circulating blood volume over gestation; therefore, they must lose a relatively larger volume of Table 7-4 Signs and symptoms of advancing stages of hemorrhagic shock Class I Class II Class III Class IV Blood loss (mL) Up to 750 750–1500 1500–2000 >2000 Blood loss (%BV) Up to 15% 15%–30% 30%–40% >40% Pulse rate <100 >100 >120 >140 Blood pressure Normal Normal Decreased Decreased Pulse pressure (mm Hg) Normal or increased Decreased Decreased Decreased Respiratory rate 14–20 >20–30 30–40 >35 Urine output (mL/h) >30 >20–30 5–15 Negligible CNS/mental status Slightly anxious Mildly anxious Anxious and confused Confused and lethargic BV = blood volume; CNS = central nervous system. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 171 Trauma Persistent Hypotension Patients with ongoing hemodynamic instability, whether “nonresponders” or “transient responders,” require systematic evaluation and prompt intervention.The 4 spectrum of disease in patients with persistent hypotension ranges from overwhelming multisystem injury to easily reversible problems such as a tension pneumothorax. One must first consider the four categories of shock that may be the underlying cause: hemorrhagic, cardiogenic, neurogenic, and septic. In patients with persistent hypotension and tachycardia, cardiogenic or hemorrhagic shock are the likely causes. Ultrasound evaluation of the pericardium, pleural cavities, and abdomen in combination with plain radiographs of the chest and pelvis will usually identify the source of hemorrhagic and/or cardiogenic shock. Evaluation of the CVP may further assist in distinguishing between these two categories. A patient with distended neck veins and a CVP of >15 cm H2O is likely to be in cardiogenic shock. The CVP may be falsely elevated, however, if the patient is agitated and straining, or fluid administration is overzealous; isolated readings must be interpreted with caution. A patient with flat neck veins and a CVP of <5 cm H2O is likely hypovolemic due to ongoing hemorrhage. Serial base deficit measurements are helpful; a persistent base arterial deficit of >8 mmol/L implies ongoing cellular shock.19,20 Serum lactate is also used to monitor the patient’s physiologic response to resuscitation.21 Evolving technology, such as near infrared spectroscopy, may provide noninvasive monitoring of oxygen delivery to tissue.22 Except for patients transferred from outside facilities >12 hours after injury, few patients present in septic shock in the trauma bay. Patients with neurogenic shock as a component of hemodynamic instability often are recognized during the disability section of the primary survey to have paralysis, but those patients chemically paralyzed before physical examination may be misdiagnosed. The differential diagnosis of cardiogenic shock in trauma patients is: (a) tension pneumothorax, (b) pericardial tamponade, (c) blunt cardiac injury, (d) myocardial infarction, and (e) bronchovenous air embolism. Tension pneumothorax, the most frequent cause of cardiac failure, and pericardial tamponade have been discussed earlier. Although as many as one-third of patients sustaining significant blunt chest trauma experience some degree of blunt cardiac injury, few such injuries result in hemodynamic embarrassment. Patients with electrocardiographic (ECG) abnormalities or dysrhythmias require continuous ECG monitoring and antidysrrhythmic treatment as needed. Unless myocardial infarction is suspected, there is no role for routine serial measurement of cardiac enzyme levels—they lack specificity and do not predict significant dysrhythmias.23 In patients who have no identified injuries who are being considered for discharge from the ED, the combination of a normal EKG and troponin level at admission and 8 hours later, rules out significant blunt cardiac injury.24 The patient with hemodynamic instability requires appropriate resuscitation and may benefit from hemodynamic monitoring to optimize preload and guide inotropic support. Echocardiography (ECHO) is performed to exclude valvular or septal injuries, and the most common finding is right ventricular dyskinesia due to the anterior orientation of the right versus left ventricle. Transthoracic and transesophageal ECHO are now becoming routine in many surgical intensive care units (SICUs).25,26 Patients with refractory cardiogenic shock may occasionally require placement of an intra-aortic balloon pump to decrease myocardial work and enhance coronary perfusion. Acute myocardial infarction may be the cause of a motor vehicle collision or other trauma in older patients. Although optimal initial management includes treatment for the evolving infarction, such as lytic therapy and emergent angioplasty, these decisions must be individualized in accordance with the patient’s other injuries. Air embolism is a frequently overlooked lethal complication of pulmonary injury. Air emboli can occur after blunt or penetrating trauma, where air from an injured bronchus enters an adjacent injured pulmonary vein (bronchovenous fistula) and returns air to the left heart. Air accumulation in the left ventricle impedes diastolic filling, and during systole air is pumped into the coronary arteries, disrupting coronary perfusion. The typical case is a patient with a penetrating thoracic injury who is hemodynamically stable but experiences cardiac arrest after being intubated and placed on positive pressure ventilation. The patient should immediately be placed in Trendelenburg’s position to trap the air in the apex of the left ventricle. Emergency thoracotomy is followed by cross-clamping of the pulmonary hilum on the side of the injury to prevent further introduction of air (Fig. 7-14). Air is aspirated from the apex of the left ventricle and then the aortic root with an 18-gauge needle and 50-mL syringe. Vigorous massage is used to force the air bubbles through the coronary arteries; if this is unsuccessful, a tuberculin syringe is used to aspirate air bubbles from the right coronary artery. Once circulation is restored, the patient should be kept in Trendelenburg’s position with the pulmonary hilum clamped until the pulmonary venous injury is controlled operatively. Persistent hypotension due to uncontrolled hemorrhage is associated with high mortality. A rapid search for the source or sources of hemorrhage includes visual inspection with knowledge of the injury mechanism, FAST, and chest and pelvic radiographs. During diagnostic evaluation, type O RBCs (O-negative for women of childbearing age) and thawed AB plasma should be administered at a ratio of 2:1. Type-specific RBCs should be administered as soon as available. The acute coagulopathy of trauma is now well recognized, and underscores the importance of pre-emptive blood component administration. The resurgent interest in viscoelastic hemostatic assays (thrombelastography [TEG] and thrombelastometry [ROTEM]) has facilitated the appropriate and timely use of clotting adjuncts, including the prompt recognition of fibrinolysis. In patients with clear indications for operation, essential films should be taken and the CHAPTER 7 blood before manifesting signs and symptoms of hypovolemia (see Special Trauma Populations). Based on the initial response to fluid resuscitation, hypovolemic injured patients can be separated into three broad categories: responders, transient responders, and nonresponders. Individuals who are stable or have a good response to the initial fluid therapy as evidenced by normalization of vital signs, mental status, and urine output are unlikely to have significant ongoing hemorrhage, and further diagnostic evaluation for occult injuries can proceed in an orderly fashion (see “Secondary Survey”). At the other end of the spectrum are patients classified as “nonresponders” who have persistent hypotension despite aggressive resuscitation. These patients mandate immediate identification of the source of hypotension with appropriate intervention to prevent a fatal outcome. Transient responders are those who respond initially to volume loading with improvement in vital signs, but then deteriorate hemodynamically again. This group of patients can be challenging to triage for definitive management. 172 PART I BASIC CONSIDERATIONS Figure 7-14. A. A Satinsky clamp is used to clamp the pulmonary hilum to prevent further bronchovenous air embolism. B. Sequential sites of aspiration include the left ventricle, the aortic root, and the right coronary artery. patient transported to the OR immediately. Such patients include those with blunt trauma and massive hemothorax, those with penetrating trauma and an initial chest tube output of >1 L, and those with abdominal trauma and ultrasound evidence of extensive hemoperitoneum. In patients with gunshot wounds to the chest or abdomen, a chest and abdominal film, with radiopaque markers at the wound sites, should be obtained to determine the trajectory of the bullet or location of a retained fragment. For example, a patient with a gunshot wound to the upper abdomen should have a chest radiograph to ensure that the bullet did not traverse the diaphragm causing intrathoracic injury. Similarly, a chest radiograph is important in a patient with a gunshot wound to the right chest to evaluate the left hemithorax. If a patient arrives with a penetrating weapon remaining in place, the weapon should not be removed in the ED, because it could be tamponading a lacerated blood vessel (Fig. 7-15). The surgeon should extract the offending instrument in the controlled environment of the OR, ideally once an incision has been made with adequate exposure. In situations where knives are embedded in the head or neck, preoperative imaging may be useful to anticipate arterial injuries. In patients without clear operative indications and persistent hypotension, one should systematically evaluate the five potential sources of blood loss: scalp, chest, abdomen, pelvis, and extremities. Significant bleeding at the scene may be noted by paramedics, but its quantification is unreliable. Examination should seek active bleeding from a scalp laceration that may be readily controlled with clips or staples. Thoracoabdominal trauma should be evaluated with a combination of chest radiograph, FAST, and pelvic radiograph. If the FAST results are negative and no other source of hypotension is obvious, diagnostic peritoneal aspiration should be entertained.27 Extremity examination and radiographs should be used to search for associated fractures. Fracture-related blood loss, when additive, may Figure 7-15. If a weapon is still in place, it should be removed in the operating room, because it could be tamponading a lacerated blood vessel. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Once the immediate threats to life have been addressed, a thorough history is obtained and the patient is examined in a systematic fashion. The patient and surrogates should be queried to obtain an AMPLE history (Allergies, Medications, Past illnesses or Pregnancy, Last meal, and Events related to the injury). The physical examination should be literally head to toe, with special attention to the patient’s back, axillae, and perineum, because injuries here are easily overlooked. All potentially seriously injured patients should undergo digital rectal examination to evaluate for sphincter tone, presence of blood, rectal perforation, or a high-riding prostate; this is particularly critical in patients with suspected spinal cord injury, pelvic fracture, or transpelvic gunshot wounds. Vaginal examination with a speculum should be performed in women with pelvic fractures to exclude an open fracture. Specific injuries, their associated signs and symptoms, diagnostic options, and treatments are discussed in detail later in this chapter. Adjuncts to the physical examination include vital sign and CVP monitoring, ECG monitoring, nasogastric tube placement, Foley catheter placement, radiographs, hemoglobin, urinalysis, and base deficit measurements, and repeat FAST exam. A nasogastric tube should be inserted in all intubated patients to decrease the risk of gastric aspiration but may not be necessary in the awake patient. Nasogastric tube placement in patients with complex mid-facial fractures is contraindicated; rather, a tube should be placed orally if required. Nasogastric tube evaluation of stomach contents for blood may suggest occult gastroduodenal injury or the errant path of the nasogastric tube on a chest film may indicate a left diaphragm injury. A Foley catheter should be inserted in patients unable to void to decompress the bladder, obtain a urine specimen, and monitor urine output. Gross hematuria demands evaluation of the genitourinary system for injury. Foley catheter placement should be deferred until urologic evaluation in patients with signs of urethral injury: blood at the meatus, perineal or scrotal hematomas, or a highriding prostate. Although policies vary at individual institutions, Mechanisms and Patterns of Injury In general, more energy is transferred over a wider area during blunt trauma than from a penetrating wound. As a result, blunt trauma is associated with multiple widely distributed injuries, whereas in penetrating wounds the damage is localized to the path of the bullet or knife. In blunt trauma, organs that cannot yield to impact by elastic deformation are most likely to be injured, namely, the solid organs (liver, spleen, and kidneys). For penetrating trauma, organs with the largest surface area when viewed from the front are most prone to injury (small bowel, liver, and colon). Additionally, because bullets and knives usually follow straight lines, adjacent structures are commonly injured (e.g., the pancreas and duodenum). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 173 Trauma Secondary Survey most agree patients in extremis with need for Foley catheter placement should undergo one attempt at catheterization; if the catheter does not pass easily, a percutaneous suprapubic cystostomy should be considered. Selective radiography and laboratory tests are done early in the evaluation after the primary survey. For patients with severe blunt trauma, chest and pelvic radiographs should be obtained. Historically, a lateral cervical spine radiograph was also obtained, hence the reference to the big three films, but currently patients preferentially undergo CT scanning of the spine rather than plain film radiography. For patients with truncal gunshot wounds, anteroposterior and at times lateral radiographs of the chest and abdomen are warranted. It is important to mark the entrance and exit sites of penetrating wounds with ECG pads, metallic clips, or staples so that the trajectory of the missile can be estimated. Limited one-shot extremity radiographs also may be taken. In critically injured patients, blood samples for a routine trauma panel (type and cross-match, complete blood count, blood chemistries, coagulation studies, and arterial blood gas analysis) should be sent to the laboratory. For less severely injured patients only a complete blood count and urinalysis may be required. Because older patients may present in subclinical shock, even with minor injuries, routine analysis of an arterial blood gas in patients over the age of 55 should be considered. Repeat FAST is performed if there are any signs of abdominal injury or unexplained blood loss. Many trauma patients cannot provide specific information about the mechanism of their injury. Emergency medical service personnel and police are trained to evaluate an injury scene and should be questioned while they are present in the ED. For automobile collisions, the speed of the vehicles involved, angle of impact, use of restraints, airbag deployment, condition of the steering wheel and windshield, amount of intrusion, ejection of the patient from the vehicle, and fate of other passengers should be ascertained. For other injury mechanisms, critical information includes such things as height of a fall, surface impact, helmet use, and weight of an object by which the patient was crushed. In patients sustaining gunshot wounds, velocity, caliber, distance, and presumed path of the bullet are important, if known. For patients with stab wounds, the length and type of object is helpful. Finally, some patients experience a combination of blunt and penetrating trauma. Do not assume that someone who was stabbed was not also assaulted; the patient may have a multitude of injuries and cannot be presumed to have only injuries associated with the more obvious penetrating mechanism. In short, these details of information are critical to the clinician to determine overall mechanism of injury and anticipate its associated injury patterns. CHAPTER 7 be a potential source of the patient’s hemodynamic instability. Each rib fracture can produce 100 to 200 mL of blood loss; for tibial fractures, 300 to 500 mL; for femur fractures, 800 to 1000 mL; and for pelvic fractures >2000 mL. Although no single injury can account for the patient’s hemodynamic instability, the sum of the injuries may result in life-threatening blood loss. The diagnostic measures advocated earlier are those that can be easily performed in the trauma bay. Transport of a hypotensive patient out of the ED for computed tomographic (CT) scanning is hazardous; monitoring is compromised, and the environment is suboptimal for dealing with acute problems. The surgeon must accompany the patient and be prepared to abort the CT scan with diversion to the OR. This dilemma is becoming less common in many trauma centers where CT scanning is done in the ED. The concept of hypotensive resuscitation in the ED remains controversial, and it is primarily relevant for patients with penetrating vascular injuries. Experimental work suggests that an endogenous sealing clot of an injured artery may be disrupted at an SBP of >90 mm Hg28; thus, many believe that this should be the preoperative blood pressure target for patients with potential torso arterial injuries. On the other hand, optimal management of traumatic brain injury (TBI) includes maintaining the SBP >100 mm Hg,29 and thus, hypotensive resuscitation is not appropriate for most blunt trauma patients. 174 PART I BASIC CONSIDERATIONS Trauma surgeons often separate patients who have sustained blunt trauma into categories according to their risk for multiple injuries: those sustaining high energy transfer injuries and those sustaining low energy transfer injuries. Injuries involving high energy transfer include auto-pedestrian accidents, motor vehicle collisions in which the car’s change of velocity (ΔV) exceeds 20 mph or in which the patient has been ejected, motorcycle collisions, and falls from heights >20 ft.30 In fact, for motor vehicle accidents the variables strongly associated with life-threatening injuries, and hence reflective of the magnitude of the mechanism, are death of another occupant in the vehicle, extrication time of >20 minutes, ΔV >20 mph, lack of restraint use, and lateral impact.30 Low-energy trauma, such as being struck with a club or falling from a bicycle, usually does not result in widely distributed injuries. However, potentially lethal lacerations of internal organs can occur, because the net energy transfer to any given location may be substantial. In blunt trauma, particular constellations of injury or injury patterns are associated with specific injury mechanisms. For example, when an unrestrained driver sustains a frontal impact, the head strikes the windshield, the chest and upper abdomen hit the steering column, and the legs or knees contact the dashboard. The resultant injuries can include facial fractures, cervical spine fractures, laceration of the thoracic aorta, myocardial contusion, injury to the spleen and liver, and fractures of the pelvis and lower extremities. When such patients are evaluated, the discovery of one of these injuries should prompt a search for the others. Collisions with side impact also carry the risk of cervical spine and thoracic trauma, diaphragm rupture, and crush injuries of the pelvic ring, but solid organ injury usually is limited to either the liver or spleen based on the direction of impact. Not surprisingly, any time a patient is ejected from the vehicle or thrown a significant distance from a motorcycle, the risk of any injury exists. Penetrating injuries are classified according to the wounding agent (i.e., stab wound, gunshot wound, or shotgun wound). Gunshot wounds are subdivided further into high- and low-velocity injuries, because the speed of the bullet is much more important than its weight in determining kinetic energy. High-velocity gunshot wounds (bullet speed >2000 ft/s) are infrequent in the civilian setting. Shotgun injuries are divided into close-range (<20 feet) and long-range wounds. Close-range shotgun wounds are tantamount to high-velocity wounds because the entire energy of the load is delivered to a small area, often with devastating results. In contrast, long-range shotgun blasts result in a diffuse pellet pattern in which many pellets miss the victim, and those that do strike are dispersed and of comparatively low energy. Regional Assessment and Special Diagnostic Tests Based on mechanism, location of injuries identified on physical examination, screening radiographs, and the patient’s overall condition, additional diagnostic studies often are indicated. However, the seriously injured patient is in constant jeopardy when undergoing special diagnostic testing; therefore, the surgeon must be in attendance and must be prepared to alter plans as circumstances demand. Hemodynamic, respiratory, and mental status will determine the most appropriate course of action. With these issues in mind, additional diagnostic tests are discussed on an anatomic basis. Head Evaluation of the head includes examination for injuries to the scalp, eyes, ears, nose, mouth, facial bones, and intracranial structures. Palpation of the head will identify scalp lacerations, which should be evaluated for depth, and depressed or open skull fractures. The eye examination includes not only pupillary size and reactivity, but also examination for visual acuity and for hemorrhage within the globe. Ocular entrapment, caused by orbital fractures with impingement on the ocular muscles, is evident when the patient cannot move his or her eyes through the entire range of motion. It is important to perform the eye examination early, because significant orbital swelling may prevent later evaluation. A lateral canthotomy may be needed to relieve periorbital pressure. The tympanic membrane is examined to identify hemotympanum, otorrhea, or rupture, which may signal an underlying head injury. Otorrhea, rhinorrhea, raccoon eyes, and Battle’s sign (ecchymosis behind the ear) suggest a basilar skull fracture. Although such fractures may not require treatment, there is an association with blunt cerebrovascular injuries, cranial nerve injuries, and risk of meningitis. Anterior facial structures should be examined to rule out fractures. This entails palpating for bony step-off of the facial bones and instability of the midface (by grasping the upper palate and seeing if this moves separately from the patient’s head). A good question to ask awake patients is whether their bite feels normal to them; abnormal dental closure suggests malalignment of facial bones and a possibility for a mandible or maxillary fracture. Nasal fractures, which may be evident on direct inspection or palpation, typically bleed vigorously. This may result in the patient’s having airway compromise due to blood running down the posterior pharynx, or there may be vomiting provoked by swallowed blood. Nasal packing or balloon tamponade may be necessary to control bleeding. Examination of the oral cavity includes inspection for open fractures, loose or fractured teeth, and sublingual hematomas. All patients with a significant closed head injury (GCS score <14) should undergo CT scanning of the head. Additionally, elderly patients or those patients on antiplatelet agents or anticoagulation should be imaged despite a GCS of 15.31,32 For penetrating injuries, plain skull films may be helpful in the trauma bay to determine the trajectory of injury in hemodynamically unstable patients who cannot be transported for CT scan. The presence of lateralizing findings (e.g., a unilateral dilated pupil unreactive to light, asymmetric movement of the extremities either spontaneously or in response to noxious stimuli, or unilateral Babinski’s reflex) suggests an intracranial mass lesion or major structural damage. Such lesions include hematomas, contusions, hemorrhage into ventricular and subarachnoid spaces, and diffuse axonal injury (DAI). Epidural hematomas occur when blood accumulates between the skull and dura, and are caused by disruption of the middle meningeal artery or other small arteries in that potential space, typically after a skull fracture (Fig. 7-16). Subdural hematomas occur between the dura and cortex and are caused by venous disruption or laceration of the parenchyma of the brain. Due to associated parenchymal injury, subdural hematomas have a much worse prognosis than epidural collections. Hemorrhage into the subarachnoid space may cause vasospasm and further reduce cerebral blood flow. Intraparenchymal hematomas and contusions can occur anywhere within the brain. DAI results from high-speed deceleration injury and represents direct axonal damage from shear effects. CT scan may demonstrate blurring of the gray and white matter interface and multiple small punctate hemorrhages, but magnetic resonance imaging is a more accurate test. Although prognosis for these injuries VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 175 CHAPTER 7 Trauma Figure 7-16. Epidural hematomas (A) have a distinctive convex shape on computed tomographic scan, whereas subdural hematomas (B) are concave along the surface of the brain. is extremely variable, early evidence of DAI is associated with a poor outcome. Stroke syndromes should prompt a search for carotid or vertebral artery injury using multislice CT angiography (CTA) (Fig. 7-17). Significant intracranial penetrating injuries usually are produced by bullets from handguns, but an array of other weapons or instruments can injure the cerebrum via the orbit or through the thinner temporal region of the skull. Although the diagnosis usually is obvious, in some instances wounds in the auditory canal, mouth, and nose can be elusive. Prognosis is variable, but virtually all supratentorial wounds that injure both hemispheres are fatal. Neck All blunt trauma patients should be assumed to have cervical spine injuries until proven otherwise. During cervical examination one must maintain cervical spine precautions A and in-line stabilization. Due to the devastating consequences of quadriplegia, a diligent evaluation for occult cervical spine injuries is mandatory. In the awake patient, the presence of posterior midline pain or tenderness should provoke a thorough radiologic evaluation. Additionally, intubated patients, patients with distracting injuries, or another identified spine fracture should undergo CT imaging. A ligamentous injury may not be visible with standard imaging techniques.33 Flexion and extension views or MRI are obtained to further evaluate patients at risk or those with persistent symptoms, but generally are not done in the acute setting. Spinal cord injuries can vary in severity. Complete injuries cause either quadriplegia or paraplegia, depending on the level of injury. These patients have a complete loss of motor function and sensation two or more levels below the bony injury. B VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 7-17. A. A right middle cerebral infarct noted on a computed tomographic scan of the head. Such a finding should prompt imaging to rule out an associated extracranial cerebrovascular injury. B. An internal carotid artery pseudoaneurysm documented by angiography. 176 PART I BASIC CONSIDERATIONS Figure 7-18. A laryngeal fracture results in air tracking around the trachea along the prevertebral space (arrows). Patients with high spinal cord disruption are at risk for shock due to physiologic disruption of sympathetic fibers. Significant neurologic recovery is rare. However, there are several partial or incomplete spinal cord injury syndromes where the prognosis is better. Central cord syndrome typically occurs in older persons who experience hyperextension injuries. Motor function, pain, and temperature sensation are preserved in the lower extremities but diminished in the upper extremities. Some functional recovery usually occurs, but is often not a return to normal. Anterior cord syndrome is characterized by diminished motor function, pain, and temperature sensation below the level of the injury, but position sensing, vibratory sensation, and crude touch are maintained. Prognosis for recovery is poor. Brown-Séquard syndrome is usually the result of a penetrating injury in which one-half of the spinal cord is transected. This lesion is characterized by the ipsilateral loss of motor function, proprioception, and vibratory sensation, whereas pain and temperature sensation are lost on the contralateral side. During the primary survey, identification of injuries to the neck with exsanguination, expanding hematomas, airway obstruction, or aerodigestive injuries is a priority. A more subtle injury that may not be identified is a fracture of the larynx due to blunt trauma. Signs and symptoms include hoarseness, subcutaneous emphysema (Fig. 7-18), and a palpable fracture. Penetrating injuries of the anterior neck that violate the platysma are potentially life-threatening because of the density of critical structures in this region. Although operative exploration is appropriate in some circumstances, selective nonoperative management has been proven safe (Fig. 7-19).34 Indications for immediate operative intervention for penetrating cervical injury include hemodynamic instability, significant external hemorrhage, or evidence of aerodigestive injury. The management Hemodynamically Unstable Uncontrolled Hemorrhage Hard signs: massive hemoptysis, rapidly expanding hematoma Zone I Penetrating Neck Injury Hemodynamically Stable Soft signs: dysphagia, venous bleeding, subcutaneous emphysema, hematoma, hoarseness, stridor, odynophagia Zone II CTA neck/ chest angiography esophagram bronchoscopy + + Operative Exploration Zone III + angioembolization for Zone III Zone I Asymptomatic Zone II CTA neck/ chest angiography esophagram bronchoscopy + Transcervical GSW All Others Observe Zone III Figure 7-19. Algorithm for the management of penetrating neck injuries. CT = computed tomography; CTA = computed tomographic angiography; GSW = gunshot wound. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 177 CHAPTER 7 Trauma III Figure 7-21. Persistence of a hemothorax despite two tube thoracostomies is termed a caked hemothorax and is an indication for prompt thoracotomy. II I Figure 7-20. For the purpose of evaluating penetrating injuries, the neck is divided into three zones. Zone I is to the level of the clavicular heads and is also known as the thoracic outlet. Zone II is located between the clavicles and the angle of the mandible. Zone III is above the angle of the mandible. algorithm for hemodynamically stable patients is based on the presenting symptoms and anatomic location of injury, with the neck being divided into three distinct zones (Fig. 7-20). 5 Zone I is inferior to the clavicles encompassing the thoracic outlet structures, zone II is between the thoracic outlet and the angle of the mandible, and zone III is above the angle of the mandible. Due to technical difficulties of injury exposure and varying operative approaches, a precise preoperative diagnosis is desirable for symptomatic zone I and III injuries. Therefore, these patients should ideally undergo diagnostic imaging before operation if they remain hemodynamically stable. Management of patients is further divided into those who are symptomatic and those who are not (Fig 7-19). Specific symptoms or signs that should be identified include dysphagia, hoarseness, hematoma, venous bleeding, minor hemoptysis, and subcutaneous emphysema. Symptomatic patients should undergo CTA with further evaluation or operation based upon the imaging findings; less than 15% of penetrating cervical trauma requires neck exploration.35 Asymptomatic patients are typically observed for 6 to12 hours. The one caveat is asymptomatic patients with a transcervical gunshot wound; these patients should undergo CTA to determine the track of the bullet. CTA of the neck and chest determines trajectory of the injury tract; further studies are performed based on proximity to major structures.35 Such additional imaging includes angiography, soluble contrast esophagram followed by barium esophagram, esophagoscopy, or bronchoscopy. Angiographic diagnosis, particularly of zone III injuries, can then be managed by selective angioembolization. Chest Blunt trauma to the chest may involve the chest wall, thoracic spine, heart, lungs, thoracic aorta and great vessels, and rarely the esophagus. Most of these injuries can be evaluated by physical examination and chest radiography, with supplemental CT scanning based on initial findings. Any patient who undergoes an intervention in the ED—endotracheal intubation, central line placement, tube thoracostomy—needs a repeat chest radiograph to document the adequacy of the procedure. This is particularly true in patients undergoing tube thoracostomy for a pneumothorax or hemothorax. Patients with persistent pneumothorax, large air leaks after tube thoracostomy, or difficulty ventilating should undergo fiber-optic bronchoscopy to exclude a tracheobronchial injury or presence of a foreign body. Patients with hemothorax must have a chest radiograph documenting complete evacuation of the chest; a persistent hemothorax that is not drained by two chest tubes is termed a caked hemothorax and mandates immediate thoracotomy (Fig. 7-21). Occult thoracic vascular injury must be diligently sought due to the high mortality of a missed lesion. Widening of the mediastinum on initial anteroposterior chest radiograph, caused by a hematoma around an injured vessel that is contained by the mediastinal pleura, suggests an injury of the great vessels. The mediastinal abnormality may suggest the location of the arterial injury (i.e., left-sided hematomas are associated with descending torn aortas, whereas right-sided hematomas are commonly seen with innominate injuries) (Fig. 7-22). Posterior rib fractures, sternal fractures with laceration of small vessels, and mediastinal venous bleeding also can produce similar hematomas. Other chest radiographic findings suggestive of an aortic tear are summarized in Table 7-5 (Fig. 7-23). However, at least 7% of patients with a descending torn aorta have a normal chest radiograph.36 Therefore, screening spiral CT 6 scanning is performed based on the mechanism of injury: high-energy deceleration motor vehicle collision with frontal or lateral impact (> 30 mph frontal impact and >23 mph lateral impact), motor vehicle collision with ejection, falls of >25 ft, or direct impact (horse kick to chest, snowmobile or ski collision VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 178 PART I BASIC CONSIDERATIONS Figure 7-22. Location of the hematoma within the mediastinal silhouette suggests the type of great vessel injury. A predominant hematoma on the left suggests the far more common descending torn aorta (A; arrows), whereas a hematoma on the right indicates a relatively unusual but life-threatening innominate artery injury (B; arrows). with tree). 37,38 In >95% of patients who survive to reach the ED, the aortic injury occurs just distal to the left subclavian artery, where it is tethered by the ligamentum arteriosum (Fig. 7-24). In 2% to 5% of patients the injury occurs in the ascending aorta, in the transverse arch, or at the diaphragm. Reconstructions with multislice CTA obviate the need for invasive arteriography.37 For penetrating thoracic trauma, physical examination, plain posteroanterior and lateral chest radiographs with metallic markings of wounds, pericardial ultrasound, and CVP measurement will identify the majority of injuries. Injuries of the esophagus and trachea are exceptions. Bronchoscopy should be performed to evaluate the trachea in patients with a persistent air leak from the chest tube or mediastinal air. Because esophagoscopy can miss injuries following an apparent normal endoscopy, patients at risk should undergo soluble contrast esophagraphy followed by barium examination to look for extravasation of contrast to identify an injury.39 As with neck injuries, hemodynamically stable patients with transmediastinal gunshot wounds should undergo CT scanning to determine the path of the bullet; this identifies the vascular or visceral structures at risk for injury Table 7-5 Findings on chest radiograph suggestive of a descending thoracic aortic tear 1. Widened mediastinum 2. Abnormal aortic contour 3. Tracheal shift 4. Nasogastric tube shift 5. Left apical cap 6. Left or right paraspinal stripe thickening 7. Depression of the left main bronchus 8. Obliteration of the aorticopulmonary window 9. Left pulmonary hilar hematoma Figure 7-23. Chest film findings associated with descending torn aorta include apical capping (A; arrows) and tracheal shift (B; arrows). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 179 CHAPTER 7 Trauma Figure 7-24. Imaging to diagnose descending torn aorta includes computed tomographic angiography (A), with three-dimensional reconstructions (B, anterior; C, posterior) demonstrating the proximal and distal extent of the injury (arrows). and directs angiography or endoscopy as appropriate. If there is a suspicion of a subclavian artery injury, brachial-brachial indices should be measured, but >60% of patients with an injury may not have a pulse deficit.40 Therefore, CTA should be performed based on injury proximity to intrathoracic vasculature. Finally, with wounds identified on the chest, penetrating trauma should not be presumed to be isolated to the thorax. Injury to contiguous body cavities (i.e., the abdomen and neck) must be excluded; plain radiographs are a rapid, effective screening modality. Abdomen The abdomen is a diagnostic black box. Fortunately, with few exceptions, it is not necessary to determine in the emergency department which intra-abdominal organs are injured, only whether an exploratory laparotomy is necessary. However, physical examination of the abdomen can be unreliable in making this determination, and drugs, alcohol, and head and spinal cord injuries complicate clinical evaluation. The presence of abdominal rigidity and hemodynamic compromise is an undisputed indication for prompt surgical exploration. For the remainder of patients, a variety of diagnostic adjuncts are used to identify abdominal injury. The diagnostic approach differs for penetrating trauma and blunt abdominal trauma. As a rule, minimal evaluation is 7 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 180 Hemodynamically Unstable PART I Anterior Abdomen BASIC CONSIDERATIONS RUQ GSW Penetrating Abdominal Trauma Tangential*, Back/Flank CT Scan + Operating Room Hemodynamically Stable Left-sided thoracoabdominal Back/Flank SW AASW with + LWE** DPL vs. laparoscopy CT Scan Serial Exams/ Labs + + Evisceration/ Peritonitis *Tangential GSWs may also be evaluated with diagnostic laparoscopy. ** A positive local wound exploration is defined as violation of the posterior fascia. Figure 7-25. Algorithm for the evaluation of penetrating abdominal injuries. AASW = anterior abdominal stab wound; CT = computed tomography; DPL = diagnostic peritoneal lavage; GSW = gunshot wound; LWE = local wound exploration; RUQ = right upper quadrant; SW = stab wound. required before laparotomy for gunshot or shotgun wounds that penetrate the peritoneal cavity, because over 90% of patients have significant internal injuries. Anterior truncal gunshot wounds between the fourth intercostal space and the pubic symphysis whose trajectory as determined by radiograph or wound location indicates peritoneal penetration should undergo laparotomy (Fig. 7-25). The exception is penetrating trauma isolated to the right upper quadrant; in hemodynamically stable patients with trajectory confined to the liver by CT scan, nonoperative observation may be reasonable.41 In obese patients, if the gunshot wound is thought to be tangential through the subcutaneous tissues, CT scan can delineate the track and exclude peritoneal violation. Laparoscopy is another option to assess peritoneal penetration for tangential wounds. If there is doubt, however, it is always safer to explore the abdomen. In the scenario of tangential high energy GSWs, however, it is possible to sustain a transmitted intraperitoneal hollow visceral injury due to a blast insult. Gunshot wounds to the back or flank are more difficult to evaluate because of the retroperitoneal location of the injured abdominal organs. Triple-contrast CT scan can delineate the trajectory of the bullet and identify peritoneal violation or retroperitoneal entry, but may not identify the specific injuries. In contrast to gunshot wounds, stab wounds that penetrate the peritoneal cavity are less likely to injure intra-abdominal organs. Anterior abdominal stab wounds (from costal margin to inguinal ligament and bilateral midaxillary lines) should be explored under local anesthesia in the ED to determine if the fascia has been violated. Injuries that do not penetrate the peritoneal cavity do not require further evaluation, and the patient may be discharged from the ED. Patients with fascial penetration must be further evaluated for intra-abdominal injury, because there is up to a 50% chance of requiring laparotomy. Debate remains over whether the optimal diagnostic approach is serial examination, diagnostic peritoneal lavage (DPL), or CT scanning; the most recent evidence supports serial examination and laboratory evaluation.42,43 Patients with stab wounds to the right upper quadrant can undergo CT scanning to determine trajectory and confinement to the liver for potential nonoperative care.41 Those with stab wounds to the flank and back should undergo triplecontrast CT to assess for the potential risk of retroperitoneal injuries of the colon, duodenum, and urinary tract. Penetrating thoracoabdominal wounds may cause occult injury to the diaphragm. Patients with gunshot or stab wounds to the left lower chest should be evaluated with diagnostic laparoscopy or DPL to exclude diaphragmatic injury. For patients undergoing DPL evaluation, laboratory value cutoffs to rule out diaphragm injury are different from traditional values formerly used for abdominal stab wounds (see Table 7-6). An RBC count of >10,000/μL is considered a positive finding and an indication for abdominal evaluation; patients with a DPL RBC count VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 7-6 Abdominal Trauma Thoracoabdominal Stab Wounds >10,000/mL White blood cell count >500/mL >500/mL Amylase level >19 IU/L >19 IU/L Alkaline phosphatase level >2 IU/L >2 IU/L Bilirubin level >0.01 mg/dL >0.01 mg/dL between 1000/μL and 10,000/μL should undergo laparoscopy or thoracoscopy. Diagnostic laparoscopy may be preferred in patients with a positive chest radiograph (hemothorax or pneumothorax) or in those who would not tolerate a DPL. Blunt abdominal trauma is evaluated initially by FAST examination in most major trauma centers, and this has largely supplanted DPL (Fig. 7-26). FAST is not 100% sensitive, however, so diagnostic peritoneal aspiration is warranted in hemodynamically unstable patients without a defined source of blood loss to rule out abdominal hemorrhage.27 FAST is used to identify free intraperitoneal fluid (Fig. 7-27) in Morrison’s pouch, the left upper quadrant, and the pelvis. Although this method is exquisitely sensitive for detecting intraperitoneal fluid of >250 mL, it does not reliably determine the source of hemorrhage nor grade solid organ injuries.44 Patients with fluid on FAST examination, considered a “positive FAST,” who do not have immediate indications for laparotomy and are hemodynamically stable undergo CT scanning to quantify their injuries. Injury grading using the American Association for the Surgery of Trauma grading scale (Table 7-7) is an important component of nonoperative management of solid organ injuries. Additional findings that should be noted on CT scan in patients with solid organ injury include contrast extravasation (i.e., a “blush”), the amount of intra-abdominal hemorrhage, and presence of pseudoaneurysms (Fig. 7-28). CT also is indicated for hemodynamically Hemodynamically stable No Peritonitis? No Pelvis Blunt injury to the pelvis may produce complex fractures with major hemorrhage (Fig. 7-30). Plain radiographs will reveal gross abnormalities, but CT scanning is necessary to determine the precise geometry. Sharp spicules of bone can lacerate the bladder, rectum, or vagina. Alternatively, bladder rupture may result from a direct blow to the torso if the bladder is full. CT cystography is performed if the urinalysis findings are positive for RBCs. Urethral injuries are suspected if examination reveals blood at the meatus, scrotal or perineal hematomas, or a high-riding prostate on rectal examination. Urethrograms should be obtained for stable patients before placing a Foley catheter to avoid false passage and subsequent stricture. Major vascular injuries causing exsanguination are uncommon in blunt pelvic trauma; however, thrombosis of either the arteries or veins in the iliofemoral system may occur, and CT angiography should be performed for evaluation. Life-threatening hemorrhage can be associated with pelvic fractures and may initially preclude definitive imaging. Treatment algorithms for patients with complex pelvic fractures and hemodynamic instability are presented later in the chapter. Extremities Physical examination often identifies arterial injuries, and findings are classified as either hard signs or soft signs of vascular injury (Table 7-8). In general, hard signs constitute FAST + No Yes Yes No FAST + Yes Equivocal Laparotomy + No Candidate for nonoperative management or patient with cirrhosis Indications for CT: -Altered mental status -Confounding injury -Gross hematuria -Pelvic fracture -Abdominal tenderness -Unexplained Hct <35% No Repeat FAST in 30 minutes Yes Yes Abdominal CT DPA Figure 7-26. Algorithm for the initial evaluation of a patient with suspected blunt abdominal trauma. CT = computed tomography; DPA = diagnostic peritoneal aspiration; FAST = focused abdominal sonography for trauma; Hct = hematocrit. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Trauma Red blood cell count >100,000/mL 181 CHAPTER 7 Criteria for “positive” finding on diagnostic peritoneal lavage stable patients for whom the physical examination is unreliable. Despite the increasing diagnostic accuracy of multidetector CT scanners, identification of intestinal injuries remains a limitation. Bowel injury is suggested by findings of thickened bowel wall, “streaking” in the mesentery, free fluid without associated solid organ injury, or free intraperitoneal air.45,46 Patients with free intra-abdominal fluid without solid organ injury are closely monitored for evolving signs of peritonitis; if patients have a significant closed head injury or cannot be serially examined, DPL should be performed to exclude bowel injury. If DPL is pursued, an infraumbilical approach is used (Fig. 7-29). After placement of the catheter, a 10-mL syringe is connected and the abdominal contents aspirated (termed a diagnostic peritoneal aspiration). The aspirate is considered to show positive findings if >10 mL of blood is aspirated. If <10 mL is withdrawn, a liter of normal saline is instilled. The effluent is withdrawn via siphoning and sent to the laboratory for RBC count, white blood cell (WBC) count, and determination of amylase, bilirubin, and alkaline phosphatase levels. Values representing positive findings are summarized in Table 7-6. 182 PART I BASIC CONSIDERATIONS Figure 7-27. Focused abdominal sonography for trauma imaging detects intra-abdominal hemorrhage. Hemorrhage is presumed when a fluid stripe is visible between the right kidney and liver (A), between the left kidney and spleen (B), or in the pelvis (C). indications for operative exploration, whereas soft signs are indications for further testing or observation. Bony fractures or knee dislocations should be realigned before definitive vascular examination. On-table angiography may be useful to localize the arterial injury and thus, limit tissue dissection in patients with hard signs of vascular injury. For example, a patient with an absent popliteal pulse and femoral shaft fracture due to a bullet that entered the lateral hip and exited below the medial knee could have injured either the femoral or popliteal artery anywhere along its course (Fig. 7-31). In management of vascular trauma, controversy exists regarding the treatment of patients with soft signs of injury, particularly those with injuries in proximity to major vessels. It is known that some of these patients will have arterial injuries that require repair. The most common approach has been to measure SBP using Doppler ultrasonography and compare the value for the injured side with that for the uninjured side, termed the A-A index.47 If the pressures are within 10% of each other, a significant injury is unlikely and no further evaluation is performed. If the difference is >10%, CT angiography or arteriography is indicated. Others argue that there are occult injuries, such as pseudoaneurysms or injuries of the profunda femoris or peroneal arteries, which may not be detected with this technique. If hemorrhage occurs from these injuries, compartment syndrome and limb loss may occur. Although busy trauma centers continue to debate this issue, the surgeon who is obliged to treat the occasional injured patient may be better served by performing CT angiography in selected patients with soft signs. Blunt or penetrating trauma to the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 183 Table 7-7 American Association for the Surgery of Trauma grading scales for solid organ injuries Grade I <10% of surface area <1 cm in depth Grade II 10%–50% of surface area 1–3 cm Grade III >50% of surface area or >10 cm in depth >3 cm Grade IV 25%–75% of a hepatic lobe Grade V >75% of a hepatic lobe Grade VI Hepatic avulsion Liver Injury Grade Splenic Injury Grade Grade I <10% of surface area <1 cm in depth Grade II 10%–50% of surface area 1–3 cm Grade III >50% of surface area or >10 cm in depth >3 cm Grade IV >25% devascularization Hilum Grade V Shattered spleen Complete devascularization extremities requires an evaluation for fractures, ligamentous injury, and neurovascular injury. Plain radiographs are used to evaluate fractures, whereas ligamentous injuries, particularly those of the knee and shoulder, can be imaged with magnetic resonance imaging. GENERAL PRINCIPLES OF MANAGEMENT Over the past 25 years there has been a remarkable change in management practices and operative approach for the injured patient. With the advent of CT scanning, nonoperative management of solid organ injuries has replaced routine operative exploration. Those patients who do require operation may be treated with less radical resection techniques, such as splenorrhaphy or partial nephrectomy. Colonic injuries, previously mandating colostomy, are now repaired primarily in virtually all cases. Additionally, the type of anastomosis has shifted from a doublelayer closure to a continuous running single-layer closure; this method is technically equivalent to and faster than the interrupted multilayer techniques.48 Adoption of damage control surgical techniques in physiologically deranged patients has resulted in limited initial operative time, with definitive injury repair delayed until after resuscitation in the surgical intensive care unit (SICU) with physiologic restoration.49 Abdominal drains, once considered mandatory for parenchymal injuries and some anastomoses, have disappeared; fluid collections are managed by percutaneous techniques. Newer endovascular techniques such as stenting of arterial injuries and angioembolization are routine Figure 7-28. Computed tomographic images reveal critical information about solid organ injuries, such as associated contrast extravasation from a grade IV laceration of the spleen (A; arrows) and the amount of subcapsular hematoma in a grade III liver laceration (B; arrows). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Trauma Laceration CHAPTER 7 Subcapsular Hematoma 184 PART I BASIC CONSIDERATIONS Figure 7-29. Diagnostic peritoneal lavage is performed through an infraumbilical incision unless the patient has a pelvic fracture or is pregnant. A. The linea alba is sharply incised, and the catheter is directed into the pelvis. B. The abdominal contents should initially be aspirated using a 10-mL syringe. adjuncts. Blunt cerebrovascular injuries have been recognized as a significant, preventable source of neurologic morbidity and mortality. The use of preperitoneal pelvic packing for unstable pelvic fractures as well as early fracture immobilization with external fixators are paradigm shifts in management. Finally, the institution of massive transfusion protocols balances the benefit of blood component therapy against immunologic risk. Viscoelastic hemostatic assays (TEG and ROTEM) have been shown to be superior to traditional laboratory tests, and have been central to the evolving concept of goal-directed hemostasis.50 These conceptual changes have significantly improved survival of critically injured patients; they have been promoted and critically reviewed by academic trauma centers via forums such as the American College of Surgeons Committee on Trauma, the American Association for the Surgery of Trauma, the International Association of Trauma Surgery and Intensive Care, the Pan-American Trauma Congress, and other surgical organizations. Transfusion Practices Injured patients with life-threatening hemorrhage develop an acute coagulopathy of trauma (ACOT). Cohen et al51 have shown convincingly that activated protein C is a key element, although the complete mechanism remains to be elucidated. Fibrinolysis is another important component of the ACOT; present in only 5% of injured patients requiring hospitalization, but 20% in those requiring massive transfusion.52 Fresh whole blood, arguably the optimal replacement, is not available in the United States. Rather, its component parts, packed red blood cells (PRBCs), fresh-frozen plasma, platelets, and cryoprecipitate, are administered. Specific transfusion triggers for individual blood components exist. Although current critical care guidelines indicate that PRBC transfusion should occur once the patient’s hemoglobin level is <7 g/dL,53 in the acute phase of resuscitation a hemoglobin of 10 g/dL is suggested to facilitate hemostasis.54 The traditional thresholds for blood component replacement in the patient manifesting a coagulopathy have been INR >1.5, PTT >1.5 normal, platelet count > 50,000/ μL, and fibrinogen >100 mg/dl. However, these guidelines have been replaced by TEG and ROTEM criteria in many trauma centers. Such guidelines are designed to limit the transfusion of immunologically active blood components and decrease the risk of transfusion-associated lung injury and secondary multiple organ failure.55,56 In the critically injured patient requiring large amounts of blood component therapy, a massive transfusion protocol should be followed (Fig. 7-32). This approach calls for administration of various components in a specific ratio during transfusion to achieve restoration of blood volume and correction of coagulopathy. Although the optimal ratio is yet to be determined, current scientific evidence indicates a presumptive 1:2 red cell:plasma ratio in patients at risk for massive transfusion (10 units of PRBCs in 6 hours).57-60 Because complete typing and cross-matching takes up to 45 minutes, patients requiring emergent transfusions are given type O, type-specific, or biologically compatible RBCs. Blood typing, and to a lesser extent cross-matching, is essential to avoid life-threatening intravascular hemolytic transfusion reactions. Trauma centers and their associated blood banks must have the capability of transfusing tremendous quantities of blood components, because it is not unusual to have 100 component units transfused during one procedure and have the patient survive. Massive transfusion VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 185 CHAPTER 7 Trauma Figure 7-30. The three types of mechanically unstable pelvis fractures are lateral compression (A), anteroposterior compression (B), and vertical shear (C). protocols, established preemptively, permit coordination of the activities of surgeons, anesthesiologists, and blood bank directors to facilitate transfusion at these rates should a crisis occur. Postinjury coagulopathy is associated with core hypothermia and metabolic acidosis, termed the bloody vicious cycle.49 8 The pathophysiology is multifactorial and includes Table 7-8 Signs and symptoms of peripheral arterial injury Hard Signs (Operation Mandatory) Soft Signs (Further Evaluation Indicated) Pulsatile hemorrhage Proximity to vasculature Absent pulses Significant hematoma Acute ischemia Associated nerve injury A-A index of <0.9 Thrill or bruit A-A index = systolic blood pressure on the injured side compared with that on the uninjured side. inhibition of temperature-dependent enzyme-activated coagulation cascades, platelet dysfunction, endothelial abnormalities, and fibrinolytic activity. Such coagulopathy may be insidious, so the surgeon must be cognizant of subtle signs such as excessive bleeding from the cut edges of skin. Although the coagulopathic “ooze” may seem minimal compared with the torrential hemorrhage from a hole in the aorta, blood loss from the entire area of dissection can lead to exsanguination. Point-of-care TEG results, which provide a comprehensive assessment of clot capacity and fibrinolysis, can be available within 10 minutes. This concept has been termed . In contrast, traditional laboratory tests of coagulation capability (i.e., INR, PTT, fibrinogen levels, and platelet count) requires at least 30 minutes. Such a delay is particularly troublesome for patients who have lost two blood volumes while waiting for the test results to return. Using damage control techniques to limit operative time and provide physiologic restoration in the SICU can be lifesaving (see section Damage Control Surgery). Prophylactic Measures All injured patients undergoing an operation should receive preoperative antibiotics. The type of antibiotic is determined VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 186 PART I BASIC CONSIDERATIONS Figure 7-31. On-table angiography in the operating room isolates the area of vascular injury to the superficial femoral artery in a patient with a femoral fracture after a gunshot wound to the lower extremity. by the anticipated source of contamination in the abdomen or other operative region; additional doses should be administered during the procedure based on blood loss and the half-life of the antibiotic. Extended postoperative antibiotic therapy is administered only for contaminated open fractures. Tetanus prophylaxis is administered to all patients according to published guidelines. Trauma patients are at risk for venous thromboembolism and its associated morbidity and mortality. In fact, pulmonary embolus can occur much earlier in the patient’s hospital course than previously believed.61 Patients at higher risk for venous thromboembolism are those with multiple fractures of the pelvis and lower extremities, coma or spinal cord injury, and requiring ligation of large veins in the abdomen and lower extremities. Morbidly obese patients and those over 55 years of age are at additional risk. Administration of low molecular weight heparin (LMWH) is initiated as soon as bleeding has been controlled and there is stable intracranial pathology. Higher doses of LMWH are required in injured patients to attain adequate anti-Xa levels, and antiplatelet therapy should probably be added. In high-risk patients, removable inferior vena caval filters should be considered if there are prolonged contraindications to administration of LMWH. Additionally, pulsatile compression stockings (also termed sequential compression devices) are used routinely unless there is a fracture. A final prophylactic measure that is usually not considered is thermal protection. Hemorrhagic shock impairs perfusion and metabolic activity throughout the body, with resultant decrease in heat production and body temperature. Removing the patient’s clothes causes a second thermal insult, and infusion of cold PRBCs or room temperature crystalloid exacerbates the Massive Transfusion Protocol Trigger: Uncontrolled hemorrhage • e.g., SBP < 90mmHg Despite 3 ½ Liter Crystalloid (50mL/kg) • e.g., EBL >150 mL/min • e.g., pH<7.1; body temperature <34°C; ISS > 25 Surgery & Anesthesia Response Blood Bank Response Continued Treatment of Shock Hemorrhage Control Correct Hypothermia Correct Acidosis Normalize Ca++ Check labs q30 min as needed Ongoing Component Therapy PT, PTT > 1.5 control 2 units thawed plasma rapidTEG-ACT >110 sec 2 units thawed plasma Platelet count < 50,000/mcL 1 unit of apheresis platelets rapidTEG-MA < 55mm 1 unit of apheresis platelets Fibrinogen < 100 mg/dL 10 units pooled cryoprecipitate rapidTEG-angle < 63 degrees 10 units pooled cryoprecipitate rapidTEG EPL > 15% 5g amicar Shipment PRBCs FFP 1 4 2 2 4 2 3 4 2 4 4 2 Platelets Cryo 1 10 1 10 Shipments are delivered every 30 min until Massive Transfusion Protocol is terminated. Each shipment’s quantity can be doubled at the request of Surgery or Anesthesia. Shipments > 4 are determined by patient’s clinical course and lab values. Figure 7-32. Denver Health Medical Center’s Massive Transfusion Protocol. ACT = activated clotting time; Cryo = cryoprecipitate; FFP = fresh-frozen plasma; INR = International Normalized Ratio; MA = maximum amplitude; PRBCs = packed red blood cells; PTT = partial thromboplastin time; SBP = systolic blood pressure; TEG = thromboelastography; EPL = estimated percent lysis. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Cervical Exposure Operative exposure for midline structures of the neck (e.g.,trachea, thyroid, bilateral carotid sheaths) is Figure 7-33. A. Unilateral neck exploration is performed through an incision along the anterior border of the sternocleidomastoid muscle; exposure of the carotid artery requires early division of the facial vein. B. The distal internal carotid artery is exposed by dividing the ansa cervicalis, which permits mobilization of the hypoglossal nerve. C. Further exposure is facilitated by resection of the posterior belly of the digastric muscle. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 187 Trauma Operative Approaches and Exposure obtained through a collar incision; this is typically performed two finger breadths above the sternal notch, but can be varied based on the level of anticipated injury. After subplatysmal flap elevation, the strap muscles are divided in the midline to gain access to the central neck compartment. More superior and lateral structures are accessed by extending the collar incision upward along the sternocleidomastoid muscle; this may be done bilaterally if necessary. Unilateral neck exploration is done through an incision extending from the mastoid down to the clavicle, along the anterior border of the sternocleidomastoid muscle (Fig. 7-33). The carotid sheath, containing the carotid artery, jugular vein, and vagus nerve, is opened widely to examine these structures. The facial vein, which marks the carotid bifurcation, is usually ligated for exposure of the internal carotid artery. CHAPTER 7 problem. As a result, injured patients can become hypothermic, with temperatures below 34°C (93.2°F) upon arrival in the OR. Hypothermia aggravates coagulopathy and provokes myocardial irritability. Therefore, prevention must begin in the ED by maintaining a comfortable ambient temperature, covering patients with warm blankets, and administering warmed IV fluids and blood products. Additionally, in the OR a Bair Hugger warmer (the upper body or lower body blanket) and heated inhalation via the ventilatory circuit is instituted. For cases of severe hypothermia (temperature <30°C [86°F]), arteriovenous rewarming should be considered. 188 PART I 3 BASIC CONSIDERATIONS 2 1 Figure 7-34. Options for thoracic exposure include the most versatile incision, the anterolateral thoracotomy (1), as well as a median sternotomy (2) and a “trap door” thoracotomy (3). Any thoracic incision may be extended into a supraclavicular or anterior neck incision for wider exposure. Exposure of the distal carotid artery in zone III is difficult (see Fig. 7-33). The first step is division of the ansa cervicalis to facilitate mobilization of the hypoglossal nerve. Next, the posterior portion of the digastric muscle, which overlies the internal carotid, is transected. The glossopharyngeal and vagus nerves are also mobilized and retracted as necessary. If accessible, the styloid process and attached muscles are removed. At this point anterior displacement of the mandible (subluxation) may be helpful. In desperate situations, the vertical ramus of the mandible may be divided. However, this maneuver often entails resection of the parotid gland and the facial nerve is at risk for exposure of the distal internal carotid. Thoracic Incisions An anterolateral thoracotomy, with the patient placed supine, is the most versatile incision for emergent thoracic exploration. The location of the incision is in the fifth interspace, in the inframammary line (Fig. 7-34). If access is needed to both pleural cavities, the original incision can be extended across the sternum with a Lebsche knife, into a “clamshell” thoracotomy (Fig. 7-35). If the sternum is divided, the internal mammary arteries should be ligated to prevent blood loss. The heart, lungs, descending aorta, pulmonary hilum, and esophagus are accessible with this approach. For control of the great vessels, the superior portion of the sternum may be divided with extension of the incision into the neck considered. A method advocated for access to the proximal left subclavian artery is through a fourth interspace anterolateral thoracotomy, superior sternal extension, and left supraclavicular incision (“trap door” thoracotomy). Although the trap door procedure is appropriate after resuscitative thoracotomy, the proximal left subclavian artery can be accessed more easily via a sternotomy with a supraclavicular extension. If the left subclavian artery is injured outside the thoracic outlet, vascular control can be obtained via the sternotomy and definitive repair done through the supraclavicular incision. Emergent median sternotomy is limited to anterior stab wounds to the heart. Typically, these patients have pericardial tamponade and undergo placement of a pericardial drain before a semiurgent median sternotomy is performed. Patients in extremis, however, should undergo anterolateral thoracotomy. B Figure 7-35. A. A “clamshell” thoracotomy provides exposure to bilateral thoracic cavities. B. Sternal transection requires individual ligation of both the proximal and distal internal mammary arteries on the undersurface of the sternum. Median sternotomy with cervical extension is used for rapid exposure in patients with presumed proximal subclavian, innominate, or proximal carotid artery injuries. Care must be taken to avoid injury to the phrenic and vagus nerves that pass over the subclavian artery and to the recurrent laryngeal nerve passing posteriorly. Posterolateral thoracotomies are used for exposure of injuries to the trachea or main stem bronchi near the carina (right posterolateral thoracotomy), tears of the descending thoracic aorta (left posterolateral thoracotomy with left heart bypass), and intrathoracic esophageal injuries. Emergent Abdominal Exploration Abdominal exploration in adults is performed using a generous midline incision because of its versatility. For children under the age of 6, a transverse incision may be advantageous. Making the incision is faster with a scalpel than with an electrosurgical unit; incisional abdominal wall bleeding should be ignored until intra-abdominal sources of hemorrhage are controlled. Liquid and clotted blood are evacuated with multiple laparotomy pads to identify the major source(s) of active bleeding. After blunt trauma the spleen and liver should be palpated first and packed if fractured, and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 189 CHAPTER 7 Trauma Figure 7-37. The Pringle maneuver, performed with a vascular clamp, occludes the hepatic pedicle containing the portal vein, hepatic artery, and common bile duct. Figure 7-36. A sagittal view of packs placed to control hepatic hemorrhage. Lap = laparotomy. the infracolic mesentery inspected to exclude a zone I vascular injury. In contrast, after a penetrating wound the search for bleeding should pursue the trajectory of the penetrating device. If the patient has an SBP of <70 mmHg when the abdomen is opened, digital pressure or a clamp should be placed on the aorta at the diaphragmatic hiatus. After the source of hemorrhage is localized, direct digital occlusion (vascular injury) or laparotomy pad packing (solid organ injury) is used to control bleeding (Fig. 7-36). If the liver is the source in a hemodynamically unstable patient, additional control of bleeding is obtained by clamping the hepatic pedicle with a vascular clamp or Rummel tourniquet (Pringle maneuver) (Fig. 7-37). Similarly, clamping the splenic hilum may more effectively control bleeding than packing alone. When the spleen is mobilized, it should be gently rotated medially to expose the lateral peritoneum; this peritoneum and endoabdominal fascia are incised, which allows blunt dissection of the spleen and pancreas as a composite from the retroperitoneum anterior to Gerota’s fascia (Fig. 7-38). Rapid exposure of the intra-abdominal vasculature can prove challenging in the face of exsanguinating hemorrhage. Proximal control of the aorta is obtained at the diaphragmatic hiatus; if an aortic injury is supraceliac, transecting the left crus of diaphragm or extending the laparotomy via a left thoracotomy may be necessary. The first decision is whether the patient has a supracolic or an infracolic vascular injury. Supracolic injuries (aorta, celiac axis, proximal superior mesenteric artery [SMA], and left renal arteries) are best approached a left medial visceral rotation (Fig. 7-39). This is done by incising the lateral peritoneal reflection (white line of Toldt) beginning at the distal descending colon and extending the incision along the colonic splenic flexure, around the posterior aspect of the spleen, and behind the gastric fundus, ending at the esophagus. The left Figure 7-38. To mobilize the spleen, an incision is made into the endoabdominal fascia 1 cm lateral to the reflection of the peritoneum onto the spleen (A). While the spleen is gently rotated medially, a plane is developed between the pancreas and left kidney (B). With complete mobilization, the spleen can reach the level of the abdominal incision. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 190 PART I BASIC CONSIDERATIONS Figure 7-40. A right medial visceral rotation is used to expose the infrahepatic vena cava. Figure 7-39. A left medial visceral rotation is used to expose the abdominal aorta. colon, spleen, pancreas, and stomach are then rotated toward the midline. The authors prefer to leave the kidney in situ when mobilizing the viscera because this exaggerates the separation of the renal vessels from the SMA. The operative approach for SMA injuries is based on the level of injury. Fullen zone I SMA injuries, located posterior to the pancreas, are best exposed by a left medial visceral rotation. Fullen zone II SMA injuries, extending from the pancreatic edge to the middle colic branch, on the other hand, are approached via the lesser sac along the inferior edge of the pancreas at the base of the transverse mesocolon; the pancreatic body may be divided to gain proximal vascular access. More distal SMA injuries, Fullen zones III and IV, are approached directly within the mesentery. A venous injury behind the pancreas, from the junction of the superior mesenteric, splenic, and portal veins, is accessed by dividing the neck of the pancreas. Inferior vena cava injuries are approached by a right medial visceral rotation (Fig. 7-40). Proximal control is obtained just above the iliac bifurcation with direct pressure via a sponge stick; the injury is identified by cephalad dissection along the anterior surface of the inferior vena cava. A Satinsky clamp can be used to control anterior caval wounds. Injuries of the iliac vessels pose a unique problem for emergent vascular control due to the number of vessels, their close proximity, and cross circulation. Proximal control at the infrarenal aorta arrests the arterial bleeding and avoids splanchnic and renal ischemia; however, venous injuries are not controlled with aortic clamping. Tamponade with a folded laparotomy pad held directly over the bleeding site usually will establish hemostasis sufficient to prevent exsanguination. If hemostasis is not adequate to expose the vessel proximal and distal to the injury, sponge sticks can be strategically placed on either side of the injury and carefully adjusted to improve hemostasis. Alternatively, complete pelvic vascular isolation (Fig. 7-41) may be required to control hemorrhage for adequate visualization of the Figure 7-41. Pelvic vascular isolation. A. Initially, clamps are placed on the aorta, inferior vena cava, and bilateral external iliac vessels. B. With continued dissection, the clamps can be moved progressively closer to the vascular injury to limit unwarranted ischemia. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 191 CHAPTER 7 Trauma Figure 7-42. The right common iliac artery can be divided to expose the bifurcation of the inferior vena cava and the right common iliac vein. injuries. The right common iliac artery obscures the bifurcation of the vena cava and the right iliac vein; the iliac artery may require division to expose venous injuries in this area (Fig. 7-42). The artery must be repaired after the venous injury is treated, however, because of limb-threatening ischemia. Once overt hemorrhage is controlled, sources of enteric contamination are identified by serially running along the small and large bowel, looking at all surfaces. Associated hematomas should be unroofed to rule out adjacent bowel injury. The anterior and posterior aspects of the stomach should be inspected, which requires opening the lesser sac for complete visualization. Duodenal injuries should be evaluated with a wide Kocher maneuver. During exploration of the lesser sac, visualization and palpation of the pancreas is done to exclude injury. Palpating the anterior surface is not sufficient, because the investing fascia may mask a pancreatic injury; mobilization, including evaluation of the posterior aspect, is critical. After injuries are identified, whether to use damage control techniques or perform primary repair of injuries is based on the patient’s intraoperative physiologic status (see sections, Damage Control Surgery and Treatment of Specific Injuries). In a patient with multisystem trauma, enteral access via gastrostomy tube or needle-catheter jejunostomy should be considered. If abdominal closure is indicated after the patient’s injuries are addressed, the abdomen is irrigated with warm saline and the midline fascia is closed with a running heavy suture. The skin is closed selectively based on the amount of intra-abdominal contamination. Vascular Repair Techniques Initial control of vascular injuries is accomplished digitally by applying enough direct pressure to stop the hemorrhage. Sharp dissection with fine scissors is used to define the injury and mobilize sufficient length for proximal and distal control. Fogarty thromboembolectomy should be done proximally and distally to optimize collateral blood flow. Heparinized saline (50 units/mL) is then injected into the proximal and distal ends of the injured vessel to prevent small clot formation on the exposed intima and media. Ragged edges of the injury site should be débrided using sharp dissection. Intravascular shunts are used when there are multiple lifethreatening injuries or the arterial injury is anticipated to require saphenous vein interposition reconstruction. Options for the treatment of vascular injuries are listed in Table 7-9. Arterial repair should always be done for the aorta, carotid, innominate, brachial, superior mesenteric, proper hepatic, renal, iliac, femoral, and popliteal arteries. Named arteries that usually tolerate ligation include the right or left hepatic artery and the celiac artery. In the lower extremities, at least one artery with distal runoff should be salvaged. Arterial injuries that may be treated nonoperatively include small pseudoaneurysms, intimal dissections, small intimal flaps, and small arteriovenous fistulas in the extremities. Follow-up imaging is performed 1 to 2 weeks after injury to confirm healing. Venous repair should be performed for injuries of the superior vena cava, the inferior vena cava proximal to the renal veins, and the portal vein, although the portal vein may be ligated in extreme cases. The SMV should be repaired optimally, but >80% of patients will survive following ligation. Similarly the left renal vein can usually be ligated adjacent to the IVC due to collateral decompression. The type of operative repair for a vascular injury is based on the extent and location of injury. Lateral suture repair is preferred for arterial injuries with minimal loss of tissue. End-to-end Table 7-9 Options for the treatment of vascular injuries Observation Ligation Lateral suture repair End-to-end primary anastomosis Interposition grafts Autogenous vein Polytetrafluoroethylene graft Dacron graft Transpositions Extra-anatomic bypass Interventional radiology Stents Embolization VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 192 PART I BASIC CONSIDERATIONS Figure 7-43. Small arteries repaired with an end-to-end anastomosis are prone to stricture. Enlarging the anastomosis by beveling the cut ends of the injured vessel can minimize this problem. A curved hemostat is a useful adjunct to create the curve. primary anastomosis is performed if the vessel can be repaired without tension. Arterial defects of 1 to 2 cm often can be bridged by mobilizing the severed ends of the vessel after ligating small branches. The surgeon should not be reluctant to divide small branches to obtain additional length, because most injured patients have normal vasculature, and the preservation of potential collateral flow is not as important as in revascularization for atherosclerosis. The aorta, subclavian artery, and brachial artery, however, are difficult to mobilize for additional length. To avoid postoperative stenosis, particularly in smaller arteries, beveling or spatulation should be used so that the completed anastomosis is slightly larger in diameter than the native artery (Fig. 7-43). The authors emphasize the parachute technique to ensure precision placement of the posterior suture line (Fig. 7-44). If this technique is used, traction must be maintained on both ends of the suture, or leakage from the posterior aspect of the suture line may occur. A single temporary suture 180 degrees from the posterior row may be used to maintain alignment for challenging anastomoses. Interposition grafts are used when end-to-end anastomosis cannot be accomplished without tension despite mobilization. For vessels <6 mm in diameter (e.g., internal carotid, brachial, superficial femoral, and popliteal arteries), autogenous saphenous vein from the contralateral groin should be used, because polytetrafluoroethylene (PTFE) grafts of <6 mm have a prohibitive rate of thrombosis. Larger arteries (e.g., subclavian, innominate, aorta, common iliac) are bridged by PTFE grafts. PTFE is preferred over Dacron because of the reported decreased risk of infection.62 Aortic or iliac arterial injuries may be complicated by enteric contamination from colon or small bowel injuries. There is a natural reluctance to place artificial grafts in such circumstances, but graft infections are rare and the time required to perform an axillofemoral bypass is excessive.63 Therefore, after the control of hemorrhage, bowel contamination is contained and the abdomen irrigated before placing PTFE grafts.64 After placement of the graft, it is covered with peritoneum or omentum before definitive treatment of the enteric injuries. Figure 7-44. The parachute technique is helpful for accurate placement of the posterior sutures of an anastomosis when the arterial end is fixed and an interposition graft is necessary. Traction must be maintained on both ends of the suture to prevent loosening and leakage of blood. Six stitches should be placed before the graft is pulled down to the artery. Transposition procedures can be used when an artery has a bifurcation and one vessel can be ligated safely. Injuries of the proximal internal carotid can be treated by mobilizing the adjacent external carotid, dividing it distal to the internal injury, and performing an end-to-end anastomosis between it and the distal internal carotid (Fig. 7-45). The proximal stump of the internal carotid is oversewn, with care taken to avoid a blind pocket where a clot may form. Injuries of the common and external iliac arteries can be handled in a similar fashion (Fig. 7-46), while maintaining flow in at least one internal iliac artery. Venous injuries are inherently more difficult to reconstruct due to their propensity to thrombose. Small injuries without loss of tissue can be treated with lateral suture repair. More complex repairs with interposition grafts may thrombose but this typically occurs gradually over 1 to 2 weeks. During this time adequate collateral circulation develops, which is sufficient to avoid acute venous hypertension. Therefore, it is reasonable to use ringed PTFE for venous interposition grafting and accept a gradual, but eventual, thrombosis while allowing time for collateral circulation to develop. Such an approach is reasonable for venous injuries of the superior vena cava, suprarenal vena cava, SMV, and popliteal vein because ligation of these is associated with significant morbidity. In the remainder of venous injuries the vein may be ligated. In such patients, chronic venous hypertensive complications in the lower extremities often can be avoided by (a) temporary use of elastic bandages (Ace wraps) applied from the toes to the hips at the end of the procedure, and (b) temporary continuous elevation of the lower extremities to 30 to 45 degrees. These measures should be maintained for 1 week; if the patient has no peripheral edema with ambulation, these maneuvers are no longer required. Damage Control Surgery The recognition of the bloody vicious cycle and the introduction of damage control surgery (DCS) have improved the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ A B C Figure 7-46. Transposition procedures can be used for iliac artery injuries to eliminate the dilemma of placing an interposition polytetrafluoroethylene graft in the presence of enteric contamination. A. Right common iliac artery transposed to left common iliac artery. B. Left internal iliac artery transposed to the distal right common iliac artery. C. Right internal iliac artery transposed to the right external iliac artery. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Trauma Figure 7-45. Carotid transposition is an effective approach for treating injuries of the proximal internal carotid artery. 193 CHAPTER 7 survival of critically injured patients. Conceptually, the bloody vicious cycle, first described in 1981, is the lethal combination of coagulopathy, hypothermia, and metabolic acidosis (Fig. 7-47).49 Hypothermia from evaporative and conductive heat loss and diminished heat production occurs despite the use of warming blankets and blood warmers. The metabolic acidosis of shock is exacerbated by aortic clamping, administration of vasopressors, massive RBC transfusions, and impaired myocardial performance. The acute coagulopathy of trauma, described previously, is compounded by hemodilution, hypothermia, and acidosis. Once the cycle starts, each component magnifies the other, which leads to a downward spiral and ultimately a fatal arrhythmia. The purpose of DCS is to limit operative time so that the patient can be returned to the SICU for physiologic restoration and the cycle thereby broken. Indications to limit the initial operation and institute DCS techniques include a combination of refractory hypothermia (temperature <35°C), profound acidosis, (arterial pH <7.2, base deficit <15 mmol/L), and refractory coagulopathy.49,65 The decision to abbreviate a trauma laparotomy is made intraoperatively as the patient’s clinical course becomes clearer and laboratory values become available.66 The goal of DCS is to control surgical bleeding and limit GI spillage. The operative techniques used are temporary measures, with definitive repair of injuries delayed until the patient is physiologically replete. Controlling surgical bleeding while preventing ischemia is of utmost importance during DCS. Aortic injuries must be repaired using an interposition PTFE graft. Although celiac artery injuries may be ligated, the SMA must maintain flow, and the early insertion of an intravascular shunt is advocated. Similarly, perfusion of the iliac system and infrainguinal vessels can be restored with a vascular shunt, with interposition graft placement delayed until hours later. Venous injuries are 194 Severe Trauma PART I ImmunoActivation Blood Loss BASIC CONSIDERATIONS Tissue Injury Activation/Consumption of Complement System Iatrogenic Factors Massive RBC Transfusion Core Hypothermia Cellular Shock Progressive Systemic Coagulopathy Metabolic Acidosis Hypocalcemia FF P re sis ta FF P nt se ns Acute Endogenous Coagulopathy itiv e Clotting Factor Deficiencies Pre-existing Diseases Figure 7-47. The bloody vicious cycle. FFP = fresh-frozen plasma; RBC = red blood cell. preferentially treated with ligation in damage control situations, except for the suprarenal inferior vena cava and popliteal vein. For extensive solid organ injuries to the spleen or one kidney, excision is indicated rather than an attempt at operative repair. For hepatic injuries, perihepatic packing of the liver will usually tamponade bleeding (see Fig. 7-36). Translobar gunshot wounds of the liver are best controlled with balloon catheter tamponade, whereas deep lacerations can be controlled with Foley catheter inflation deep within the injury track (Fig. 7-48). For thoracic injuries requiring DCS several options exist. For Figure 7-48. A. An intrahepatic balloon used to tamponade hemorrhage from transhepatic penetrating injuries is made by placing a red rubber catheter inside a 1-inch Penrose drain, with both ends of the Penrose drain ligated. B. Once placed inside the injury tract, the balloon is inflated with saline until hemorrhage stops. C. A Foley catheter with a 30-mL balloon can be used to halt hemorrhage from deep lacerations to the liver. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ TREATMENT OF SPECIFIC INJURIES 195 Head Injuries VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Trauma bleeding peripheral pulmonary injuries, wedge resection using a stapler is performed. In penetrating injuries, pulmonary tractotomy is used to divide the parenchyma (Fig. 7-49); individual vessels and bronchi are then ligated using a 3-0 polydioxanone suture (PDS) and the track left open. Patients who sustain more proximal injuries may require formal pulmonary resection but pneumonectomy is poorly tolerated. Cardiac injuries may be temporarily controlled using a running 3-0 nonabsorbable polypropylene suture or skin staples. Pledgeted repair should be performed for the relatively thin right ventricle. The second key component of DCS is limiting enteric content spillage. Small GI injuries (stomach, duodenum, small intestine, and colon) may be controlled using a rapid whipstitch of 2-0 polypropylene. Complete transection of the bowel or segmental damage is controlled using a GIA stapler, often with resection of the injured segment. Alternatively, open ends of the bowel may be ligated using umbilical tapes to limit spillage. Pancreatic injuries, regardless of location, are packed and the evaluation of ductal integrity postponed. Urologic injuries may require catheter diversion. Before the patient is returned to the SICU, the abdomen must be temporarily closed. Originally, penetrating towel clips were used to approximate the skin; however, the ensuing bowel edema often produces a delayed abdominal compartment syndrome. Currently, temporary closure of the abdomen is accomplished using an antimicrobial surgical incise drape (Ioban, 3M Health Care, St Paul, MN) (Fig. 7-50). In this technique, the bowel is covered with a fenestrated subfascial sterile drape (45 × 60 cm Steri-Drape 3M Health Care), and two Jackson-Pratt drains are placed along the fascial edges; this is then covered using an Ioban drape, which allows closed suction to control reperfusion-related ascitic fluid egress while providing adequate space for bowel expansion to prevent abdominal compartment syndrome. During the initial DCS stage, the subfascial sterile drape is not covered by a blue towel so that the status of the bowel and hemorrhage control can be assessed. Return to the OR within 24 hours is planned once the patient clinically improves, as evidenced by normothermia, normalization of coagulation test results, and correction of acidosis. CHAPTER 7 Figure 7-49. Pulmonary tractotomy divides the pulmonary parenchyma using either a transection/anastomosis (TA) or gastrointestinal anastomosis (GIA) stapler. The opened track permits direct access to injured vessels or bronchi for individual ligation. Intracranial Injuries CT scanning, performed on all patients with a significant closed head injury (GCS score <14), identifies and quantitates intracranial lesions. Patients with intracranial hemorrhage, including epidural hematoma, subdural hematoma, subarachnoid hemorrhage, intracerebral hematoma or contusion, and diffuse axonal injury, are admitted to the SICU. In patients with abnormal findings on CT scans and GCS scores of ≤8, intracranial pressure (ICP) should be monitored using fiberoptic intraparenchymal devices or intraventricular catheters.29 Although an ICP of 10 mm Hg is believed to be the upper limit of normal, therapy generally is not initiated until ICP is >20 mm Hg.29 Indications for operative intervention to remove spaceoccupying hematomas are based on the clot volume, amount of midline shift, location of the clot, GCS score, and ICP.29 A shift of >5 mm typically is considered an indication for evacuation, but this is not an absolute rule. Smaller hematomas that are in treacherous locations, such as the posterior fossa, may require drainage due to brain stem compression or impending herniation. Removal of small hematomas may also improve ICP and cerebral perfusion in patients with elevated ICP that is refractory to medical therapy. Patients with diffuse cerebral edema resulting in excessive ICP may require a decompressive craniectomy, although a recent AAST multicenter trial questions the benefits.67,68 Patients with open or depressed skull fractures, with or without sinus involvement, may require operative intervention. Penetrating injuries to the head require operative intervention for hemorrhage control, evacuation of blood, skull fracture fixation, or débridement. General surgeons in communities without emergency neurosurgical coverage should have a working knowledge of burr hole placement in the event that emergent evacuation is required for a life-threatening epidural hematoma (Fig. 7-51).69 The typical clinical course of an epidural hematoma is an initial loss of consciousness, a lucid interval, and recurrent loss of consciousness with an ipsilateral fixed and dilated pupil. While decompression of subdural hematomas may be delayed, epidural hematomas require evacuation within 70 minutes.68 The final stages of this sequence are caused by blood accumulation that forces the temporal lobe medially, with resultant compression of the third cranial nerve and eventually the brain stem. The burr hole is made on the side of the dilated pupil to decompress the intracranial space. After stabilization, the patient is transferred to a facility with neurosurgical capability for formal craniotomy. In addition to operative intervention, postinjury care directed at limiting secondary injury to the brain is critical. The goal of resuscitation and management in patients with head injuries is to avoid hypotension (SBP of <100 mm Hg) and hypoxia (partial pressure of arterial oxygen of <60 or arterial oxygen saturation of <90).29 Attention, therefore, is focused on maintaining cerebral perfusion rather than merely lowering ICP. Resuscitation efforts aim for a euvolemic state and an SBP of >100 mm Hg. Cerebral perfusion pressure (CPP) is equal to the mean arterial pressure minus the ICP, with a target range of >50 mm Hg.29 CPP can be increased by either lowering ICP or raising mean arterial pressure. Sedation, osmotic diuresis, paralysis, ventricular drainage, and barbiturate coma are used in sequence, with coma induction being the last resort. The partial pressure of carbon dioxide (Pco2) should be maintained in a normal range (35–40 mm Hg), but for temporary management of acute 196 PART I BASIC CONSIDERATIONS A B C D Figure 7-50. Temporary closure of the abdomen entails covering the bowel with a fenestrated subfascial 45 × 60 cm sterile drape (A), placing Jackson-Pratt drains along the fascial edge (B), and then occluding with an Ioban drape (C, D). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 197 CHAPTER 7 Trauma Figure 7-52. Three-dimensional computed tomographic scan illustrating Le Fort II maxillary (L) and alveolar (A) fractures, and fracture of the mandible (M) at the midline and at the weaker condyle (C). (Image used with permission from Vincent D. Eusterman, MD, DDS.) Figure 7-51. A burr hole is made for decompression of an epidural hematoma as a life-saving maneuver. One or more branches of the external carotid artery usually must be ligated to gain access to the skull. No attempt should be made to control intracranial hemorrhage through the burr hole. Rather, the patient’s head should be wrapped with a bulky absorbent dressing and the patient transferred to a neurosurgeon for definitive care. intracranial hypertension, inducing cerebral vasoconstriction by hyperventilation to a Pco2 of <30 mm Hg is occasionally warranted. Moderate hypothermia (32°–33°C [89.6°–91.4°F]) has been proposed to improve neurologic outcomes when maintained for at least 48 hours, but studies to date have not validated this concept.29,70,71 Patients with intracranial hemorrhage should be monitored for postinjury seizures, and prophylactic anticonvulsant therapy (e.g., phenytoin [dilantin]) is indicated for 7 days after injury. 29, 72 Maxillofacial Injuries Maxillofacial injuries are common with multisystem trauma and require coordinated management by the trauma surgeon and the specialists in otolaryngology, plastic surgery, ophthalmology, and oral and maxillofacial surgery. Delay in addressing these systems that control vision, hearing, smelling, breathing, eating, and phonation may produce dysfunction and disfigurement with serious psychological impact. The maxillofacial complex is divided into three regions; the upper face containing the frontal sinus and brain, the midface containing the orbits, nose, and zygomaticomaxillary complex, and the lower face containing the mandible. High-impact kinetic energy is required to fracture the frontal sinus, orbital rims, and mandible, whereas low-impact forces will injure the nasal bones and zygoma. The most common scenario, which at times may be lifethreatening, is bleeding from facial fractures.73 Temporizing measures include nasal packing, Foley catheter tamponade of posterior nasal bleeding, and oropharyngeal packing. Prompt angioembolization will halt exsanguinating hemorrhage. Fractures of tooth-bearing bone are considered open fractures and require antibiotic therapy and semiurgent repair to preserve the airway as well as the functional integrity of the occlusion (bite) and the aesthetics of the face. Orbital fractures may compromise vision, produce muscle injury causing diplopia, or change orbital volume to produce a sunken appearance to the orbit. Nose and nasoethmoidal fractures should be assessed carefully to identify damage to the lacrimal drainage system or to the cribriform plate producing cerebrospinal fluid rhinorrhea. After initial stabilization, a systematic physical examination of the head and neck should be performed that also includes cranial nerve examination and three-dimensional CT scanning of the maxillofacial complex (Fig. 7-52). Cervical Injuries Spine Treatment of injuries to the cervical spine is based on the level of injury, the stability of the spine, the presence of subluxation, the extent of angulation, the level of neurologic deficit, and the overall condition of the patient. In general, physiciansupervised axial traction, via cervical tongs or the more commonly used halo vest, is used to reduce subluxations and stabilize the injury. Immobilization of injuries also is achieved with spinal orthoses (braces), particularly in those with associated thoracolumbar injuries. Surgical fusion typically is performed in patients with neurologic deficit, those with angulation of >11 degrees or translation of >3.5 mm, and those who remain unstable after halo placement. Indications for immediate operative intervention are deterioration in neurologic function and fractures or dislocations with incomplete deficit. Historically, methylprednisolone was administered to patients with acute spinal cord injury after blunt injury, with clinical data suggesting VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 198 PART I BASIC CONSIDERATIONS a small benefit to initiating a 24-hour infusion if started within 3 hours and a 48-hour infusion if started 3 to 8 hours.74 Current guidelines, however, no longer recommend steroids for acute injuries.75 The role and timing of operative surgical decompression after acute spinal cord injury is debated. However, evidence supports urgent decompression of bilateral locked facets in patients with incomplete tetraplegia or with neurologic deterioration. Urgent decompression in acute cervical spinal cord injury is safe. Performing surgery within 24 hours may decrease length of stay and complications.76 Complete injuries of the spinal cord remain essentially untreatable. Yet, approximately 3% of patients who present with flaccid quadriplegia have concussive injuries, and these patients represent the very few who seem to have miraculous recoveries. Vascular Cervical vascular injuries due to either blunt or penetrating trauma can result in devastating neurologic sequelae or exsanguination. Penetrating injuries to the carotid artery and internal jugular vein usually are obvious on operative neck exploration. The principles of vascular repair techniques (discussed previously) apply to carotid injuries, and options for repair include end-to-end primary repair (often possible with mobilization of the common carotid), graft interposition, and transposition procedures. All carotid injuries should be repaired except in patients who present in coma with a delay in transport. Prompt revascularization of the internal carotid artery, using a temporary Pruitt-Inahara shunt, should be considered in patients arriving in profound shock. Otherwise, carotid shunting should be done selectively as in elective carotid endarterectomy but the patient should be systemically anticoagulated. Currently, we administer heparin with an ACT target of 250 sec. Tangential wounds of the internal jugular vein should be repaired by lateral venorrhaphy, but extensive wounds are efficiently addressed by ligation. However, it is not advisable to ligate both jugular veins due to potential intracranial hypertension. Vertebral artery injuries due to penetrating trauma are difficult to control operatively because of the artery’s protected location within the foramen transversarium. Although exposure from an anterior approach can be accomplished by removing the anterior elements of the bony canal and the tough fascia covering the artery between the elements, typically the most efficacious control of such injuries is angioembolization. Fogarty catheter balloon occlusion, however, is useful for controlling acute bleeding if encountered during neck exploration. Blunt injury to the carotid or vertebral arteries may cause dissection, thrombosis, or pseudoaneurysm, typically in the surgically inaccessible distal internal carotid (Fig. 7-53).77 Early recognition and management of these injuries is paramount, because patients treated with antithrombotics have a stroke rate of <1% compared with stroke rates of 20% in untreated patients. Because treatment must be instituted during the latent period Figure 7-53. The Denver grading scale for blunt cerebrovascular injuries. Grade I: irregularity of the vessel wall, dissection/intramural hematoma with <25% luminal stenosis. Grade II: visualized intraluminal thrombus or raised intimal flap, or dissection/intramural hematoma with 25% or more luminal narrowing. Grade III: pseudoaneurysm. Grade IV: vessel occlusion. Grade V: vessel transection. CAI = carotid artery injury; VAI = vertebral artery injury. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 9 (aspirin 325 mg/d or clopidogrel 75 mg/d). The types of antithrombotic treatment appear equivalent in published studies to date, and the duration of treatment is empirically recommended to be 6 months.79,80 The role of carotid stenting for grade III internal carotid artery injuries remain controversial. Thrombosis of the internal jugular veins caused by blunt trauma can occur unilaterally or bilaterally and is often discovered incidentally, because most patients are asymptomatic. Bilateral thrombosis 199 CHAPTER 7 between injury and onset of neurologic sequelae, diagnostic imaging is performed based on identified risk factors (Fig. 7-54).78 After identification of an injury, antithrombotics are administered if the patient does not have contraindications (intracranial hemorrhage, falling hemoglobin level with solid organ injury or pelvic fracture). Heparin, started without a loading dose at 15 units/kg per hour, is titrated to achieve a PTT between 40 and 50 seconds or antiplatelet agents are initiated Trauma Signs/Symptoms of BCVI Potential arterial hemorrhage from neck/nose/mouth Cervical bruit in pt < 50 yrs old Expanding cervical hematoma Focal neurologic defect: TIA, hemiparesis, vertebrobasilar symptoms, Horner’s Syndrome Neurologic deficit inconsistent with head CT Stroke on CT or MRI Equivocal Finding or High Clinical Suspicion Yes Negative Multi-Slice Stop CTA* Positive No Risk Factors for BCVI High energy transfer mechanism associated with: Displaced mid-face fracture (LeFort II or III) Mandible fracture Complex skull fracture/basilar skull fracture/occipital condyle fracture CHI consistent with DAI and GCS < 6 Cervical subluxation or ligamentous injury Cervical spine fractures Near hanging with anoxic brain injury Clothesline type injury or seat belt abrasion with significant swelling, pain, or altered MS TBI with thoracic injuries Scalp degloving Thoracic vascular injuries Blunt cardiac rupture Arteriogram Grade I Injury Grade II-IV Injury Surgically Accessible? Yes No Grade V Injury Surgically Accessible? Yes Operative Repair Yes No Endovascular Treatment Antithrombotic Therapy: Heparin (PTT 40-50 sec) or Antiplatelet Therapy Repeat CTA in 7-10 days Injury Healed? Yes Discontinue Antithrombotics No Antithrombotics for 3-6 months and re-image No Stop Consider endovascular stenting for severe luminal narrowing or expanding pseudoaneurysm * CTA with multidetector-row CT, 16-channel or higher. If fewer than 16 channels, interpret CTA with caution; digital subtraction arteriography is gold standard. Figure 7-54. Screening and treatment algorithm for blunt cerebrovascular injuries (BCVIs). Angio = angiography; ASA = acetylsalicylic acid; BRB = bright red blood; CHI = closed head injury; C-spine = cervical spine; CT = computed tomography; DAI = diffuse axonal injury; GCS = Glasgow Coma Scale score; MRI = magnetic resonance imaging; MS = mental status; Neg = negative; pt = patient; PTT = partial thromboplastin time; TIA = transient ischemic attack. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 200 can aggravate cerebral edema in patients with serious head injuries; stent placement should be considered in such patients if ICP remains elevated. Aerodigestive Subclinical fractures of the larynx and trachea PART I BASIC CONSIDERATIONS may manifest as cervical emphysema. Fractures documented by CT scan are usually repaired. Common injuries include thyroid cartilage fractures, rupture of the thyroepiglottic ligament, disruption of the arytenoids or vocal cord tears, and cricoid fractures. After débridement of devitalized tissue, tracheal injuries are repaired end-to-end using a single layer of interrupted absorbable sutures. Associated injuries of the esophagus are common in penetrating injuries due to its close proximity. After débridement and repair, vascularized tissue is interposed between the repaired esophagus and trachea, and a closed suction drain is placed. The sternocleidomastoid muscle or strap muscles are useful for interposition and help prevent postoperative fistulas. Chest Injuries The most common injuries from both blunt and penetrating thoracic trauma are hemothorax and pneumothorax. More than 85% of patients can be definitively treated with a chest tube. The indications for thoracotomy include significant initial or ongoing hemorrhage from the tube thoracostomy and specific imaging-identified diagnoses (Table 7-10). One caveat concerns the patient who presents after a delay. Even when the initial chest tube output is 1.5 L, if the output ceases and the lung is re-expanded, the patient may be managed nonoperatively if hemodynamically stable. Great Vessels Over 90% of thoracic great vessel injuries are due to penetrating trauma, although blunt injury to the innominate, subclavian, or descending aorta may cause a pseudoaneurysm or frank rupture.40,81,82 Simple lacerations of the ascending or transverse aortic arch can be repaired with lateral aortorrhaphy. Repair of posterior injuries, or those requiring interposition grafting of the arch, require full cardiopulmonary bypass, and repair of complex injuries may require circulatory arrest. Innominate artery injuries are repaired using the bypass exclusion technique,82 which avoids the need for cardiopulmonary A Table 7-10 Indications for operative treatment of thoracic injuries • I nitial tube thoracostomy drainage of >1000 mL (penetrating injury) or >1500 mL (blunt injury) • Ongoing tube thoracostomy drainage of >200 mL/h for 3 consecutive hours in noncoagulopathic patients • Caked hemothorax despite placement of two chest tubes • Selected descending torn aortas • Great vessel injury (endovascular techniques may be used in selected patients) • Pericardial tamponade • Cardiac herniation • Massive air leak from the chest tube with inadequate ventilation • Tracheal or main stem bronchial injury diagnosed by endoscopy or imaging • Open pneumothorax • Esophageal perforation • Air embolism bypass. Bypass grafting from the proximal aorta to the distal innominate with a prosthetic tube graft is performed before the postinjury hematoma is entered. The PTFE graft is anastomosed end to side from the proximal undamaged aorta and anastomosed end-to-end to the innominate artery (Fig. 7-55). The origin of the innominate is then oversewn at its base to exclude the pseudoaneurysm or other injury. Subclavian artery injuries can be repaired using lateral arteriorrhaphy or PTFE graft interposition; due to its multiple branches and tethering of the artery, end-to-end anastomosis is not advocated if there is a significant segmental loss. Descending thoracic aortic injuries may require urgent if not emergent intervention. However, operative intervention for intracranial or intra-abdominal hemorrhage or unstable pelvic fractures takes precedence. To prevent aortic rupture, B C Figure 7-55. A. Angiography reveals a 1-cm pseudoaneurysm of the innominate artery origin. B. In the first stage of the bypass exclusion technique, a 12-mm polytetrafluoroethylene graft is anastomosed end to side from the proximal undamaged aorta, tunneled under the vein, and anastomosed end to end to the innominate artery. C. The origin of the innominate is then oversewn at its base to exclude the pseudoaneurysm. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 201 CHAPTER 7 LA Trauma pharmacologic therapy with a selective β1 antagonist, esmolol, should be instituted in the trauma bay, with a target SBP of <100 mm Hg and heart rate of <100/min.36,83 Endovascular stenting is now the mainstay of treatment, but open operative reconstruction is warranted, or necessary, in select patients.84,85 Endovascular techniques are particularly appropriate in patients who cannot tolerate single lung ventilation, patients >60- years-old who are at risk for cardiac decompensation with aortic clamping, or patients with uncontrolled intracranial hypertension. While endograft sizing has improved, the major question is long-term outcome in younger patients. Open repair of the descending aorta is accomplished using partial left heart bypass.86 With the patient in a right lateral decubitus position, the patient’s hips and legs are rotated 45 degrees toward the supine position to gain access to the left groin for common femoral artery cannulation. Using a left posterolateral thoracotomy, the fourth rib is transected to expose the aortic arch and left pulmonary hilum. Partial left heart bypass is performed by cannulating the superior pulmonary vein with return through the left common femoral artery (Fig. 7-56). A centrifugal pump is used to provide flow rates of 2.5 to 4 L/min to maintain a distal perfusion pressure of >65 mm Hg. This prevents ischemic injury of the spinal cord as well as the splanchnic bed, and reduces left ventricular afterload.36 Heparinization is not required, a significant benefit in patients with multiple injuries, particularly in those with intracranial hemorrhage. Unless contraindicated, however, low-dose heparin (100 units/kg) typically is administered to a target ACT of 250 sec to prevent thromboembolic events. Once bypass is initiated, vascular clamps are applied on the aorta between the left common carotid and left subclavian arteries, on the left subclavian, and on the aorta distal to the injury. In most patients a short PTFE graft (usually 18 mm in diameter) is placed using a running 3-0 polypropylene suture. However, primary arterial repair should be done when possible. Air and thrombus are flushed from the aortic graft before the final suture is tied, and the occluding vascular clamps are removed. The patient is then weaned from the centrifugal pump, the cannulas are removed, and primary repair of the cannulated vessels is performed. Removal of air or potential clot in the pulmonary vein is important during decannulation to avoid left heart emboli to the systemic circulation. Figure 7-56. When repairing a tear of the descending thoracic aorta, perfusion of the spinal cord while the aorta is clamped is achieved by using partial left heart bypass. The venous cannula is inserted into the left superior pulmonary vein because it is less prone to tearing than the left atrium (LA). Heart Blunt and penetrating cardiac injuries have widely differing presentations and therefore disparate treatments. Survivable penetrating cardiac injuries consist of wounds that can be repaired operatively; most are stab wounds. Before repair of the injury is attempted, hemorrhage should be controlled; injuries to the atria can be clamped with a Satinsky vascular clamp, whereas digital pressure is used to occlude the majority of ventricular wounds. Foley catheter occlusion of larger stellate lesions may be effective, but even minimal traction may enlarge the original injury. Temporary control of hemorrhage, and at times definitive repair, may be accomplished with skin staples for left ventricular lacerations; the myocardial edges of the laceration must coapt in diastole for stapling to be technically feasible. Definitive repair of cardiac injuries is performed with either running 3-0 polypropylene suture or interrupted, pledgeted 2-0 polypropylene suture (Fig. 7-57).87 Use of Figure 7-57. A variety of techniques may be necessary to repair cardiac wounds. Generally, pledget support is used for the relatively thin-walled right ventricle. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 202 PART I BASIC CONSIDERATIONS pledgets may be particularly important in the right ventricle to prevent sutures from pulling through the thinner myocardium. Injuries adjacent to coronary arteries should be repaired using horizontal mattress sutures, because use of running sutures results in coronary occlusion and distal infarction. Gunshot wounds may result in stellate lesions or contused, extremely friable myocardium adjacent to the wound. When the edges of such complex wounds cannot be fully approximated and hence the repair is not hemostatic, the authors have used surgical adhesive (BioGlue) to achieve hemostasis.88 Occasionally, interior structures of the heart may be damaged. Intraoperative auscultation or postoperative hemodynamic assessment usually identifies such injuries.89 Echocardiography (ECHO) can diagnose the injury and quantitate its effect on cardiac output. Immediate repair of valvular damage or septal defects rarely is necessary and would require cardiopulmonary bypass, but structural intracardiac lesions may progress and, thus, patients must have a follow-up ECHO. Patients with blunt cardiac injury typically present with persistent tachycardia or conduction disturbances, but occasionally present with tamponade due to atrial or right ventricular rupture. There are no pathognomonic ECG findings, and cardiac enzyme levels do not correlate with the risk of cardiac complications.23 Therefore, patients for whom there is high clinical suspicion of cardiac contusion and who are hemodynamically stable should be monitored for dysrhythmias for 24 hours by telemetry. Patients with hemodynamic instability should undergo ECHO to evaluate for wall motion abnormalities, pericardial fluid, valvular dysfunction, chordae rupture, or diminished ejection fraction. If such findings are noted or if vasoactive agents are required, cardiac function can be continuously monitored using a pulmonary artery catheter and serial SICU transthoracic or transesophageal ECHO. Trachea, Bronchi, and Lung Parenchyma Less than 1% of all injured patients sustain intrathoracic tracheobronchial injuries, and only a small number require operative intervention. Although penetrating injuries may occur throughout the tracheobronchial system, blunt injuries most commonly occur within 2.5 cm of the carina. For patients with a massive air leak requiring emergent exploration, initial control of the injury to provide effective ventilation is obtained by passing an endotracheal tube either beyond the injury or into the contralateral mainstem bronchus. Principles of repair are similar to those for repair of cervical tracheal injuries. Devitalized tissue is débrided, and primary end-to-end anastomosis with 3-0 PDS suture is performed. Dissection should be limited to the area of injury to prevent disruption of surrounding bronchial vasculature and ensuing ischemia and stricture. Suture lines should be encircled with vascularized tissue, either pericardium, intercostal muscle, or pleura. Expectant management is employed for bronchial injuries that are less than one-third the circumference of the airway and have no evidence of a persistent major air leak.11,12 In patients with peripheral bronchial injuries, indicated by persistent air leaks from the chest tube and documented by endoscopy, bronchoscopically directed fibrin glue sealing may be useful. The majority of pulmonary parenchymal injuries are suspected based upon identification of a pneumothorax; the vast majority is managed by tube thoracostomy. Identified parenchymal injuries encountered during thoracic exploration for a massive hemothorax are managed without resection as much as possible. Peripheral lacerations with persistent bleeding can be managed with stapled wedge resection using a stapler. For central injuries, the current treatment is pulmonary tractotomy, which permits selective ligation of individual bronchioles and bleeders, prevents the development of an intraparenchymal hematoma or air embolism, and reduces the need for formal lobar resection (see Fig. 7-49).90,91 A stapling device, preferably the longest stapler available, is inserted directly into the injury track and positioned along the thinnest section of overlying parenchyma. The injury track is thus filleted open, which allows direct access to the bleeding vessels and leaking bronchi. The majority of injuries are definitively managed with selective ligation, and the defect is left open. Occasionally, tractotomy reveals a more proximal vascular injury that must be treated with formal lobectomy. Injuries severe enough to mandate pneumonectomy usually are fatal because of right heart decompensation.92 One parenchymal injury that may be discovered during thoracic imaging is a posttraumatic pulmonary pseudocyst, colloquially termed a pneumatocele.93 Traumatic pneumatoceles typically follow a benign clinical course and are treated with aggressive pain management, pulmonary toilet, and serial chest radiography to monitor for resolution of the lesion. If the patient has persistent fever or leukocytosis, however, chest CT is done to evaluate for an evolving abscess, because pneumatoceles may become infected. CT-guided catheter drainage may be required in such cases, because 25% of patients do not respond to antibiotic therapy alone. Surgery, ranging from partial resection to anatomic lobectomy, is indicated for unresolving complex pneumatoceles or infected lesions refractory to antibiotic therapy and drainage. The most common complication after thoracic injury is development of an empyema. Management is based on CT diagnostic criteria.94 Percutaneous drainage is indicated for a single loculation without appreciable rind. While fibrinolytics are often used for empyema there is a paucity of data to support their use. Early decortication via video-assisted thoracic surgery should be done promptly in patients with multiple loculations or a pleural rind of >1 cm.95 Antibiotic treatment is based on definitive culture results, but presumptive antibiotics should cover MRSA in the SICU. Esophagus Due to the proximity of the structures, esophageal injuries often occur with tracheobronchial injuries, particularly in cases of penetrating trauma. Operative options are based on the extent and location of esophageal injury. With sufficient mobilization, a primary single-layer end-to-end anastomosis may be performed after appropriate débridement. As with cervical repairs, if there are two suture lines in close approximation (trachea or bronchi and esophagus) interposition of a vascularized pedicle is warranted to prevent fistula formation. Perforations at the gastroesophageal junction may be treated with repair and Nissan fundoplication or, for destructive injuries, segmental resection and gastric pull-up. With large destructive injuries or delayed presentation of injuries, esophageal exclusion with wide drainage, diverting loop esophagostomy, and placement of a gastrostomy tube should be considered. Chest Wall and Diaphragm Virtually all chest wall injuries, consisting of rib fractures and laceration of intercostal vessels, are treated nonoperatively with pain control, pulmonary toilet or ventilatory management, and drainage of the pleural VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Abdominal Injuries Liver and Extrahepatic Biliary Tract The liver’s large size makes it the organ most susceptible to blunt trauma, and it is frequently involved in upper torso penetrating wounds. Nonoperative management of solid organ injuries is pursued in hemodynamically stable patients who do not have overt peritonitis or other indications for laparotomy. Patients with > grade II injuries should be admitted to the SICU with frequent hemodynamic monitoring, determination of hemoglobin, and abdominal examination. The only absolute contraindication to nonoperative management is hemodynamic instability. Factors such as high injury grade, large hemoperitoneum, contrast extravasation, or pseudoaneurysms may predict complications or failure of nonoperative management. Angioembolization and endoscopic retrograde cholangiopancreatography (ERCP) are useful adjuncts that can improve the success rate of nonoperative management.97,98 The indication for angiography to control hepatic hemorrhage is transfusion of 4 units of RBCs in 6 hours or 6 units of RBCs in 24 hours without hemodynamic instability. In the 15% of patients for whom emergent laparotomy is mandated, the primary goal is to arrest hemorrhage. Initial control of hemorrhage is best accomplished using perihepatic packing and manual compression. With extensive injuries and major hemorrhage a Pringle maneuver should be done immediately. Intermittent release of the Pringle is helpful to attenuate hepatic cellular loss. In either case, the edges of the liver laceration should be opposed for local pressure control of bleeding. Hemorrhage from most major hepatic injuries can be controlled with effective perihepatic packing. The right costal margin is elevated, and the pads are strategically placed over and around the bleeding site (see Fig. 7-36). Additional pads should be placed between the liver, diaphragm, and anterior chest wall until the bleeding has been controlled. Sometimes 10 to 15 pads may be required to control the hemorrhage from an extensive right lobar injury. Packing of injuries of the left lobe is not as effective, because there is insufficient abdominal and thoracic wall anterior to the left lobe to provide adequate compression with the abdomen open. Fortunately, hemorrhage from the left lobe usually can be controlled by mobilizing the lobe and compressing it between the surgeon’s hands. If the patient has persistent bleeding despite packing, injuries to the hepatic artery, portal vein, and retrohepatic vasculature should be considered. A Pringle maneuver can help delineate the source of hemorrhage. In fact, hemorrhage from hepatic artery and portal vein injuries will halt with the application of a vascular clamp across the portal triad; whereas, bleeding from the hepatic veins and retrohepatic vena cava will continue. Injuries of the portal triad vasculature should be addressed immediately. In general, ligation from the celiac axis to the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 203 Trauma Figure 7-58. Significant sternal displacement (A; arrows) can be reduced and stabilized with sternal plating (B). Regardless of the etiology, acute injuries are usually repaired through an abdominal approach to manage potential associated intraperitoneal visceral injury. After delineation of the injury, the chest should be evacuated of all blood and particulate matter, and thoracostomy tube placed if not previously done. Allis clamps are used to approximate the diaphragmatic edges, and the defect is closed with a running No. 1 polypropylene suture. Occasionally, large avulsions or shotgun wounds with extensive tissue loss will require polypropylene or biologic mesh to bridge the defect. Alternatively, transposition of the diaphragm cephalad one to two intercostal spaces may allow repair without undue tension.61 CHAPTER 7 space as indicated. Early institution of effective pain control is essential. The authors advocate pre-emptive rib blocks with 0.25% bupivacaine hydrochloride (Marcaine) in the trauma bay, followed by thoracic wall pain catheters.96 Epidural anesthesia is reserved for multiple segmental fractures. Persistent hemorrhage from a chest tube after blunt trauma most often is due to injured intercostal arteries; for unusual persistent bleeding (see Table 7-10), thoracotomy with direct ligation or angioembolization may be required to arrest hemorrhage. In cases of extensive flail chest segments or markedly displaced rib fractures, open reduction and internal fixation of the fracture with plates may be warranted. The current role of operative rib fixation remains controversial. Chest wall defects, particularly those seen with open pneumothorax, are repaired using local approximation of tissues or tissue transfer for coverage. Scapular and sternal fractures rarely require operative intervention but are markers for significant thoracoabdominal force during injury; significant displacement may benefit from sternal plating (Fig. 7-58). Careful examination and imaging should exclude associated injuries, including blunt cardiac injury and descending aortic tears. On the other hand, clavicle fractures often are isolated injuries and should be managed with pain control and immobilization. The exception is posterior dislocation of the clavicular head, which may injure the subclavian vessels. Blunt diaphragmatic injuries usually result in a linear tear, and most injuries are large, whereas penetrating injuries are variable in size and location depending on the agent of injury. 204 PART I BASIC CONSIDERATIONS level of the common hepatic artery at the gastroduodenal arterial branch is tolerated due to the extensive collaterals, but the proper hepatic artery should be repaired. The right or left hepatic artery, or in urgent situations the portal vein, may be selectively ligated; occasionally, lobar necrosis will necessitate delayed anatomic resection. If the right hepatic artery is ligated, cholecystectomy also should be performed. If the vascular injury is a stab wound with clean transection of the vessels, primary end-to-end repair is done. If the injury is destructive, temporary shunting should be performed followed by interposition reversed saphenous vein graft (RSVG). Blunt avulsions of the portal structures are particularly problematic if located at the hepatic plate, flush with the liver; hemorrhage control at the liver can be attempted with directed packing or Fogarty catheters. If the avulsion is more proximal, at the superior border of the pancreatic body or even retropancreatic, the pancreas must be transected to gain access for hemorrhage control and repair. If massive venous hemorrhage is seen from behind the liver despite use of the Pringle maneuver, the patient likely has a hepatic vein or retrohepatic vena cava injury. If bleeding can be controlled with perihepatic packing, the packing should be left undisturbed and the patient observed in the SICU. Placement of a hepatic vein stent by interventional radiology may be considered. If bleeding continues despite repeated attempts at packing, then direct repair, with or without hepatic vascular isolation, should be attempted. Three techniques have been used to accomplish hepatic vascular isolation: (a) direct repair with suprahepatic and infrahepatic clamping of the vena cava and stapled assisted parenchymal resection;99 (b) temporary shunting of the retrohepatic vena cava; and (c) venovenous bypass (Fig. 7-59).100 Figure 7-59. Venovenous bypass permits hepatic vascular isolation with continued venous return to the heart. IMV = inferior mesenteric vein; IVC = inferior vena cava; SMV = superior mesenteric vein. Numerous methods for the definitive control of hepatic parenchymal hemorrhage have been developed. Minor lacerations may be controlled with manual compression applied directly to the injury site. Topical hemostatic techniques include the use of an electrocautery (with the device set at 100 watts), argon beam coagulator, microcrystalline collagen, thrombinsoaked gelatin foam sponge, fibrin glue, and BioGlue. Suturing of the hepatic parenchyma with a blunt tipped 0 chromic suture (e.g., a “liver suture”) can be an effective hemostatic technique. A running suture is used to approximate the edges of shallow lacerations, whereas deeper lacerations are approximated using interrupted horizontal mattress sutures placed parallel to the edge of the laceration. When the suture is tied, tension is adequate when visible hemorrhage ceases or the liver blanches around the suture. Caution must be used to prevent hepatic necrosis. This technique of placing large liver sutures controls bleeding through reapproximation of the liver laceration rather than direct ligation of bleeding vessels. Aggressive finger fracture to identify bleeding vessels followed by individual clip or suture ligation was advocated previously but currently has a limited role in hemostasis. Hepatic lobar arterial ligation may be appropriate for patients with recalcitrant arterial hemorrhage from deep within the liver and is a reasonable alternative to a deep hepatotomy, particularly in unstable patients. Omentum can be used to fill large defects in the liver. The tongue of omentum not only obliterates potential dead space with viable tissue but also provides an excellent source of macrophages. Additionally, the omentum can provide buttressing support for parenchymal sutures. Translumbar penetrating injuries are particularly challenging, because the extent of the injury cannot be fully visualized. As discussed later in “Damage Control Surgery,” options include intraparenchymal tamponade with a Foley catheter or balloon occlusion (see Fig. 7-48).101 If tamponade is successful with either modality, the balloon is left inflated for 24 to 48 hours followed by sequential deflation and removal at a second laparotomy. Hepatotomy with ligation of individual bleeders occasionally may be required; however, division of the overlying viable hepatic tissue may cause considerable blood loss in the coagulopathic patient. Finally, angioembolization is an effective adjunct in any of these scenarios and should be considered early in the course of treatment. Several centers have reported patients with devastating hepatic injuries or necrosis of the entire liver who have undergone successful hepatic transplantation.102 Clearly this is dramatic therapy, and the patient must have all other injuries delineated, particularly those of the central nervous system, and have an excellent chance of survival excluding the hepatic injury. Because donor availability will limit such procedures, hepatic transplantation for trauma will continue to be performed only in extraordinary circumstances. Cholecystectomy is performed for injuries of the gallbladder and after operative ligation of the right hepatic artery. Injuries of the extrahepatic bile ducts are a challenge due to their small size and thin walls. Because of the proximity of other portal structures and the vena cava, associated vascular injuries are common. These factors may preclude primary repair. Small lacerations with no accompanying loss or devitalization of adjacent tissue can be treated by the insertion of a T tube through the wound or by lateral suturing using 6-0 monofilament absorbable suture. Virtually all transections and any injury associated with significant tissue loss will require a Roux-en-Y choledochojejunostomy.103 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 7-60. Complications after hepatic trauma include bilomas (A; arrow), hepatic duct injuries (B), and hepatic necrosis after hepatic artery ligation or embolization (C). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 205 Trauma evaluated for infectious complications, patients with complex hepatic injuries typically have intermittent “liver fever” for the first 5 days after injury. Aside from hemorrhage and hepatic necrosis, additional complications after significant hepatic trauma include bilomas, arterial pseudoaneurysms, and biliary fistulas (Fig. 7-60). Bilomas are loculated collections of bile, which may or may not be infected. If infected, they should be treated like an abscess via percutaneous drainage. Although small, sterile bilomas eventually will be reabsorbed, larger fluid collections should be drained. Biliary ascites, due to the disruption of a major bile duct, often requires reoperation and wide drainage. Primary repair of the injured intrahepatic duct is unlikely to be successful. Resectional débridement is indicated for the removal of peripheral portions of nonviable hepatic parenchyma. Pseudoaneurysms and biliary fistulas are rare complications in patients with hepatic injuries. Because hemorrhage from hepatic injuries often is treated without isolating individual bleeding vessels, arterial pseudoaneurysms may develop, with the potential for rupture. Rupture into a bile duct results in hemobilia, which is characterized by intermittent episodes of right upper quadrant pain, upper GI hemorrhage, and jaundice. If the aneurysm ruptures into a portal vein, portal venous hypertension with bleeding esophageal varices may occur. Either scenario is best managed with hepatic arteriography and CHAPTER 7 The anastomosis is performed using a single-layer interrupted technique with 5-0 monofilament absorbable suture. To reduce anastomotic tension, the jejunum should be sutured to the areolar tissue of the hepatic pedicle or porta hepatis. Injuries of the hepatic ducts are almost impossible to satisfactorily repair under emergent circumstances. One approach is to intubate the duct for external drainage and attempt a repair when the patient recovers or attempt stenting via ERC. Alternatively, the duct can be ligated if the opposite lobe is normal and uninjured. Patients undergoing perihepatic packing for extensive liver injuries typically are returned to the OR for pack removal 24 hours after initial injury. Earlier exploration may be indicated in patients with evidence of ongoing hemorrhage. Signs of rebleeding are usually conspicuous, and include a falling hemoglobin, accumulation of blood clots under the temporary abdominal closure device, and bloody output from drains; the magnitude of hemorrhage is reflected in ongoing hemodynamic instability and metabolic monitoring. Postoperative hemorrhage should be re-evaluated in the OR once the patient’s coagulopathy is corrected. Alternatively, angioembolization is appropriate for complex injuries. Patients with hepatic ischemia due to prolonged intraoperative use of the Pringle maneuver have an expected elevation but subsequent resolution of transaminase levels, whereas patients requiring hepatic artery ligation may have frank hepatic necrosis. Although febrile patients should be 206 PART I BASIC CONSIDERATIONS embolization. Biliovenous fistulas, causing jaundice due to rapid increases in serum bilirubin levels, should be treated with ERCP and sphincterotomy. Rarely, a biliary fistulous communication will form with intrathoracic structures in patients with associated diaphragm injuries, resulting in a bronchobiliary or pleurobiliary fistula. Due to the pressure differential between the biliary tract (positive) and the pleural cavity (negative), the majority require operative closure. Occasionally, endoscopic sphincterotomy with stent placement will be required to address the pressure differential, and the pleurobiliary fistula will close spontaneously. Spleen Until the 1970s, splenectomy was considered mandatory for all splenic injuries. Recognition of the immune function of the spleen refocused efforts on operative splenic salvage in the 1980s.104,105 After demonstrated success in pediatric patients, however, nonoperative management has become the preferred means of splenic salvage. The identification of contrast extravasation as a risk factor for failure of nonoperative management led to liberal use of angioembolization. The role of selective angioembolization (SAE) in splenic salvage remains controversial with some groups advocated pre-emptive SAE.106 It is clear, however, that up to 20% of patients with splenic trauma warrant early splenectomy and that failure of nonoperative management often represents inappropriate patient selection.107,108 Unlike hepatic injuries, which usually rebleed within 48 hours, delayed hemorrhage or rupture of the spleen can occur up to weeks after injury. Indications for early intervention include initiation of blood transfusion within the first 12 hours and hemodynamic instability. Splenic injuries are managed operatively by splenectomy, partial splenectomy, or splenic repair (splenorrhaphy), based on the extent of the injury and the physiologic condition of the patient. Splenectomy is indicated for hilar injuries, pulverized splenic parenchyma, or any >grade II injury in a patient with coagulopathy or multiple injuries. The authors use autotransplantation of splenic implants (Fig. 7-61) to achieve partial immunocompetence in younger patients who do not have an associated enteric injury. Drains are not used. Partial splenectomy can be employed in patients in whom only the superior or inferior pole has been injured. Hemorrhage from the raw splenic Figure 7-62. Interrupted pledgeted sutures may effectively control hemorrhage from the cut edge of the spleen. edge is controlled with horizontal mattress sutures, with gentle compression of the parenchyma (Fig. 7-62). As with hepatic injuries, splenorrhaphy hemostasis is achieved by topical methods (electrocautery; argon beam coagulation; application of thrombin-soaked gelatin foam sponges, fibrin glue, or BioGlue), envelopment of the injured spleen in absorbable mesh, and pledgeted suture repair. After splenectomy or splenorrhaphy, postoperative hemorrhage may be due to loosening of a tie around the splenic vessels, an improperly ligated or unrecognized short gastric artery, or recurrent bleeding from the spleen if splenic repair was used. An immediate postsplenectomy increase in platelets and WBCs is normal; however, beyond postoperative day 5, a WBC count above 15,000/mm3 and a platelet/WBC ratio of <20 are strongly associated with sepsis and should prompt a thorough search for underlying infection.109 A common infectious complication after splenectomy is a subphrenic abscess, which should be managed with percutaneous drainage. Additional sources of morbidity include a concurrent but unrecognized iatrogenic injury to the pancreatic tail during rapid splenectomy resulting in pancreatic ascites or fistula, and a gastric perforation during short gastric ligation. Enthusiasm for splenic salvage was driven by the rare, but often fatal, complication of overwhelming postsplenectomy Figure 7-61. Autologous splenic transplantation is performed by placing sections of splenic parenchyma, 40 × 40 × 3 mm in size, into pouches in the greater omentum. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Stomach and Small Intestine Little controversy exists VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 207 Trauma regarding the repair of injuries to the stomach or small bowel because of a rich blood supply. Gastric wounds can be oversewn with a running single-layer suture line or closed with a stapler. If a single-layer closure is chosen, full-thickness bites should be taken to ensure hemostasis from the well-vascularized gastric wall. The most commonly missed gastric injury is the posterior wound of a totally penetrating injury. Injuries also can be overlooked if the wound is located within the mesentery of the lesser curvature or high in the posterior fundus. To delineate a questionable injury, the stomach can be digitally occluded at the pylorus while methylene blue-colored saline is instilled via a nasogastric tube. Alternatively, air can be introduced via the NG tube with the abdomen filled with saline. Partial gastrectomy may be required for destructive injuries, with resections of the distal antrum or pylorus reconstructed using a Billroth procedure. Patients with injuries that damage both Latarjet nerves or vagi should undergo a drainage procedure (see Chap. 26). Small intestine injuries can be repaired using a transverse running 3-0 PDS suture if the injury is less than one- third the circumference of the bowel. Destructive injuries or multiple penetrating injuries occurring close together are treated with segmental resection followed by end-to-end anastomosis using a continuous, single-layer 3-0 polypropylene suture.111 Mesenteric injuries may result in an ischemic segment of intestine, which mandates resection. Following repair of GI tract injuries, there is an obligatory postoperative ileus. Return of bowel function is indicated by a decrease in gastrostomy or nasogastric tube output. The topic of nutrition is well covered in other chapters, but a few issues warrant mention. Multiple studies have confirmed the importance of early total enteral nutrition (TEN) in the trauma population, particularly its impact in reducing septic complications.112 The route of enteral feedings (stomach vs. small bowel) tends to be less important, because gut tolerance appears equivalent unless there is upper GI tract pathology. Although early enteral nutrition is the goal, evidence of bowel function should be apparent before advancing to goal tube feedings. Overzealous jejunal feeding can lead to small bowel necrosis in the patient recovering from profound shock. Patients undergoing monitoring for nonoperative management of grade II or higher solid organ injuries should receive nothing by mouth for at least 48 hours in case they require an operation. Although there is general reluctance to initiate TEN in patients with an open abdomen, a recent multicenter trial demonstrates TEN in the postinjury open abdomen is feasible.113 For those patients without a bowel injury, TEN was associated with higher fascial closure rates, decreased complications, and decreased mortality. TEN in patients with bowel injuries does not appear to alter fascial closure rates, complications, or mortality; hence EN appears to be neither advantageous nor detrimental in these patients. Prospective randomized controlled trials are warranted to further clarify the role of EN in this subgroup. Once resuscitation is complete, initiation of TEN, even at trophic levels (20 mL/h), should be considered in all injured patients with an open abdomen. Duodenum and Pancreas The spectrum of injuries to the duodenum includes hematomas, perforation (blunt blow-outs, lacerations from stab wounds, or blast injury from gunshot wounds), and combined pancreaticoduodenal injuries. The majority of duodenal hematomas are managed nonoperatively with nasogastric suction and parenteral nutrition. Patients with suspected associated perforation, suggested by clinical deterioration or imaging with retroperitoneal free air or contrast extravasation, should undergo operative exploration. A marked drop in nasogastric tube output heralds resolution of the hematoma, which typically occurs within 2 weeks; repeat imaging to confirm these clinical findings is optional. If the patient shows no clinical or radiographic improvement within 3 weeks, operative evaluation is warranted. Small duodenal perforations or lacerations should be treated by primary repair using a running single-layer suture of 3-0 monofilament. The wound should be closed in a direction that results in the largest residual lumen. Challenges arise when there is a substantial loss of duodenal tissue. Extensive injuries of the first portion of the duodenum (proximal to the duct of Santorini) can be repaired by débridement and end-toend anastomosis because of the mobility and rich blood supply of the distal gastric atrium and pylorus. In contrast, the second portion is tethered to the head of the pancreas by its blood supply and the ducts of Wirsung and Santorini; therefore, no more than 1 cm of duodenum can be mobilized away from the pancreas, and this does not effectively alleviate tension on the suture line. Moreover, suture repair using an end-to-end anastomosis in the second portion often results in an unacceptably narrow lumen. Therefore, defects in the second portion of the duodenum should be patched with a vascularized jejunal graft. Duodenal injuries with tissue loss distal to the papilla of Vater and proximal to the superior mesenteric vessels are best treated by Roux-en-Y duodenojejunostomy with the distal portion of the duodenum oversewn (Fig. 7-63). In particular, injuries in the distal third and fourth portions of the duodenum (behind the mesenteric vessels) should be resected, and a duodenojejunostomy performed on the left side of the superior mesenteric vessels. Optimal management of pancreatic trauma is determined by where the parenchymal damage is located and whether the intrapancreatic common bile duct and main pancreatic duct remain intact. Patients with pancreatic contusions (defined as injuries that leave the ductal system intact) can be treated nonoperatively or with closed suction drainage if undergoing laparotomy for other indications. Patients with proximal pancreatic injuries, defined as those that lie to the right of the superior mesenteric vessels, are also managed with closed suction drainage,114 In contrast, distal pancreatic injuries are managed based upon ductal integrity. Pancreatic duct disruption can be identified through direct exploration of the parenchymal laceration, operative pancreatography, ERCP, or magnetic resonance cholangiopancreatography. Patients with distal ductal disruption undergo distal pancreatectomy, preferably with splenic preservation. Injuries to the pancreatic head add an additional element of complexity because the intrapancreatic portion of the common bile duct traverses this area and often converges with the pancreatic duct. In contrast to diagnosis of pancreatic duct injuries, identification of intrapancreatic common bile duct disruption is relatively simple. The first method is to squeeze the gallbladder and look for bile leaking from the pancreatic wound. Otherwise, CHAPTER 7 sepsis. Overwhelming postsplenectomy sepsis is caused by encapsulated bacteria, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are resistant to antimicrobial treatment. In patients undergoing splenectomy, prophylaxis against these bacteria is provided via vaccines administered optimally at 14 days.110 208 PART I BASIC CONSIDERATIONS Figure 7-63. Roux-en-Y duodenojejunostomy is used to treat duodenal injuries between the papilla of Vater and superior mesenteric vessels when tissue loss precludes primary repair. cholangiography, optimally via the cystic duct, is diagnostic. Definitive treatment of this injury entails division of the common bile duct superior to the first portion of the duodenum, with ligation of the distal duct and reconstruction with a Roux-en-Y choledochojejunostomy. For injuries to the head of the pancreas that involve the main pancreatic duct but not the intrapancreatic bile duct, there are few options. Distal pancreatectomy alone is rarely indicated due to the extended resection of normal gland and the resultant risk of pancreatic insufficiency. Central pancreatectomy preserves the common bile duct, and mobilization of the pancreatic body permits drainage into a Roux-en-Y pancreaticojejunostomy (Fig. 7-64). Although this approach avoids a pancreaticoduodenectomy (Whipple procedure), the complexity may make the pancreaticoduodenectomy more appropriate in patients with multiple injuries. Some injuries of the pancreatic head do not involve either the pancreatic or common bile duct; if no clear ductal injury is present, drains are placed. Rarely, patients sustain destructive injuries to the head of the pancreas or combined pancreaticoduodenal injuries that require pancreaticoduodenectomy. Examples of such injuries include transection of both the intrapancreatic bile duct and the main pancreatic duct in the head of the pancreas, avulsion of the papilla of Vater from the duodenum, and destruction of the entire second portion of the duodenum. In these cases of extensive injuries, damage control principles are often employed. In contrast to proximal injuries, pancreatic resection continues to be advocated for major ductal disruption in the more distal pancreas. Several options exist for treating injuries of the pancreatic body and tail. In stable patients, spleen-preserving distal pancreatectomy should be performed. An alternative, Figure 7-64. For injuries of the pancreatic head that involve the pancreatic duct but spare the common bile duct, central pancreatic resection with Roux-en-Y pancreaticojejunostomy prevents pancreatic insufficiency. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 209 CHAPTER 7 Trauma Figure 7-65. A. Pyloric exclusion is used to treat combined injuries of the duodenum and the head of the pancreas as well as isolated duodenal injuries when the duodenal repair is less than optimal. B and C. The pylorus is oversewn through a gastrotomy, which is subsequently used to create a gastrojejunostomy. The authors frequently use needle-catheter jejunostomy tube feedings for these patients. which preserves both the spleen and distal transected end of the pancreas, is either a Roux-en-Y pancreaticojejunostomy or pancreaticogastrostomy. If the patient is physiologically compromised, distal pancreatectomy with splenectomy is the preferred approach. Regardless of the choice of definitive procedure, the pancreatic duct in the proximal edge of transected pancreas should be individually ligated or occluded with a TA stapler. Application of fibrin glue over the stump may be advantageous. Pyloric exclusion often is used to divert the GI stream after high-risk, complex duodenal repairs (Fig. 7-65).115 If the duodenal repair breaks down, the resultant fistula is an end fistula, which is easier to manage and more likely to close than a lateral fistula. To perform a pyloric exclusion, first a gastrostomy is made on the greater curvature near the pylorus. The pylorus is then grasped with a Babcock clamp, via the gastrostomy, and oversewn with an O polypropylene suture. A gastrojejunostomy restores GI tract continuity. Vagotomy is not necessary because a risk of marginal ulceration has not been documented. Perhaps surprisingly, the sutures maintain diversion for only 3 to 4 weeks. Alternatively, the most durable pyloric closure is a double external staple line across the pylorus using a TA stapler. Complications should be expected after major pancreaticoduodenal injuries. Delayed hemorrhage is rare but may occur with pancreatic necrosis or abdominal infection; this usually can be managed by angioembolization. If closed suction drains have been inserted for major pancreatic trauma, these should remain in place until the patient is tolerating an oral diet or enteral nutrition. Pancreatic fistula is diagnosed after postoperative day 5 in patients with drain output of >30 mL/d and a drain amylase level three times the serum value. Pancreatic fistula develops in over 20% of patients with combined injuries and should be managed similar to fistulas after elective surgery (see Chap. 33). Similarly, a duodenal fistula, presumptively an end fistula if a pyloric exclusion has been done, will typically heal in 6 to 8 weeks with adequate drainage and control of intra-abdominal sepsis. Pancreatic pseudocysts in patients managed nonoperatively suggest a missed injury, and ERCP should be done to evaluate the integrity of the pancreatic duct. Late pseudocysts may be a complication of operative management and are treated much like those in patients with pancreatitis (see Chap. 33). Intra-abdominal abscesses are common and routinely managed with percutaneous drainage. Colon and Rectum Currently, three methods for treating colonic injuries are used: primary repair, end colostomy, and primary repair with diverting ileostomy. Primary repairs include lateral suture repair or resection of the damaged segment with reconstruction by ileocolostomy or colocolostomy. All suturing and anastomoses are performed using a running single-layer technique (Fig. 7-66).111 The advantage of definitive treatment must be balanced against the possibility of anastomotic leakage if suture lines are created under suboptimal conditions. Alternatively, although use of an end colostomy requires a second operation, an unprotected suture line with the potential for breakdown is avoided. Numerous large retrospective and several prospective studies have now clearly demonstrated that primary repair is safe and effective in virtually all patients with penetrating wounds.116 Colostomy is still appropriate in a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 210 PART I BASIC CONSIDERATIONS Figure 7-66. Technique for bowel repair and anastomosis. A. The running, single-layer suture is started at the mesenteric border. B. Stitches are spaced 3 to 4 mm from the edge of the bowel and advanced 3 to 4 mm, including all layers except the mucosa. C. The continuous suture is tied near the antimesenteric border. few patients, but the current dilemma is how to select which patients should undergo the procedure. Currently, the overall physiologic status of the patient, rather than local factors, directs decision making. Patients with devastating left colon injuries requiring damage control are clearly candidates for temporary colostomy. Diverting ileostomy with colocolostomy, however, is used for most other high-risk patients. Rectal injuries are similar to colonic injuries with respect to the ecology of the luminal contents, overall structure, and blood supply of the wall, but access to extraperitoneal injuries is limited due to the surrounding bony pelvis. Therefore, indirect treatment with intestinal diversion usually is required. The current options are loop ileostomy and sigmoid loop colostomy. These are preferred because they are quick and easy to perform, and provide essentially total fecal diversion. For sigmoid colostomy, technical elements include: (a) adequate mobilization of the sigmoid colon so that the loop will rest on the abdominal wall without tension, (b) maintenance of the spur of the colostomy (the common wall of the proximal and distal limbs after maturation) above the level of the skin with a one-half-inch nylon rod or similar device, (c) longitudinal incision in the tenia coli, and (d) immediate maturation in the OR (Fig. 7-67). If the injury is accessible (e.g., in the posterior intraperitoneal portion of the rectum), repair of the injury should also be attempted. However, it is not necessary to explore the extraperitoneal rectum to repair a distal perforation. If the rectal injury is extensive, another option is to divide the rectum at the level of the injury, oversew or staple the distal rectal pouch if possible, and create an end colostomy (Hartmann’s procedure). Extensive injuries may warrant presacral drainage with Penrose drains placed along Waldeyer’s fascia via a perianal incision (see Fig. 7-67). In rare instances in which destructive injuries are present, an abdominoperineal resection may be necessary to avert lethal pelvic sepsis. Complications related to colorectal injuries include intraabdominal abscess, fecal fistula, wound infection, and stomal complications. Intra-abdominal abscesses occur in approximately 10% of patients, and most are managed with percutaneous drainage. Fistulas occur in 1% to 3% of patients and usually present as an abscess or wound infection with subsequent continuous drainage of fecal output; the majority will heal spontaneously with routine care (see Chap. 29). Stomal complications (necrosis, stenosis, obstruction, and prolapse) occur in 5% of patients and may require either immediate or delayed reoperation. Stomal necrosis should be carefully monitored, because spread beyond the mucosa may result in septic complications, including necrotizing fasciitis of the abdominal wall. Penetrating injuries that involve both the rectum and adjacent bony structures are prone to development of osteomyelitis. Bone biopsy is performed for diagnosis and bacteriologic analysis, and treatment entails longterm IV antibiotic therapy and occasionally débridement. Abdominal and Pelvic Vasculature Injury to the major arteries and veins in the abdomen can be a technical challenge.117–121 Although penetrating trauma indiscriminately affects all blood vessels, blunt trauma most commonly involves renal vasculature and occasionally the abdominal aorta. Patients with a penetrating aortic wound who survive to reach the OR frequently have a contained hematoma within the retroperitoneum. Due to lack of mobility of the abdominal aorta, few injuries are amenable to primary repair. Small lateral perforations may be controlled with 4-0 polypropylene suture or a PTFE patch, but end-to-end interposition grafting with a PTFE tube graft is the most common repair. Blunt injuries are typically extensive intimal tears of the infrarenal aorta and are exposed via a direct approach; most require an interposition graft. To avoid future vascularenteric fistulas, the vascular suture lines should be covered with omentum. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 211 CHAPTER 7 Trauma Figure 7-67. Loop colostomy will completely divert the fecal flow, allowing the low rectal injury to heal. For extensive wounds, presacral drains are inserted through a perianal incision (box) and advanced along Waldeyer’s fascia (dashed line). Penetrating wounds to the superior mesenteric artery (SMA) are typically encountered upon exploration for a gunshot wound, with “black bowel” and associated supramesocolic hematoma being pathognomonic. Blunt avulsions of the SMA are rare but should be considered in patients with a seat belt sign who have midepigastric pain or tenderness and associated hypotension. For injuries of the SMA, temporary damage control with a Pruitt-Inahara shunt can prevent extensive bowel necrosis; additionally, temporary shunting allows control of visceral contamination before placement of a PTFE graft. For definitive repair, end-to-end interposition RSVG from the proximal SMA to the SMA past the point of injury can be performed if there is no associated pancreatic injury. Alternatively, if the patient has an associated pancreatic injury, the graft should be tunneled from the distal aorta beneath the duodenum to the distal SMA. For proximal SMV injuries, digital compression for hemorrhage control is followed by attempted venorrhaphy; ligation is an option in a life-threatening situation, but the resultant bowel edema requires aggressive fluid resuscitation. Temporary abdominal closure and a second-look operation to evaluate bowel viability should be done. Transpelvic gunshot wounds or blunt injuries with associated pelvic fractures are the most common scenarios in patients with iliac artery injuries. As with abdominal vascular injuries, a Pruitt-Inahara shunt can be used for temporary shunting of the vessel for damage control. Definitive interposition grafting with excision of the injured segment is appropriate (see “Vascular Repair Techniques”). Careful monitoring for distal embolic events and reperfusion injury necessitating fasciotomy is imperative. In general, outcome after pelvic vascular injuries is related to (a) the technical success of the vascular reconstruction and (b) associated soft tissue and nerve injuries. Vascular repairs rarely fail after the first 12 hours, whereas, soft tissue infection is a limb threat for several weeks. Following aortic interposition grafting, the patient’s SBP should not exceed 120 mm Hg for at least the first 72 hours postoperatively. Patients requiring ligation of an inferior vena cava injury often develop marked bilateral lower extremity edema. To limit the associated morbidity the patient’s legs should be wrapped with elastic bandages from the toes to the hips and elevated at a 45- to 60-degree angle. For superior mesenteric vein injuries, either ligation or thrombosis after venorrhaphy results in marked bowel edema; fluid resuscitation should be aggressive and abdominal pressure monitoring routine in these patients. Prosthetic graft infections are rare complications, but prevention of bacteremia is imperative67; administration of antibiotics perioperatively and treatment of secondary infections is indicated. Long-term arterial graft complications such as stenosis or pseudoaneurysms are uncommon, and routine graft surveillance rarely is performed. Consequently, long-term administration of antiplatelet agents or antithrombotics is not routine. Genitourinary Tract When undergoing laparotomy for trauma, the best policy is to explore all penetrating wounds to the kidneys.122 Parenchymal renal injuries are treated with hemostatic and reconstructive techniques similar to those used for injuries of the liver and spleen: topical methods (electrocautery; argon beam coagulation; application of thrombin-soaked gelatin foam sponge, fibrin glue, or BioGlue) and pledgeted suture repair. Two caveats are recognized, however: The collecting system should be closed separately, and the renal capsule should be preserved to close over the repair of the collecting system (Fig. 7-68). Renal vascular injuries are common after penetrating trauma and may be deceptively tamponaded, which results in delayed hemorrhage. Arterial reconstruction using graft interposition should be attempted for renal preservation. For destructive parenchymal or irreparable renovascular injuries, nephrectomy may be the only option; a normal contralateral kidney must be palpated, because unilateral renal agenesis occurs in 0.1% of patients. Over 90% of blunt renal injuries are treated nonoperatively. Hematuria typically resolves within a few days with bed rest, although rarely bleeding is so persistent that bladder VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 212 PART I BASIC CONSIDERATIONS Figure 7-68. When renorrhaphy is undertaken, effective repair is assisted by attention to several key points: A. Vascular occlusion controls bleeding and permits adequate visualization. B. The renal capsule is carefully preserved. C. The collecting system is closed separately with absorbable suture. D. The preserved capsule is closed over the collecting system repair. irrigation to dispel blood clots is warranted. Persistent gross hematuria may require embolization, whereas urinomas can be drained percutaneously. Operative intervention after blunt trauma is limited to renovascular injuries and destructive parenchymal injuries that result in hypotension. The renal arteries and veins are uniquely susceptible to traction injury caused by blunt trauma. As the artery is stretched, the inelastic intima and media may rupture, which causes thrombus formation and resultant stenosis or occlusion. The success rate for renal artery repair approaches 0%, but an attempt is reasonable if the injury is <5 hours old or if the patient has a solitary kidney or bilateral injuries.123 Image-guided endostent placement is now employed for many of these injuries recognized by CT scanning. Reconstruction after blunt renal injuries may be difficult, however, because the injury is typically at the level of the aorta. If repair is not possible within this time frame, leaving the kidney in situ does not necessarily lead to hypertension or abscess formation. The renal vein may be torn or completely avulsed from the vena cava due to blunt trauma. Typically, the large hematoma causes hypotension, which leads to operative intervention. During laparotomy for blunt trauma, expanding or pulsatile perinephric hematomas should be explored. If necessary, emergent vascular control can be obtained by placing a curved vascular clamp across the hilum from an inferior approach. Techniques of repair and hemostasis are similar to those described earlier. Injuries to the ureters are uncommon but may occur in patients with pelvic fractures and penetrating trauma. An injury may not be identified until a complication (i.e., a urinoma) becomes apparent. If an injury is suspected during operative exploration but is not clearly identified, methylene blue or indigo carmine is administered IV with observation for extravasation. Injuries are repaired using 5-0 absorbable monofilament, and mobilization of the kidney may reduce tension on the anastomosis. Distal ureteral injuries can be treated by reimplantation facilitated with a psoas hitch and/or Boari flap. In damage control circumstances, the ureter can be ligated on both sides of the injury and a nephrostomy tube placed. Bladder injuries are subdivided into those with intraperitoneal extravasation and those with extraperitoneal extravasation. Ruptures or lacerations of the intraperitoneal bladder are operatively closed with a running, single-layer, 3-0 absorbable monofilament suture. Laparoscopic repair is becoming common in patients not requiring laparotomy for other injuries. Extraperitoneal ruptures are treated nonoperatively with bladder decompression for 2 weeks. Urethral injuries are managed by bridging the defect with a Foley catheter, with or without direct suture repair. Strictures are not uncommon but can be managed electively. Female Reproductive Tract Gynecologic injuries are rare. Occasionally the vaginal wall will be lacerated by a bone fragment from a pelvic fracture. Although repair is not mandated, it should be performed if physiologically feasible. More important, however, is recognition of the open fracture, need for possible drainage, and potential for pelvic sepsis. Penetrating injuries to the vagina, uterus, fallopian tubes, and ovaries are also uncommon, and routine hemostatic techniques are used. Repair of a transected fallopian tube can be attempted but probably is unjustified, because a suboptimal repair will increase the risk of tubal pregnancy. Transection at the injury site with proximal ligation and distal salpingectomy is a more prudent approach. Pelvic Fracture Hemorrhage Control Patients with pelvic fractures who are hemodynamically unstable are a diagnostic and therapeutic challenge for the trauma team. These injuries often occur in conjunction with other life-threatening injuries, and there is no universal agreement VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 213 Resuscitate with 2 L crystalloid – measure base deficit – rule out thoracic source (portable chest radiograph) – sheet the pelvis. If immediate red blood cell (RBC) transfusion, discuss the role pelvic packing (alert the operating room). Immediate notification: Attending Trauma Surgeon, Attending Orthopaedic Surgeon, blood bank resident, IR fellow FAST Exam Trauma Negative Positive 2 units RBCs/ED trauma bay Operating Room Laparotomy, HD Unstable HD Stable Pelvic Fixation and Pelvic Packing Assess Tube Thoracostomy Output Operating Room: Yes SICU + CT scans** Hemodynamically Stable? No Pelvic Fixation and Pelvic Packing Re-ultrasound Abdomen Assess Tube Thoracostomy Output Ongoing Transfusion Requirements after packing? (>4 units RBCs from pelvic source with normal coags) Yes No Angiography SICU ** normalize coagulation status, abdominal CT scan if no laparotomy done. Figure 7-69. Management algorithm for patients with pelvic fractures with hemodynamic instability. CT = computed tomography; ED = emergency department; FAST = focused abdominal sonography for trauma; HD = hemodynamic; PLT = platelets; PRBCs = packed red blood cells; SICU = surgical intensive care unit. among clinicians on management. Current management algorithms in the United States incorporate variable time frames for bony stabilization and fixation, as well as hemorrhage control by preperitoneal pelvic packing and/or angioembolization. Early institution of a multidisciplinary approach with the involvement of trauma surgeons, orthopedic surgeons, interventional radiologists, the director of the blood bank, and anesthesiologists is imperative due to high associated mortality rates (Fig. 7-69). Evaluation in the ED focuses on identification of injuries mandating operative intervention (e.g., massive hemothorax, ruptured spleen) and injuries related to pelvic fracture that alter management (e.g., injuries to the iliac artery). Immediate temporary stabilization with sheeting of the pelvis or application of commercially available compression devices should be performed. In high risk patients, (e.g. autopedestrian accident) with profound shock, this should be done before radiographic confirmation. If the patient’s primary source of bleeding is the fracturerelated hematoma, several options exist for hemorrhage control. Because 85% of bleeding due to pelvic fractures is venous or bony in origin the authors advocate immediate external fixation and preperitoneal pelvic packing.124,125 Anterior external fixation decreases pelvic volume, which promotes tamponade of venous bleeding and prevents secondary hemorrhage from the shifting of bony elements. Pelvic packing, in which six laparotomy pads (four in children) are placed directly into the paravesical space through a small suprapubic incision, provides tamponade for the bleeding (Fig. 7-70). Pelvic packing also eliminates the often difficult decision by the trauma surgeon: OR vs. interventional radiology? All patients can be rapidly transported to the OR and packing can be accomplished in under 30 minutes. In the authors’ experience, this results in hemodynamic stability and abrupt cessation of the need for ongoing blood transfusion in the majority of cases.125 Patients also can undergo additional procedures such as laparotomy, thoracotomy, external fixation of extremity fractures, open fracture débridement, or craniotomy. Currently, angiography is reserved for patients with evidence of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 7 Transfuse fresh frozen plasma (FFP) and RBC 1:2; 1 apheresis unit of platelets for each 5 units RBCs; perform thromboelastography. 214 PART I BASIC CONSIDERATIONS Figure 7-70. A. Pelvic packing is performed through a 6- to 8-cm midline incision made from the pubic symphysis cephalad, with division of the midline fascia. B. The pelvic hematoma often dissects the preperitoneal and paravesical space down to the presacral region, which facilitates packing; alternatively, blunt digital dissection opens the preperitoneal space for packing. C. Three standard surgical laparotomy pads are placed on each side of the bladder, deep within the preperitoneal space; the fascia is closed with an O polydioxanone monofilament suture and the skin with staples. ongoing pelvic bleeding after admission to the SICU (>4 units of RBCs in the first 12 postoperative hours after the coagulopathy is corrected). Patients undergo standard posttrauma resuscitative SICU care, and the pelvic packs are removed within 48 hours, a time frame chosen empirically based on the authors’ experience with liver packing. The authors elect to repack the patient’s pelvis if there is persistent oozing and perform serial washouts of the preperitoneal space if it appears infected. Another clinical challenge is the open pelvic fracture. In many instances the wounds are located in the perineum, and the risk of pelvic sepsis and osteomyelitis is high. To reduce the risk of infection, performance of a diverting sigmoid colostomy is recommended. The pelvic wound is manually débrided and then irrigated daily with a high-pressure pulsatile irrigation system until granulation tissue covers the wound. The wound is then left to heal by secondary intention with a wound vacuumassisted wound closure (VAC) device. Extremity Vascular Injuries, Fractures, and Compartment Syndromes Patients with injured extremities often require a multidisciplinary approach with involvement of trauma, orthopedic, and plastic surgeons to address vascular injuries, fractures, soft tissue injuries, and compartment syndromes. Immediate stabilization of fractures or unstable joints is done in the ED using Hare traction, knee immobilizers, or plaster splints. In patients with open fractures the wound should be covered with povidone iodine (Betadine)-soaked gauze and antibiotics administered. Options for fracture fixation include external fixation or open reduction and internal fixation with plates or intramedullary nails. Vascular injuries, either isolated or in combination with fractures, require emergent repair. Common combined injuries include clavicle/first rib fractures and subclavian artery injuries, dislocated shoulder/proximal humeral fractures and axillary artery injuries, supracondylar fractures/elbow dislocations and brachial artery injuries, femur fracture and superficial femoral artery injuries, and knee dislocation and popliteal vessel injuries. On-table angiography in the OR facilitates rapid intervention and is warranted in patients with evidence of limb threat at ED arrival. Arterial access for on-table lower extremity angiography can be obtained percutaneously at the femoral vessels with a standard arterial catheter, via femoral vessel exposure and direct cannulation, or with superficial femoral artery (SFA) exposure just above the medial knee. Controversy exists regarding which should be done first, fracture fixation or arterial repair. The authors prefer placement of temporary intravascular shunts first with arterial occlusions to minimize ischemia during fracture treatment, with definitive vascular repair following. Rarely, immediate amputation may be considered due to the severity of orthopedic and neurovascular injuries. This is particularly true if primary nerve transection is present in addition to fracture and arterial injury.126 Collaborative decision making by the trauma, orthopedic, and plastic/reconstructive team is essential. Operative intervention for vascular injuries should follow standard principles of repair (see “Vascular Repair Techniques”). For subclavian or axillary artery repairs, 6-mm PTFE VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 215 CHAPTER 7 Trauma Figure 7-71. A. The popliteal space is commonly accessed using a single medial incision (the detached semitendinosus, semimembranosus, and gracilis muscles are identified by different suture types). B. Alternatively, a medial approach with two incisions may be used. Insertion of a Pruitt-Inahara shunt (arrow) provides temporary restoration of blood flow, which prevents ischemia during fracture treatment. graft and RSVG are used. Because associated injuries of the brachial plexus are common, a thorough neurologic examination of the extremity is mandated before operative intervention. Operative approach for a brachial artery injury is via a medial upper extremity longitudinal incision; proximal control may be obtained at the axillary artery, and an S-shaped extension through the antecubital fossa provides access to the distal brachial artery. The injured vessel segment is excised, and an end-to-end interposition RSVG graft is performed. Upper extremity fasciotomy is rarely required unless the patient manifests preoperative neurologic changes or diminished pulse upon revascularization, or the time to operative intervention is extended. For SFA injuries, external fixation of the femur typically is performed, followed by end-to-end RSVG of the injured SFA segment. Close monitoring for calf compartment syndrome is mandatory. Preferred access to the popliteal space for an acute injury is the medial one-incision approach with detachment of the semitendinosus, semimembranosus, and gracilis muscles (Fig. 7-71). Another option is a medial approach with two incisions using a longer RSVG, but this requires interval ligation of the popliteal artery and geniculate branches. Rarely, with open wounds a straight posterior approach with an S-shaped incision can be used. If the patient has an associated popliteal vein injury, this should be repaired first with a PTFE interposition graft while the artery is shunted. For an isolated popliteal artery injury, RSVG is performed with an end-to-end anastomosis. Compartment syndrome is common, and presumptive fourcompartment fasciotomies are warranted in patients with combined arterial and venous injury. Once the vessel is repaired and restoration of arterial flow documented, completion angiography should be done in the OR if there is no palpable distal pulse. Vasoparalysis with verapamil, nitroglycerin, and papaverine may be used to treat vasoconstriction (Table 7-11). Compartment syndromes, which can occur anywhere in the extremities, involve an acute increase in pressure inside a closed space, which impairs blood flow to the structures within. Causes of compartment syndrome include arterial hemorrhage into a compartment, venous ligation or thrombosis, crush injuries, and reperfusion injury. In conscious patients, pain is the prominent symptom, and active or passive motion of muscles in the involved compartment increases the pain. Paresthesias may Table 7-11 Arterial vasospasm treatment guideline Step 1: Intra-arterial alteplase (tissue plasminogen activator) 5 mg/20 mL bolus If spasm continues, proceed to step 2. Step 2: Intra-arterial nitroglycerin 200 μg/20 mL bolus Repeat same dose once as needed. If spasm continues, proceed to step 3. Step 3: Inter-arterial verapamil 10 mg/10 mL bolus If spasm continues, proceed to step 4. Step 4: Inter-arterial papaverine drip 60 mg/50 mL given over 15 min also be described. In the lower extremity, numbness between the first and second toes is the hallmark of early compartment syndrome in the exquisitely sensitive anterior compartment and its enveloped deep peroneal nerve. Progression to paralysis can occur, and loss of pulses is a late sign. In comatose or obtunded patients, the diagnosis is more difficult to secure. In patients with a compatible history and a tense extremity, compartment pressures should be measured with a hand-held Stryker device. Fasciotomy is indicated in patients with a gradient of <35 mm Hg (gradient = diastolic pressure – compartment pressure), ischemic periods of >6 hours, or combined arterial and venous injuries. The lower extremity is most frequently involved, and compartment release is performed using a two-incision, fourcompartment fasciotomy (Fig. 7-72). Of note, the soleus muscle must be detached from the tibia to decompress the deep flexor compartment. SURGICAL INTENSIVE CARE MANAGEMENT Postinjury Resuscitation ICU management of the trauma patient, either with direct admission from the ED or after emergent operative intervention, is considered in distinct phases, because there are differing goals VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 216 PART I BASIC CONSIDERATIONS Figure 7-72. A. The anterior and lateral compartments are approached from a lateral incision, with identification of the fascial raphe between the two compartments. Care must be taken to avoid the superficial peroneal nerve running along the raphe. B. To decompress the deep flexor compartment, which contains the tibial nerve and two of the three arteries to the foot, the soleus muscle must be detached from the tibia. and priorities. The period of acute resuscitation, typically lasting for the first 12 to 24 hours after injury, combines several key principles: optimizing tissue perfusion, ensuring normothermia, and restoring coagulation. There are a multitude of management algorithms aimed at accomplishing these goals, the majority of which involve goal-directed resuscitation with initial volume loading to attain adequate preload, followed by judicious use of inotropic agents or vasopressors.127 Although the optimal hemoglobin level remains debated, during shock resuscitation a hemoglobin level of >10 g/dL is generally accepted to optimize hemostasis and ensure adequate oxygen delivery. After the first 24 hours of resuscitation, a more judicious transfusion trigger of a hemoglobin level of <7 g/dL in the euvolemic patient limits the adverse inflammatory effects of stored RBCs. The resuscitation of the severely injured trauma patient may require a considerable amount of crystalloid resuscitation, but recent trends have focused on limiting crystalloid loading. Although early colloid administration is appealing, evidence to date does not support this concept. In fact, optimizing crystalloid administra- tion is a challenging aspect of early care (i.e., balancing cardiac performance against generation of an abdominal compartment syndrome and generalized tissue edema). Invasive monitoring with pulmonary artery catheters is controversial but may be a necessary adjunct in occasional patients with multiple injuries who require advanced inotropic support. Not only do such devices allow minute-to-minute monitoring of the patient, but the added information on the patient’s volume status, cardiac function, peripheral vascular tone, and metabolic response to injury permits appropriate therapeutic intervention. With added information on the patient’s cardiac function, cardiac indices and oxygen delivery become important variables in the ongoing ICU management. Resuscitation to values of >500 mL/min per square meter for the oxygen delivery index and >3.8 L/min per square meter for the cardiac index are the goals.133 Pulmonary artery catheters also enable the physician to monitor response to vasoactive agents. Although norepinephrine is the agent of choice for patients with low systemic vascular resistance who are unable to maintain a mean arterial VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ The abdominal compartment syndrome is classified as pathologic intra-abdominal hypertension due to intra-abdominal injury (primary) or splanchnic reperfusion after massive resuscitation (secondary). Secondary abdominal compart10 ment syndrome may result from any condition requiring extensive crystalloid resuscitation, including extremity trauma, chest trauma, or even postinjury sepsis. The sources of increased intra-abdominal pressure include gut edema, ascites, bleeding, and packs. A diagnosis of intra-abdominal hypertension cannot reliably be made by physical examination; therefore, it is obtained by measuring the intraperitoneal pressure. The most common technique is to measure the patient’s bladder pressure. Fifty milliliters of saline is instilled into the bladder via the aspiration port of the Foley catheter with the drainage tube clamped, and a three-way stopcock and water manometer is placed at the level of the pubic symphysis. Bladder pressure is then measured on the manometer in centimeters of water (Table 7-12) and correlated with the physiologic impact of abdominal compartment Abdominal compartment syndrome grading system Bladder Pressure Grade mmHg cm H2O I 10–15 13–20 II 16–25 21–35 III 26–35 36–47 IV >35 >48 syndrome. Conditions in which the bladder pressure is unreliable include bladder rupture, external compression from pelvic packing, neurogenic bladder, and adhesive disease. Increased abdominal pressure affects multiple organ systems (Fig. 7-73). Abdominal compartment syndrome, as noted earlier, is defined as intra-abdominal hypertension sufficient to produce physiologic deterioration and frequently manifests via such end-organ sequelae as decreased urine output, increased pulmonary inspiratory pressures, decreased cardiac preload, and increased cardiac afterload. Because any of these clinical symptoms of abdominal compartment syndrome may be attributed to the primary injury, a heightened awareness of this syndrome must be maintained. Organ failure can occur over a wide range of recorded bladder pressures. Generally, no specific bladder pressure prompts therapeutic intervention, except when the pressure is >35 mm Hg. Rather, emergent decompression is carried out when intra-abdominal hypertension reaches a level at which end-organ dysfunction occurs. Mortality is directly affected by the timing of decompression, with 60% mortality in patients undergoing presumptive decompression, 70% mortality in patients with a delay in decompression, and nearly uniform mortality in those not undergoing decompression. Usually decompression is performed operatively, either in the ICU if the patient is hemodynamically unstable or in the OR. ICU bedside laparotomy is easily accomplished, avoids transport of hemodynamically compromised patients, and requires minimal equipment (e.g., scalpel, suction device, cautery, and dressings for temporary abdominal closure). In patients with significant intra-abdominal fluid as the primary component of abdominal compartment syndrome, rather than bowel or retroperitoneal edema, decompression can be accomplished effectively via a percutaneous drain. This method is particularly applicable for nonoperative management of major liver injuries. These patients are identified by bedside ultrasound, and the morbidity of a laparotomy is avoided. When operative decompression is required with egress of the abdominal contents, temporary coverage is obtained using a subfascial 45 × 60 cm sterile drape and Ioban application (see Fig. 7-50). The performance of damage control surgery and recognition of abdominal compartment syndrome have dramatically improved patient survival, but at the cost of an open abdomen. Several management points deserve attention. Despite having a widely open abdomen, patients can develop recurrent abdominal compartment syndrome, which increases their morbidity and mortality; therefore, bladder pressure should be monitored every 4 hours, with significant increases in pressures alerting the clinician to the possible need for repeat operative VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Trauma Abdominal Compartment Syndrome 217 Table 7-12 CHAPTER 7 pressure of >60 mm Hg, patients may have an element of myocardial dysfunction requiring inotropic support. The role of relative adrenal insufficiency is another controversial area. Optimal early resuscitation is mandatory and determines when the patient can undergo definitive diagnosis as well as when the patient can be returned to the OR after initial damage control surgery. Specific goals of resuscitation before repeated “semielective” transport include a core temperature of >35°C (95°F), base deficit of <6 mmol/L, and normal coagulation indices. Although correction of metabolic acidosis is desirable, how quickly this should be accomplished requires careful consideration. Adverse sequelae of excessive crystalloid resuscitation include increased intracranial pressure, worsening pulmonary edema, and intra-abdominal visceral and retroperitoneal edema resulting in secondary abdominal compartment syndrome. Therefore, it should be the overall trend of the resuscitation rather than a rapid reduction of the base deficit that is the goal. The goal is to normalize lactate within 24 hours. In general, wounds sustained from trauma should be examined daily for progression of healing and signs of infection. Complex soft tissue wounds of the abdomen, such as degloving injuries after blunt trauma (termed Morel-Lavallee lesions), shotgun wounds, and other destructive blast injuries, are particularly difficult to manage. Following initial débridement of devitalized tissue, wound care includes wet-to-dry dressing changes twice daily or application of a VAC device. Repeated operative débridement may be necessary, and early involvement of the reconstructive surgery service for possible flap coverage is advised. Midline laparotomy wounds are inspected 48 hours postoperatively by removing the sterile surgical dressing. If an ileostomy or colostomy is required, one should inspect it daily to ensure that it is viable. If the patient develops high-grade fever, the wound should be inspected sooner to exclude an early necrotizing infection. If a wound infection is identified— as evidenced by erythema, pain along the wound, or purulent drainage—the wound should be widely opened by removing skin staples. After ensuring that the midline fascia is intact with digital palpation, the wound is initially managed with wet-to-dry dressing changes. The most common intra-abdominal complications are anastomotic failure and abscess. The choice between percutaneous and operative therapy is based on the location, timing, and extent of the collection. 218 Increased abdominal pressure ↑ ICP PART I Compression of kidneys BASIC CONSIDERATIONS ↓ Renal blood flow ↓ UOP ↓ Venous return ↓ ↓ ↓ ↑ Extremity ischemia ↑ Intrathoracic pressure Hypoxemia CO VEDV SV SVR ↑ ↓ ↑ ↑ Splanchnic ischemia decompression. Patients with an open abdomen lose between 500 and 2500 mL per day of abdominal effluent. Appropriate volume compensation for this albumin-rich fluid remains controversial, with regard to both the amount administered (replacement based on clinical indices vs. routine ½ mL replacement for every milliliter lost) as well as the type of replacement (crystalloid vs. colloid). Following resuscitation and management of specific injuries, the goal of the operative team is to close the abdomen as quickly as possible. Multiple techniques have been introduced to obtain fascial closure of the open abdomen to minimize morbidity and cost of care. Historically, for patients who could not be closed at repeat operation, approximation of the fascia with mesh (prosthetic or biologic) was used, with planned reoperation. Another option was split-thickness skin grafts applied directly to the exposed bowel for coverage; removal of the skin grafts was planned 9 to 12 months after the initial surgery, with definitive repair of the hernia by component separation. However, delayed abdominal wall reconstruction was resource invasive, with considerable patient morbidity. The advent of VAC technology has revolutionized fascial closure. The authors currently use a sequential closure technique with the wound VAC device that is based on constant fascial tension and return to the OR every 48 hours until closure is complete (Fig. 7-74). 128 The authors’ success rate with this approach exceeds 95%. This is important because among patients not attaining fascial closure, 20% suffer GI tract complications that prolong their hospital course. These include intra-abdominal abscess, enteric fistula, and bowel perforations (Fig. 7-75). Management requires frequent operative or percutaneous drainage of abscesses, control of fistulas, and prolonged nutritional support. SPECIAL POPULATIONS Pregnant Patients Airway pressures Compliance PA pressures CVP readings During pregnancy, 7% of women are injured. Motor vehicle collisions and falls are the leading causes of injury, accounting for 70% of cases. Fetal death after trauma most frequently occurs after motor vehicle collisions, but only 11% of fetal deaths are Figure 7-73. Abdominal compartment syndrome is defined by the end organ sequelae of intra-abdominal hypertension. CO = cardiac output; CVP = central venous pressure; ICP = intracranial pressure; PA = pulmonary artery; SV = stroke volume; SVR = systemic vascular resistance; UOP = urine output; VEDV = ventricular end diastolic volume. due to the death of the mother; therefore, early trauma resuscitation and management is directed not only at the mother but also at the fetus. Domestic violence is also common, affecting between 10% and 30% of pregnant women and resulting in fetal mortality of 5%. Pregnancy results in physiologic changes that may impact postinjury evaluation (Table 7-13). Heart rate increases by 10 to 15 beats per minute during the first trimester and remains elevated until delivery. Blood pressure diminishes during the first two trimesters due to a decrease in systemic vascular resistance and rises again slightly during the third trimester (mean values: first = 105/60, second = 102/55, third = 108/67). Intravascular volume is increased by up to 8 L, which results in a relative anemia but also a relative hypervolemia. Consequently a pregnant woman may lose 35% of her blood volume before exhibiting signs of shock. Pregnant patients have an increase in tidal volume and minute ventilation but a decreased functional residual capacity; this results in a diminished Pco2 and respiratory alkalosis. Also, pregnant patients may desaturate more rapidly, particularly in the supine position and during intubation. Supplemental oxygen is always warranted in the trauma patient but is particularly critical in the injured pregnant patient, because the oxygen dissociation curve is shifted to the left for the fetus compared to the mother (i.e., small changes in maternal oxygenation result in larger changes for the fetus because the fetus is operating in the steep portions of the dissociation curve). Anatomic changes contribute to these pulmonary functional alterations and are relevant in terms of procedures. With the gravid uterus enlarged, DPL should be performed in a supraumbilical site with the catheter directed cephalad. In addition, the upward pressure on the diaphragm calls for caution when placing a thoracostomy tube; standard positioning may result in an intra-abdominal location or perforation of the diaphragm. Other physiologic changes during pregnancy affect the GI, renal, and hematologic systems. The lower esophageal sphincter has decreased competency, which increases the risk for aspiration. Liver function test values increase, with the alkaline phosphatase level nearly doubling. The high levels of progesterone impair gallbladder contractions, which results in bile stasis and an increased incidence of gallstone formation; this may not VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 219 CHAPTER 7 Trauma Figure 7-74. The authors’ sequential closure technique for the open abdomen. A. Multiple white sponges (solid arrow), stapled together, are placed on top of the bowel underneath the fascia. Interrupted No. 1 polydioxanone sutures are placed approximately 5 cm apart (dashed arrow), which puts the fascia under moderate tension over the white sponge. B. After the sticky clear plastic vacuum-assisted closure (VAC) dressing is placed over the white sponges and adjacent 5 cm of skin, the central portion is removed by cutting along the wound edges. C and D. Black VAC sponges are placed on top of the white sponges and plastic-protected skin with standard occlusive dressing and suction. E. On return to the operating room (OR) 48 hours later, fascial sutures are placed from both the superior and inferior directions until tension precludes further closure; skin is closed over the fascial closure with skin staples. F. White sponges (fewer in number) are again applied and fascial retention sutures are placed with planned return to the OR in 48 hours. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 220 Table 7-13 Physiologic effects of pregnancy PART I Cardiovascular Increase in heart rate by 10–15 bpm Decreased systemic vascular resistance resulting in: (a) Increased intravascular volume (b) Decreased blood pressure during the first two trimesters BASIC CONSIDERATIONS Pulmonary Elevated diaphragm Increased tidal volume Increased minute ventilation Decreased functional residual capacity Hematopoietic Relative anemia Leukocytosis Hypercoagulability (a) Increased levels of factors VII, VIII, IX, X, XII (b) Decreased fibrinolytic activity Other Decreased competency of lower esophageal sphincter Increased enzyme levels on liver function tests Impaired gallbladder contractions Decreased plasma albumin level Decreased blood urea nitrogen and creatinine levels Hydronephrosis and hydroureter Figure 7-75. Complications after split-thickness skin graft closure of the abdomen include enterocutaneous fistulas (intubated here with a red rubber catheter) (A; arrow) and rupture of the graft with exposure of the bowel mucosa (B). affect the trauma bay evaluation but becomes important in a prolonged ICU stay. Plasma albumin level decreases from a normal of around 4.3 g/dL to an average of 3.0 g/dL. Renal blood flow increases by 30% during pregnancy, which causes a decrease in serum level of blood urea nitrogen and creatinine. The uterus may also compress the ureters and bladder, causing hydronephrosis and hydroureter. Finally, as noted earlier there is a relative anemia during pregnancy, but a hemoglobin level of <11 g/dL is considered abnormal. Additional hematologic changes include a moderate leukocytosis (up to 20,000 mm3) and a relative hypercoagulable state due to increased levels of factors VII, VIII, IX, X, and XII and decreased fibrinolytic activity. During evaluation in the ED, the primary and secondary surveys commence, with mindfulness that the mother always receives priority while conditions are still optimized for the fetus.129 This management includes provision of supplemental oxygen (to prevent maternal and fetal hypoxia), aggressive fluid resuscitation (the hypervolemia of pregnancy may mask signs of shock), and placement of the patient in the left lateral decubitus position (or tilting of the backboard to the left) to avoid caval compression. Assessment of the fetal heart rate is the most valuable information regarding fetal viability. Fetal monitoring should be performed with a cardiotocographic device that measures both contractions and fetal heart tones (FHTs). Because change in heart rate is the primary response of the fetus to hypoxia or hypotension, anything above an FHT of 160 is a concern, whereas bradycardia (FHT of <120) is considered fetal distress. Ideally, if possible, a member of the obstetrics team should be present during initial evaluation to perform a pelvic examination using a sterile speculum. Vaginal bleeding can signal early cervical dilation and labor, abruptio placentae, or placenta previa. Amniotic sac rupture can result in prolapse of the umbilical cord with fetal compromise. Strong contractions are associated with true labor and should prompt consideration of delivery and resuscitation of the neonate. Focused prenatal history taking should elicit a history of pregnancy-induced hypertension, gestational diabetes, congenital VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Geriatric Patients Table 7-14 Physiologic effects of aging Cardiovascular Increased prevalence of heart disease Fatty deposition in the myocardium, resulting in: (a) Progressive stiffening and loss of elasticity (b) Diminished stroke volume, systolic contraction, and diastolic relaxation Decrease in cardiac output of 0.5% per year Atherosclerotic disease that limits cardiac response to stress Increased risk of coronary ischemia Thickening and calcification of the cardiac valves, which results in valvular incompetence Pulmonary Loss of compliance Progressive loss of alveolar size and surface area Air trapping and atelectasis Intracranial Loss of cerebral volume, resulting in: (a) Increased risk of tearing of bridging veins with smaller injuries (b) Accumulation of a significant amount of blood before symptoms occur Senescence of the senses Other Decline in creatinine clearance by 80%–90% Osteoporosis, which causes a greater susceptibility to fractures VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Trauma Elderly trauma patients (>65 years of age) are hospitalized twice as often as those in any other age group, and this population accounts for one quarter of all trauma admissions. Although the physiology of aging separates older trauma patients from the younger generation (Table 7-14), treatment must remain individualized (some octogenarians look and physiologically act 50 years old, whereas others appear closer to 100 years). No chronologic age is associated with a higher morbidity or mortality, but a patient’s comorbidities do impact the individual’s postinjury course and outcome. For example, recognition that a patient is taking beta blockers affects the physician’s evaluation of vital signs in the ED and impacts treatment course in the ICU. Early monitoring of arterial blood gas values will identify occult shock. A base deficit of >6 mmol/L is associated with a twofold higher risk of mortality in patients over the age of 55 than in younger patients (67% vs. 30%).133 Although the published literature on geriatric traumatic brain injury is relatively sparse and uncontrolled with regard to management, some interesting points are noted. First, outcomes are worse in this age group than in their younger counterparts. Based on data from the Traumatic Coma Databank, mortality in patients with severe head injury more than doubles after the age of 55. Moreover, 25% of patients with a normal GCS score of 15 had intracranial bleeding, with an associated mortality of 50%.123 Just as there is no absolute age that predicts outcome, admission GCS score is a poor predictor of individual outcome. 221 CHAPTER 7 heart disease, preterm labor, or placental abnormalities. Asking the patient when the baby first moved and if she is currently experiencing movement of the fetus is important. Determining fetal age is key for considerations of viability. Gestational age may be estimated by noting fundal height, with the fundus approximating the umbilicus at 20 weeks and the costal margin at 40 weeks. Discrepancy in dates and size may be due to uterine rupture or hemorrhage. Initial evaluation for abdominopelvic trauma in pregnant patients should proceed in the standard manner. Ultrasound (FAST) of the abdomen should evaluate the four windows (pericardial, right and left upper quadrant, and bladder) and additionally assess FHTs, fetal movement, and sufficiency of amniotic fluid. DPL can be performed in pregnant women via a supraumbilical, open technique. Trauma radiography of pregnant patients presents a conundrum. Radiation damage has three distinct phases of damage and effect: preimplantation, during the period of organogenesis from 3 to 16 weeks, and after 16 weeks. Generally, it is accepted that “safe” doses of radiation from radiography are <5 rad.130 A chest radiograph results in a dose of 0.07 mrad; CT scan of the chest, <1 rad; and CT scan of the abdomen, 3.5 rad. It is important, therefore, to limit radiographs to those that are essential and to shield the pelvis with a lead apron when possible. If clinically warranted, however, a radiograph should be obtained. The vast majority of injuries are treated similarly whether the patient is pregnant or not. Following standard protocols for nonoperative management of blunt trauma avoids the risks associated with general anesthesia. A particular challenge in the pregnant trauma patient is a major pelvic fracture. Because uterine and retroperitoneal veins may dilate to 60 times their original size, hemorrhage from these vessels may be torrential. Fetal loss may be related to both maternal shock and direct injury to the uterus or fetal head. Penetrating injuries in this patient population also carry a high risk. The gravid uterus is a large target, and any penetrating injury to the abdomen may result in fetal injury depending on trajectory and uterine size. Gunshot wounds to the abdomen are associated with a 70% injury rate to the uterus and 35% mortality rate of the fetus. If the bullet traverses the uterus and the fetus is viable, cesarean section should be performed. On the other hand, stab wounds do not often penetrate the thick wall of the uterus. Indications for emergent cesarean section include: (a) severe maternal shock or impending death (if the fetus is delivered within 5 minutes, survival is estimated at 70%), (b) uterine injury or significant fetal distress (anticipated survival rates of >70% if FHTs are present and fetal gestational age is >28 weeks).131 Any patient with a viable pregnancy should be monitored after trauma, with the length of monitoring determined by the injury mechanism and patient physiology. Patients who are symptomatic, defined by the presence of uterine irritability or contractions, abdominal tenderness, vaginal bleeding, or blood pressure instability, should be monitored in the hospital for at least 24 hours. In addition, patients at high risk for fetal loss (those experiencing vehicle ejection or involved in motorcycle or pedestrian collisions and those with maternal tachycardia, Injury Severity Score of >9, gestational period of >35 weeks, or history of prior assault) also warrant careful monitoring.132 Patients without these risk factors who are asymptomatic can be monitored for 6 hours in the ED and sent home if no problems develop. They should be counseled regarding warning signs that mandate prompt return to the ED. 222 PART I BASIC CONSIDERATIONS Therefore, the majority of trauma centers advocate an initial aggressive approach with re-evaluation at the 72-hour mark to determine subsequent care. One of the most common sequelae of blunt thoracic trauma is rib fractures. In the aging population, perhaps due to osteoporosis, less force is required to cause a fracture. In fact, in one study, 50% of patients >65 years old sustained rib fractures from a fall of <6 ft, compared with only 1% of patients <65 years of age. Concurrent pulmonary contusion is noted in up to 35% of patients, and pneumonia complicates the injuries in 10% to 30% of patients with rib fractures, not surprisingly leading to longer ICU stays.135,136 Additionally, mortality increases linearly with the number of rib fractures. Patients who sustain more than six rib fractures have pulmonary morbidity rates of >50% and overall mortality rates of >20%. Chronologic age is not the best predictor of outcome, but the presence of pre-existing conditions, which affect a patient’s physiologic age, is associated with increased mortality rates. Injury Severity Score is probably the best overall predictor of patient outcome in the elderly; however, for any given individual its sensitivity may not be precise, and there is a time delay in obtaining sufficient information to calculate the final score. In addition to pre-existing conditions and severity of injury, the occurrence of complications compounds the risk for mortality. Pediatric Patients Twenty million children, or almost one in four children, are injured each year, with an associated cost of treating the injured child of $16 billion per year. Injury is the leading cause of death among children over the age of 1 year, with 15,000 to 25,000 pediatric deaths per year. Disability after traumatic injury is more devastating, with rates 3 to 10 times that of the death rate. Pediatric trauma involves different mechanisms, different constellations of injury, and the potential for long-term problems related to growth and development. As with adult trauma, over 85% of pediatric trauma has a blunt mechanism, with boys injured twice as often as girls.137 Falls are the most common cause of injury in infants and toddlers. In children, bicycle mishaps are the most common cause of severe injury, whereas motor vehicle-related injury predominates in adolescence. Although unintentional injuries are by far the most common type of injuries in childhood, the number of intentional injuries, such as firearm-related injury and child abuse, is increasing. ED preparation for the pediatric trauma patient includes assembling age-appropriate equipment (e.g., intubation equipment; IV catheters, including intraosseous needles and 4F singlelumen lines), laying out the Broselow Pediatric Emergency Tape (which allows effective approximation of the patient’s weight, medication doses, size of endotracheal tube, and chest tube size), and turning on heat lamps. Upon the pediatric patient’s arrival, the basic tenets of the ABCs apply, with some caveats. In children, the airway is smaller and more cephalad in position compared with that of adults, and in children younger than 10 years, the larynx is funnel shaped rather than cylindrical as in adults. Additionally, the child’s tongue is much larger in relation to the oropharynx. Therefore, a small amount of edema or obstruction can significantly reduce the diameter of the airway (thus increasing the work of breathing), and the tongue may posteriorly obstruct the airway, causing intubation to be difficult. During intubation, a Miller (straight) blade rather than a Macintosh (curved) blade may be more effective due to the acute angle of the cephalad, funnel-shaped larynx. Administration of atropine before rapid-sequence intubation will prevent bradycardia. Adequate ventilation is critical, because oxygen consumption in infants and young children is twice that in adults; onset of hypoxemia, followed by cardiac arrest, may be precipitous. Because gastric distension can inhibit adequate ventilation, placement of a nasogastric tube may facilitate effective gas exchange. Approximately one third of preventable deaths in children are related to airway management; therefore, if airway control cannot be obtained using a standard endotracheal method, surgical establishment of an airway should be considered. In children older than 11 years, standard cricothyroidotomy is performed. Due to the increased incidence of subglottic stenosis in younger patients, needle cricothyroidotomy with either a 14- or 16-gauge catheter is advocated, although it is rarely used. Alternatively, tracheostomy may be performed. In children, the standard physiologic response to hypovolemia is peripheral vasoconstriction and reflex tachycardia; this may mask significant hemorrhagic injury, because children can compensate for up to a 25% loss of circulating blood volume with minimal external signs. “Normal” values for vital signs should not necessarily make one feel more secure about the child’s volume status. Volume restoration is based on the child’s weight; two to three boluses of 20 mL/kg of crystalloid is appropriate. After initial evaluation based on the trauma ABCs, identification and management of specific injuries proceeds. Acute traumatic brain injury is the most common cause of death and disability in any pediatric age group. Although falls are the most common mechanism overall, severe brain injury most often is due to child abuse (in children <2 years) or motor vehicle collisions (in those >2 years). Head CT should be performed to determine intracranial pathology, followed by skull radiography to diagnose skull fractures. As in adults, CPP is monitored, and appropriate resuscitation is critical to prevent the secondary insults of hypoxemia and hypovolemia. Although some data indicate that the pediatric brain recovers from traumatic injury better than the adult brain, this advantage may be eliminated if hypotension is allowed to occur. As is true in adults, the vast majority of thoracic trauma is also blunt. However, because a child’s skeleton is not completely calcified, it is more pliable. Significant internal organ damage may occur without overlying bony fractures. For example, adult patients with significant chest trauma have a 70% incidence of rib fractures, whereas only 40% of children with significant chest trauma do. Pneumothorax is treated similarly in the pediatric population; patients who are asymptomatic with a pneumothorax of <15% are admitted for observation, whereas those who have a pneumothorax of >15% or who require positive pressure ventilation undergo tube decompression. Presence of a hemothorax in this age group may be particularly problematic, because the child’s chest may contain his or her entire blood volume. If the chest tube output is initially 20% of the patient’s blood volume (80 mL/kg) or is persistently >1 to 2 mL/ kg per hour, thoracotomy should be considered. Aortic injuries are rare in children, and tracheobronchial injuries are more amenable to nonoperative management. Thoracic injuries are second only to brain injuries as the main cause of death according to the National Pediatric Trauma Registry; however, the overall mortality rate of 15% correlates with the levels in many adult studies. The evaluation for abdominal trauma in the pediatric patient is similar to that in the adult. FAST is valid in the pediatric VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Entries highlighted in bright blue are key references.    1. Minino AM, Heron MP, Murphy SL, et al. Deaths: final data for 2004. Natl Vital Stat Rep. 55, August 21, 2007; 55(19): 1-120. Available at http://www.cdc.gov/nchs/data/nvsr/ nvsr55/nvsr55_19.pdf [accessed October 29, 2012].   2. National Center for Injury Prevention and Control: CDC Injury Fact Book. Atlanta: Centers for Disease Control and Prevention, November 2006. Available at http://www.cdc. gov/ncipc/fact_book/InjuryBook2006.pdf [accessed October 29, 2012].    3. Esposito TJ and Brasel KJ. Epidemiology. Mattox KL, Moore EE, Feliciano DV (eds): Trauma, 7th ed. New York: McGrawHill, 2013.    4. Eastman AB. Wherever the dart lands: toward the ideal trauma system. J Am Coll Surg. 2010;211(2):153-168.    5. MacKenzie EJ, Rivara FP, Jurkovich GJ, et al. A national evaluation of the effect of trauma-center care on mortality. N Engl J Med. 2006;354(4):366-378.   6. American College of Surgeons: Advanced Trauma Life Support, 9th ed. Chicago: American College of Surgeons, 2012.    7. Haut ER, Kalish BT, Efron DT, et al. Spine immobilization in penetrating trauma: more harm than good? J Trauma. 2010;68(1):115-120.    8. Lustenberger T, Talving P, Lam L, et al. Unstable cervical spine fracture after penetrating neck injury: a rare entity in an analysis of 1,069 patients. J Trauma. 2011;70(4):870-872.    9. Sakles JC, Mosier JM, Chiu S, Keim SM. Tracheal intubation in the emergency department: a comparison of GlideScope video laryngoscopy to direct laryngoscopy in 822 intubations. J Emerg Med. 2012;42(4):400-405. 10. Inaba K, Ives C, McClure K, et al. Radiologic evaluation of alternative sites for needle decompression of tension pneumothorax. Arch Surg. 2012;147(9):813-818. 11. Carretta A, Melloni G, Bandiera A, Negri G, Voci C, Zannini P. Conservative and surgical treatment of acute posttraumatic tracheobronchial injuries. World J Surg. 2011;35(11):2568-2574. 12. Gómez-Caro A, Ausín P, Moradiellos FJ, et al. Role of conservative medical management of tracheobronchial injuries. J Trauma. 2006;61(6):1426-1434. 13. Demetriades D, Chan LS, Bhasin P, et al. Relative bradycardia in patients with traumatic hypotension. J Trauma. 1998;45(3):534-539. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 223 Trauma REFERENCES 14. Voigt J, Waltzman M, Lottenberg L. Intraosseous vascular access for in-hospital emergency use: a systematic clinical review of the literature and analysis. Pediatr Emerg Care. 2012;28(2):185-199. 15. Weiser G, Hoffmann Y, Galbraith R, Shavit I. Current advances in intraosseous infusion - a systematic review. Resuscitation. 2012;83(1):20-26. 16. Callaham M. Pericardiocentesis in traumatic and nontraumatic cardiac tamponade. Ann Emerg Med. 1984;13(10):924-945. 17. Burlew CC, Moore EE, Moore FA, et al. Western trauma association critical decisions in Trauma: resuscitative thoracotomy. J Trauma, in press. 18. Moore EE, Knudson MM, Burlew CC, et al. WTA Study Group. Defining the limits of resuscitative emergency department thoracotomy: a contemporary Western Trauma Association perspective. J Trauma. 2011;70(2):334-339. 19. Ouellet JF, Roberts DJ, Tiruta C, et al. Admission base deficit and lactate levels in Canadian patients with blunt trauma: are they useful markers of mortality? J Trauma Acute Care Surg. 2012;72(6):1532-1535. 20. Callaway DW, Shapiro NI, Donnino MW, Baker C, Rosen CL. Serum lactate and base deficit as predictors of mortality in normotensive elderly blunt trauma patients. J Trauma 2009;66(4):1040-1044. 21. Kliegel A, Losert H, Sterz F, et al. Serial lactate determinations for prediction of outcome after cardiac arrest. Medicine (Baltimore) 2004;83(5):274-279. 22. Cohn SM, Nathens AB, Moore FA, et al. Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation. J Trauma. 2007;62:44-54. 23. Clancy K, Velopulos C, Bilaniuk JW, et al. Screening for blunt cardiac injury: An an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg. 2012;73:S301-S306. 24. Velmahos GC, Karaiskakis M, Salim A, et al. Normal electrocardiography and serum troponin I levels preclude the presence of clinically significant blunt cardiac injury. J Trauma. 2003;54(1):45-50. 25. Ferrada P, Murthi S, Anand RJ, Bochicchio GV, Scalea T. Transthoracic focused rapid echocardiographic examination: real-time evaluation of fluid status in critically ill trauma patients. J Trauma. 2011;70:56-62. 26. Arntfield RT, Millington SJ. Point of care cardiac ultrasound applications in the emergency department and intensive care unit–a review. Curr Cardiol Rev. 2012;8(2):98-108. 27. Dolich MO, McKenney MG, Varela JE, et al. 2,576 ultrasounds for blunt abdominal trauma. J Trauma. 2001; 50: 108-112. 28. Sondeen JL, Coppes VG, Holcomb JB. Blood pressure at which rebleeding occurs after resuscitation in swine with aortic injury. J Trauma. 2003; 54(Suppl):S110-S117. 29. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 24(Suppl):S1, 2007. 30. Ryb GE, Dischinger PC, Kufera JA, et al. Delta V, principal direction of force, and restraint use contributions to motor vehicle crash mortality. J Trauma. 2007;63:1000-1005. 31. Ivascu FA, Howells GA, Junn FS, Bair HA, Bendick PJ, Janczyk RJ. Predictors of mortality in trauma patients with intracranial hemorrhage on preinjury aspirin or clopidogrel. J Trauma. 2008;65(4):785-788. 32. Moore MM, Pasquale MD, Badellino M. Impact of age and anticoagulation: need for neurosurgical intervention in trauma patients with mild traumatic brain injury. J Trauma Acute Care Surg. 2012;73(1):126-130. 33. Diaz JJ Jr., Aulino JM, Collier B, et al. The early work-up for isolated ligamentous injury of the cervical spine: Does does CHAPTER 7 age group to detect intra-abdominal fluid.138 The mechanism of injury often correlates with specific injury patterns. A child sustaining a blow to the epigastrium (e.g., hitting the handlebars during a bike accident) should be evaluated for a duodenal hematoma and/or a pancreatic transection. After a motor vehicle collision in which the patient was wearing a passenger restraint, injuries comprising the “lap belt complex” or “seat belt syndrome” (i.e., abdominal wall contusion, small bowel perforation, flexion-distraction injury of the lumbar spine, diaphragm rupture, and occasionally abdominal aortic dissection) may exist. Nonoperative management of solid organ injuries, first used in children, is the current standard of care in the hemodynamically stable patient. If the patient shows clinical deterioration or hemodynamic lability, has a hollow viscus injury, or requires >40 mL/kg of packed RBCs, continued nonoperative management is not an option. Success rates of nonoperative management approach 95%, with an associated 10% to 23% transfusion rate. Blood transfusion rates, however, are significantly lower in patients managed nonoperatively than in patients undergoing operation (13% vs. 44%).139 224 PART I BASIC CONSIDERATIONS computed tomography scan have a role? J Trauma. 2005; 59:897-903. 34. Sekharan J, Dennis JW, Veldenz HC, et al. Continued experience with physical examination alone for evaluation and management of penetrating zone 2 neck injuries: Results results of 145 cases. J Vasc Surg. 2000;32:483-489. 35. Inaba K, Branco BC, Menaker J, et al. Evaluation of multidetector computed tomography for penetrating neck injury: a prospective multicenter study. J Trauma Acute Care Surg. 2012;72:576-583. 36. Fabian TC, Richardson JD, Croce MA, et al. Prospective study of blunt aortic injury: multicenter trial of the American Association for the Surgery of Trauma. J Trauma Trauma. 1997;42:374-380, 37. Dyer DS, Moore EE, Ilke DN, et al. Thoracic aortic injury: how predictive is mechanism and is chest computed tomography a reliable screening tool? A prospective study of 1,561 patients. J Trauma. 2000;48:673-682. 38. Siegel JH, Smith JA, Siddiqi SQ. Change in velocity and energy dissipation on impact in motor vehicle crashes as a function of the direction of crash: key factors in the production of thoracic aortic injuries, their pattern of associated injuries and patient survival. A Crash Injury Research Engineering Network (CIREN) study. J Trauma 2004;57(4):760-777. 39. Flowers JL, Graham SM, Ugarte MA, et al. Flexible endoscopy for the diagnosis of esophageal trauma. J Trauma. 1996; 40:261-265. 40. Cox CS Jr., Allen GS, Fischer RP, et al. Blunt vs. penetrating subclavian artery injury: Presentation, injury pattern, and outcome. J Trauma .1999;46:445-449. 41. Demetriades D, Hadjizacharia P, Constantinou C, et al. Selective nonoperative management of penetrating abdominal solid organ injuries. Ann Surg. 2006; 244:620-628. 42. Biffl WL, Cothren CC, Brasel KJ, et al. A prospective observational multicenter study of the optimal management of patients with anterior abdominal stab wounds. J Trauma. 2008; 64:250. 43. Biffl WL, Kaups KL, Pham TN, et al. Validating the Western Trauma Association algorithm for managing patients with anterior abdominal stab wounds: a Western Trauma Association multicenter trial. J Trauma. 2011;71(6):1494-1502. 44. Ochsner MG, Knudson MM, Pachter HL, et al. Significance of minimal or no intraperitoneal fluid visible on CT scan associated with blunt liver and splenic injuries: A a multicenter analysis. J Trauma. 2000; 49:505-510. 45. Yu J, Fulcher AS, Turner MA, Cockrell C, Halvorsen RA. Blunt bowel and mesenteric injury: MDCT diagnosis. Abdom Imaging. 2011;36(1):50-61. 46. LeBedis CA, Anderson SW, Soto JA. CT imaging of blunt traumatic bowel and mesenteric injuries. Radiol Clin North Am. 2012;50(1):123-136. 47. Fox N, Rajani RR, Bokhari F, et al. Evaluation and management of penetrating lower extremity arterial trauma: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg. 2012;73:S315-S320. 48. Burch JM, Franciose RJ, Moore EE, et al. Single-layer continuous vs. two-layer interrupted intestinal anastomosis—a prospective randomized study. Ann Surg. 2000; 231:832-837. 49. Moore EE. Thomas G. Orr Memorial Lecture.Staged laparotomy for the hypothermia, acidosis, and coagulopathy syndrome. Am J Surg. 1996;172:405-410. 50. Gonzalez E, Pieracci FM, Moore EE, Kashuk JL. Coagulation abnormalities in the trauma patient: the role of point-of-care thromboelastography. Semin Thromb Hemost. 2010;36:723-737. 51. Cohen MJ, Call M, Nelson M, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012;255(2): 379-385. 52. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012;73(2):365-370. 53. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. New Engl J Med. 1999; 340:409-417. 54. West MA, Shapiro MB, Nathens AB, et al. Inflammation and the host response to injury, a large-scale collaborative project: Patient-oriented research core-standard operating procedures for clinical care. IV. Guidelines for transfusion in the trauma patient. J Trauma. 2006; 61:436-439. 55. Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005; 33:721-726. 56. Moore FA, Moore EE, Sauaia A. Blood transfusion: an independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132:620-624. 57. Kashuk JL, Moore EE, Sauaia A, et al. Postinjury life- threatening coagulopathy: is 1:1 fresh frozen plasma: packed red blood cells the answer? J Trauma. 2008;65:261-270. 58. Davenport R, Curry N, Manson J, et al. Hemostatic effects of fresh frozen plasma may be maximal at red cell ratios of 1:2. J Trauma. 2011;70(1):90-95. 59. Stanworth SJ, Morris TP, Gaarder C, et al. Reappraising the concept of massive transfusion in trauma. Crit Care. 2010;14(6):R239. 60. Dzik WH, Blajchman MA, Fergusson D, et al. Clinical review: Canadian National Advisory Committee on Blood and Blood Products–Massive transfusion consensus conference 2011: report of the panel. Crit Care. 2011;15(6):242. 61. Menaker J, Stein DM, Scalea TM. Incidence of early pulmonary embolism after injury. J Trauma. 2007; 63:620-624. 62. Prager M, Polterauer P, Böhmig HJ, et al. Collagen vs. gelatin-coated Dacron vs. stretch polytetrafluoroethylene in abdominal aortic bifurcation graft surgery: results of a sevenyear prospective, randomized multicenter trial. Surgery. 2001;130(3):408-414. 63. Mattox KL. Red River anthology. J Trauma. 1997;42(3): 353-368. 64. Richardson JD, Bergamini TM, Spain DA, et al. Operative strategies for management of abdominal aortic gunshot wounds. Surgery. 1996;120(4):667-671. 65. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma. 1997;42(5):857-861. 66. Maegele M, Spinella PC, Schöchl H. The acute coagulopathy of trauma: mechanisms and tools for risk stratification. Shock. 2012;38(5):450-458. 67. Nirula R, Millar D, Greene T, et al. Decompressive craniectomy for medical management for refractory intracranial hypertension: An AAST-MITC propensity score analysis. J Trauma, in press. 68. Cooper DJ, Rosenfeld JV, Murray L, et al. DECRA Trial Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011;364(16):1493-1502. 69. Rinker C, McMurry F, Groeneweg V, et al. Emergency craniotomy in a rural level III trauma center. J Trauma. 1998; 44:984-989. 70. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008;358(23):2447-2456. 71. Kramer C, Freeman WD, Hoffman-Snyder C, et al. Therapeutic hypothermia for severe traumatic brain injury: a critically appraised topic. Neurologist. 2012;18(3):173-177. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 225 Trauma and increased pulmonary vascular resistance. Ann Surg. 1990;212:197-201. 93. Luo L, Yin L, Liu Z, Xiang Z. Posttraumatic pulmonary pseudocyst: Computed tomography findings and management in 33 patients. J Trauma and Acute Care Surg. 2012;73(5): 1225-1228. 94. Moore HB, Moore EE, Burlew CC, et al. Western Trauma Association critical decisions in trauma: Management management of parapneumonic effusion. J Trauma Acute Care Surg. 2012;73: 1372-1379. 95. de Souza A, Offner PJ, Moore EE, et al. Optimal management of complicated empyema. Am J Surg. 2000; 180:507-511. 96. Truitt MS, Murry J, Amos J, et al. Continuous intercostal nerve blockade for rib fractures: ready for primetime? J Trauma. 2011;71(6):1548-1552. 97. Kozar RA, Moore FA, Cothren CC, et al. Risk factors for hepatic morbidity following nonoperative management: multicenter study. Arch Surg. 2006; 141:451-458. 98. Malhotra AK, Fabian TC, Croce MA, et al. Blunt hepatic injury: a paradigm shift from operative to nonoperative management in the 1990s. Ann Surg . 2000;231:804-813. 99. Peitzman AB, Marsh JW. Advanced operative techniques in the management of complex liver injury. J Trauma Acute Care Surg. 2012;73(3):765-770. 100. Biffl WL, Moore EE, Franciose RJ. Venovenous bypass and hepatic vascular isolation as adjuncts in the repair of destructive wounds to the retrohepatic inferior vena cava. J Trauma. 1998; 45:400-403. 101. Poggetti RS, Moore EE, Moore FA, et al. Balloon tamponade for bilobar transfixing hepatic gunshot wounds. J Trauma. 1992; 33:694-697. 102. Delis SG, Bakoyiannis A, Selvaggi G, et al. Liver transplantation for severe hepatic trauma: experience from a single center. World J Gastroenterol. 2009;15(13):1641-1644. 103. Lillemoe KD, Melton GB, Cameron JL, et al. Postoperative bile duct strictures: management and outcome in the 1990s. Ann Surg. 2000;232:430-441. 104. Pickhardt B, Moore EE, Moore FA, et al. Operative splenic salvage in adults: a decade perspective. J Trauma. 1989; 29: 1386-1391. 105. Feliciano DV, Spjut-Patrinely V, Burch JM, et al. Splenorrhaphy: the alternative. Ann Surg. 1990; 211:569-580. 106. Stassen NA, Bhullar I, Cheng JD, et al. Selective nonoperative management of blunt splenic injury: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma and Acute Care Surg. 2012;73(5):S294-S300. 107. McIntyre LK, Schiff M, Jurkovich GJ. Failure of nonoperative management of splenic injuries: Causes and consequences. Arch Surg. 2005;140:563-568. 108. Smith HE, Biffl WL, Majercik SD, et al. Splenic artery embolization: have we gone too far? J Trauma. 2006; 61:541-546. 109. Toutouzas KG, Velmahos GC, Kaminski A, et al. Leukocytosis after posttraumatic splenectomy: a physiologic event or sign of sepsis? Arch Surg. 2002; 137:924-928. 110. Howdieshell TR, Heffernan D, Dipiro JT. Therapeutic Agents Committee of the Surgical Infection Society. Surgical infection society guidelines for vaccination after traumatic injury. Surg Infect (Larchmt). 2006;7(3):275-303. 111. Burch JM, Franciose RJ, Moore EE, et al. Single-layer continuous vs. two-layer interrupted intestinal anastomosis: a prospective randomized trial. Ann Surg Surg. 2000;231: 832-837. 112. Todd SR, Kozar RA, Moore FA. Nutrition support in adult trauma patients. Nutr Clin Pract. 2006; 21:421-429. 113. Burlew CC, Moore EE, Cuschieri J, et al; the WTA Study Group. Who should we feed? Western Trauma Association multiinstitutional study of enteral nutrition in the open abdomen after injury. J Trauma Acute Care Surg. 2012;73:1380-1387. CHAPTER 7 72. Pieracci FM, Moore EE, Beauchamp K, et al. A costminimization analysis of phenytoin vs. levetiracetam for early seizure pharmacoprophylaxis after traumatic brain injury. J Trauma Acute Care Surg. 2012;72(1):276-281. 73. Cogbill T, Cothren CC, Ahearn MK, et al. Management of severe hemorrhage associated with maxillofacial injuries: a multicenter perspective. J Trauma. 2008; 64:250. 74. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA. 1997;277:1597-1604. 75. Stahel PF, Vanderheiden T, Finn MA. Management strategies for acute spinal cord injury: current options and future perspectives. Curr Opin Crit Care. 2012;18(6):651-660. 76. Fehlings MG, Perrin RG: The timing of surgical intervention in the treatment of spinal cord injury: a systematic review of recent clinical evidence. Spine. 2006; 31:S28,-S35. 77. Biffl WL, Moore EE, Offner PJ, et al. Blunt carotid arterial injuries: implications of a new grading scale. J Trauma. 1999; 47:845-853. 78. Burlew CC, Biffl WL, Moore EE, Barnett CC, Johnson JL, Bensard DD. Blunt cerebrovascular injuries: redefining screening criteria in the era of noninvasive diagnosis. J Trauma Acute Care Surg. 2012;72(2):330-335. 79. Cothren CC, Moore EE, Biffl WL, et al. Anticoagulation is the gold standard therapy for blunt carotid injuries to reduce stroke rate. Arch Surg. 2004; 139:540-545. 80. Edwards NM, Fabian TC, Claridge JA, et al. Antithrombotic therapy and endovascular stents are effective treatment for blunt carotid injuries: results from long-term followup. J Am Coll Surg. 2007; 204:1007-1013. 81. Bladergroen M, Brockman R, Luna G, et al. A twelveyear study of cervicothoracic vascular injuries. Am J Surg. 1989;157:483-486. 82. Johnston RH, Wall MJ, Mattox KL. Innominate artery trauma: a thirty-year experience. J Vasc Surg. 1993; 17:134-139. 83. Fabian TC, Davis KA, Gavant ML, et al. Prospective study of blunt aortic injury: helical CT is diagnostic and antihypertensive therapy reduces rupture. Ann Surg. 1998;227:666. 84. Karmy-Jones R, Nicholls S, Gleason TG. The endovascular approach to acute aortic trauma. Thorac Surg Clin. 2007; 17:109-128. 85. Demetriades D, Velmahos GC, Scalea TM, et al. Diagnosis and treatment of blunt thoracic aortic injuries: changing perspectives. J Trauma. 2008;64(6):1415-1418. 86. Moore EE, Burch JM, Moore JB. Repair of the torn descending thoracic aorta using the centrifugal pump with partial left heart bypass. Ann Surg. 2004; 240:38-43. 87. Wall MJ, Tsai P, Mattox KL. Heart and Thoracic Vascular Injury. Mattox KL, Moore EE, Feliciano DV (eds): Trauma, 7th ed. New York: McGraw-Hill, 2013. 88. Jones EL, Burlew CC, Moore EE. BioGlue hemostasis of penetrating cardiac wounds in proximity to the left anterior descending coronary artery. J Trauma Acute Care Surg. 2012;72(3):796-798. 89. Cothren CC, Moore EE. Traumatic ventricular septal defect. Surgery. 2007;142:776-777. 90. Wall MJ Jr., Hirshberg A, Mattox KL. Pulmonary tractotomy with selective vascular ligation for penetrating injuries to the lung. Am J Surg. 1994; 168:665-669. 91. Cothren C, Moore EE, Biffl WL, et al. Lung-sparing techniques are associated with improved outcome compared with anatomic resection for severe lung injuries. J Trauma 2002;53:483-487. 92. Cryer HG, Mavroudis C, Yu J, et al. Shock, transfusion, and pneumonectomy. Death is due to right heart failure 226 PART I BASIC CONSIDERATIONS 114. Sharpe JP, Magnotti LJ, Weinberg JA, et al. Impact of a defined management algorithm on outcome after traumatic pancreatic injury. J Trauma Acute Care Surg. 2012;72: 100-105. 115. Vaughn GD, Frazier OH, Graham D, et al. The use of pyloric exclusion in the management of severe duodenal injuries. Am J Surg. 1977;134:785. 116. Nelson R, Singer M. Primary repair for penetrating colon injuries. Cochrane Database Syst Rev 3:CD002247, 2003. 117. Asensio JA, Britt LD, Borzotta A, et al. Multi-institutional experience with the management of superior mesenteric artery injuries. J Am Coll Surg. 2001;193:354-356. 118. Burch JM, Richardson RJ, Martin RR, et al. Penetrating iliac vascular injuries: experience with 233 consecutive patients. J Trauma. 1990; 30:1450-1459. 119. Mullins RJ, Lucas CE, Ledgerwood AM. The natural history following venous ligation for civilian injuries. J Trauma. 1980;20:737-743. 120. Roth SM, Wheeler JR, Gregory RT, et al. Blunt injury of the abdominal aorta: a review. J Trauma. 1997; 42:748-755. 121. Jurkovich GJ, Hoyt DB, Moore FA, et al. Portal triad injuries. J Trauma. 1995;39:426-434. 122. Voelzke BB, McAninch JW. Renal gunshot wounds: clinical management and outcome. J Trauma. 2009;66(3):593-600. 123. Knudson MM, Harrison PB, Hoyt DB, et al. Outcome after major renovascular injuries: A Western trauma association multicenter report. J Trauma. 2000; 49:1116-1122. 124. Cothren CC, Osborn PM, Moore EE, et al: Preperitoneal pelvic packing for hemodynamically unstable pelvic fractures: A paradigm shift. J Trauma. 62:834-839. 125. Burlew CC, Moore EE, Smith WR, et al. Preperitoneal pelvic packing/external fixation with secondary angioembolization: optimal care for life-threatening hemorrhage from unstable pelvic fractures. J Am Coll Surg. 2011;212(4):628-635. 126. Bosse MJ, MacKenzie EJ, Kellam JF, et al. An analysis of outcomes of reconstruction or amputation of leg-threatening injuries. N Engl J Med . 2002;347:1924-1931. 127. Moore FA, McKinley BA, Moore EE, et al. Inflammation and the Host Response to Injury, a large-scale collaborative project: patient-oriented research core—standard operating procedures for clinical care. III. Guidelines for shock resuscitation. J Trauma, 2006;61:82-89. 128. Burlew CC, Moore EE, Biffl WL, Bensard DD, Johnson JL, Barnett CC. One hundred percent fascial approximation can be achieved in the postinjury open abdomen with a sequential closure protocol. J Trauma Acute Care Surg. 2012;72(1):235-241. 129. Sela HY, Weiniger CF, Hersch M, Smueloff A, Laufer N, Einav S. The pregnant motor vehicle accident casualty: adherence to basic workup and admission guidelines. Ann Surg. 2011;254(2):346-352. 130. ACOG Committee on Obstetric Practice: ACOG Committee Opinion. Number 299, September 2004. Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 2004;104:647-651. 131. Morris JA, Rosenbower TJ, Jurkovich GJ, et al: . Infant survival after cesarean section for trauma. Ann Surg. 1996;223: 481-488. 132. Curet MJ, Schermer CR, Demarest GB, et al. Predictors of outcome in trauma during pregnancy: Identification of patients who can be monitored for less than 6 hours. J Trauma. 2000;49:18-24. 133. Davis JW, Kaups KL. Base deficit in the elderly: a marker of severe injury and death. J Trauma. 1998; 45:873-877. 134. Reynolds FD, Dietz PA, Higgins D, et al. Time to deterioration of the elderly, anticoagulated, minor head injury patient who presents without evidence of neurologic abnormality. J Trauma. 2003;54:492-496. 135. Bulger EM, Arneson MA, Mock CN, et al. Rib fractures in the elderly. J Trauma 2000;48:1040-1046. 136. Bergeron E, Lavoie A, Clas D, et al. Elderly trauma patients with rib fractures are at greater risk of death and pneumonia. J Trauma. 2003;54:478-485. 137. Tepas JJ. The national pediatric trauma registry: a legacy of commitment to control childhood injury. Semin Pediatr Surg. 2004;13:126-132. 138. Partrick DA, Bensard DD, Moore EE, et al. Ultrasound is an effective triage tool to evaluate blunt abdominal trauma in the pediatric population. J Trauma. 1998;45:57-63. 139. Partrick DA, Bensard DD, Moore EE, et al. Nonoperative management of solid organ injuries in children results in decreased blood utilization. J Pediatr Surg. 1999;34: 1695-1699. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 8 chapter Background Initial Evaluation Classification of Burns Burn Depth Prognosis Resuscitation 227 227 228 229 230 230 Burns Jonathan Friedstat, Fred W. Endorf, and Nicole S. Gibran Transfusion Inhalation Injury and Ventilator Management Treatment of the Burn Wound Nutrition Complications in Burn Care Surgical care of the burned patient has evolved into a specialized field incorporating the interdisciplinary skills of burn surgeons, nurses, therapists, and other healthcare specialists. However, recent mass casualty events have been a reminder that healthcare systems may be rapidly pressed to care for large numbers of burn patients. Naturally, general surgeons may be at the forefront in these events, so it is crucial that they are comfortable with the care of burned patients and well equipped to provide standard of care. BACKGROUND Burn injury historically carried a poor prognosis. With advances in fluid resuscitation1 and the advent of early excision of the burn wound,2 survival has become an expectation even for patients with severe burns. Continued improvements in critical care and progress in skin bioengineering herald a future in which functional and psychological outcomes are equally important as survival alone. With this shift in priority, the American Burn Association (ABA) has emphasized referral to specialized burn centers after early stabilization. Specific criteria should guide transfer of patients with more complex injuries or other medical needs to a burn center (Table 8-1). The ABA has published standards of care3 and 1 created a verification process to ensure that burn centers meet those standards.4 Because of increased prehospital safety measures, burn patients are being transferred longer distances to receive definitive care at regional burn centers5; recent data from one burn center with a particularly wide catchment area confirmed that even transport times averaging 7 hours did not affect the long-term outcomes of burn patients.6 INITIAL EVALUATION Initial evaluation of the burned patient involves four crucial assessments: airway management, evaluation of other injuries, estimation of burn size, and diagnosis of CO and cyanide poisoning. With direct thermal injury to the upper airway or smoke inhalation, rapid and severe airway edema is a potentially lethal threat. Anticipating the need for intubation and establishing an 231 231 232 232 233 Surgery Wound Coverage Rehabilitation Prevention Radiation Burns Future Areas of Study 233 234 235 235 235 236 early airway are critical. Perioral burns and singed nasal hairs are signs that the oral cavity and pharynx should be further evaluated for mucosal injury, but these physical findings alone do not indicate an upper airway injury. Signs of impending respiratory compromise may include a hoarse voice, wheezing, or stridor; subjective dyspnea is a particularly concerning symptom and should trigger prompt elective endotracheal intubation. In patients with combined multiple trauma, especially oral trauma, nasotracheal intubation may be useful but should be avoided if oral intubation is safe and easy. Burned patients should be first considered trauma patients, especially when details of the injury are unclear. A primary survey should be conducted in accordance with Advanced Trauma Life Support guidelines. Concurrently with the primary survey, large-bore peripheral intravenous (IV) catheters should be placed and fluid resuscitation should be initiated; for a burn larger than 40% total body surface area (TBSA), two largebore IVs are ideal. IV placement through burned skin is safe and effective but requires attention to securing the catheters. Central venous access may provide useful information as to volume status and be useful in severely burned patients. Rarely, IV resuscitation is indicated in patients with burns smaller than 15% who can usually hydrate orally. Pediatric patients with burns larger than 15% may require intraosseous access in emergent situations if venous access cannot be attained. An early and comprehensive secondary survey must be performed on all burn patients, but especially those with a history of associated trauma such as with a motor vehicle collision. Also, patients from structural fires in which the manner of egress is not known should be carefully evaluated for injuries from a possible jump or fall. Urgent radiology studies, such as a chest x-ray, should be performed in the emergency department, but nonurgent skeletal evaluation (i.e., extremity x-rays) can be done in the intensive care unit (ICU) to avoid hypothermia and delays in burn resuscitation. Hypothermia is a common prehospital complication that contributes to resuscitation failure. Patients should be wrapped with clean blankets in transport. Cooling blankets should be avoided in patients with moderate or large (>20% TBSA) burns. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 Follow American Burn Association criteria for transfer of a patient to a regional burn center. Never administer prophylactic antibiotics other than tetanus vaccination. Early excision and grafting of full-thickness and deep partialthickness burns improve outcomes. Patients with acute burn injuries should never receive prophylactic antibiotics. This intervention has been clearly demonstrated to promote development of fungal infections and resistant organism and was abandoned in the mid-1980s. A tetanus 2 booster should be administered in the emergency room. The importance of pain management for these patients has been widely recognized over the past 25 years. However, we must also consider treatment of long-term anxiety. Therefore, it is important to administer an anxiolytic such as a benzodiazepine with the initial narcotics. Most burn resuscitation formulas estimate fluid requirements using the burn size as a percentage of TBSA (%TBSA). The “rule of nines” is a crude but quick and effective method of estimating burn size (Fig. 8-1). In adults, the anterior and posterior trunk each account for 18%, each lower extremity is 18%, each upper extremity is 9%, and the head is 9%. In children under 3 years old, the head accounts for a larger relative surface area and should be taken into account when estimating burn size. Diagrams such as the Lund and Browder chart give a more accurate accounting of the true burn size in children. The importance of an accurate burn size assessment cannot be overemphasized. Superficial or first-degree burns should not be included when calculating the %TBSA, and thorough cleaning of soot and debris is mandatory to avoid confusing Table 8-1 Guidelines for referral to a burn center Partial-thickness burns greater than 10% TBSA Burns involving the face, hands, feet, genitalia, perineum, or major joints Third-degree burns in any age group Electrical burns, including lightning injury Chemical burns 4 Intravenous fluid resuscitation for patients with burns greater than 20% of total body surface area (children with burns >15% of total body surface area) should be titrated to mean arterial pressure (MAP) greater than 60 mmHg and urine output greater than 30 mL/h. soiled skin with burns. Examination of referral data suggests that physicians inexperienced with burns tend to overestimate the size of small burns and underestimate the size of large burns, with potentially detrimental effects on pretransfer resuscitation.7 An important contributor to early mortality in burn patients is carbon monoxide (CO) poisoning resulting from smoke inhalation. The affinity of CO for hemoglobin is approximately 200 to 250 times more than that of oxygen, which decreases the levels of normal oxygenated hemoglobin and can quickly lead to anoxia and death.8 Unexpected neurologic symptoms should raise the level of suspicion, and an arterial carboxyhemoglobin level must be obtained because pulse oximetry can be falsely elevated. Administration of 100% oxygen is the gold standard for treatment of CO poisoning and reduces the half-life of CO from 250 minutes in room air to 40 to 60 minutes on 100% oxygen.9 Some authors have proposed hyperbaric oxygen as an adjunctive therapy for CO poisoning.10 However, the data are mixed regarding the success of hyperbaric oxygen, and its associated logistical difficulties and complications have limited its usefulness for patients with moderate or large burns.11,12 Patients who sustain a cardiac arrest as a result of their CO poisoning have an extremely poor prognosis regardless of the success of initial resuscitation attempts.13 Hydrogen cyanide toxicity may also be a component of smoke inhalation injury. Afflicted patients may have a persistent lactic acidosis or ST elevation on electrocardiogram (ECG).14 Cyanide inhibits cytochrome oxidase, which is required for oxidative phosphorylation. 15 Treatment consists of sodium thiosulfate, hydroxocobalamin, and 100% oxygen. Sodium thiosulfate works by transforming cyanide into a nontoxic thiocyanate derivative, but it works slowly and is not effective for acute therapy. Hydroxocobalamin quickly complexes with cyanide, is excreted by the kidney, and is recommended for immediate therapy.9 In the majority of patients, the lactic acidosis will resolve with ventilation, and sodium thiosulfate treatment becomes unnecessary.16 Inhalation injury Burn injury in patients with complicated pre-existing medical disorders Patients with burns and concomitant trauma in which the burn is the greatest risk. If the trauma is the greater immediate risk, the patient may be stabilized in a trauma center before transfer to a burn center. Burned children in hospitals without qualified personnel for the care of children Burn injury in patients who will require special social, emotional, or rehabilitative intervention 228 TBSA = total body surface area. CLASSIFICATION OF BURNS Burns are commonly classified as thermal, electrical, or chemical burns, with thermal burns consisting of flame, contact, or scald burns. Flame burns are not only the most common cause for hospital admission of burns, but also have the highest mortality. This is primarily related to their association with structural fires and the accompanying inhalation injury and/or CO poisoning.17 Electrical burns make up only 4% of U.S. hospital admissions but have special concerns including the potential for cardiac arrhythmias and compartment syndromes with concurrent rhabdomyolysis. A baseline ECG is recommended in all patients VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 4.5% Front 4.5% 229 Back CHAPTER 8 9% 9% BURNS 9% 18% 1% 18% 1% 18% 18% Figure 8-1. The “rule of nines” can be used as a quick reference for estimating a patient’s burn size by dividing the body into regions to which total body surface area is allocated in multiples of nine. with an electrical injury, and a normal ECG in a low-voltage injury may preclude hospital admission. Because compartment syndrome and rhabdomyolysis are common in high-voltage electrical injuries, vigilance must be maintained for neurologic or vascular compromise, and fasciotomies should be performed even in cases of moderate clinical suspicion. Long-term neurologic and visual symptoms are not uncommon with high-voltage electrical injuries, and ophthalmologic and neurologic consultation should be obtained to better define a patient’s baseline function.18 Chemical burns are less common but potentially severe burns. The most important components of initial therapy are careful removal of the toxic substance from the patient and irrigation of the affected area with water for a minimum of 30 minutes, except in cases of concrete powder or powdered forms of lye, which should be swept from the patient to avoid activating the aluminum hydroxide with water. The offending agents in chemical burns can be systemically absorbed and may cause specific metabolic derangements. Formic acid has been known to cause hemolysis and hemoglobinuria, and hydrofluoric acid causes hypocalcemia. Hydrofluoric acid is a particularly common offender due to its widespread industrial uses. Calcium-based therapies are the mainstay of treating hydrofluoric acid burns, with topical application of calcium gluconate onto wounds19 and IV administration of calcium gluconate for systemic symptoms. Intra-arterial calcium gluconate infusion provides effective treatment of progressive tissue injury and intense pain.20,21 Patients undergoing intra-arterial therapy need continuous cardiac monitoring. Persistent refractory hypocalcemia with electrocardiac abnormalities may signal the need for emergent excision of the burned areas. BURN DEPTH Based on the original burn depth classification by Dupuytren in 1832,22 burn wounds are commonly classified as superficial (first-degree), partial-thickness (second-degree), fullthickness (third-degree), and fourth-degree burns, which affect underlying soft tissue. Partial-thickness burns are classified as either superficial or deep partial-thickness burns by depth of involved dermis. Clinically, first-degree burns are painful but do not blister, second-degree burns have dermal involvement and are extremely painful with weeping and blisters, and thirddegree burns are leathery, painless, and nonblanching. Jackson described three zones of tissue injury following burn injury.23 The zone of coagulation is the most severely burned portion and is typically in the center of the wound. As the name implies, the affected tissue is coagulated and sometimes frankly necrotic, much like a third- or fourth-degree burn, and will need excision and grafting. Peripheral to that is a zone of stasis, with variable degrees of vasoconstriction and resultant ischemia, much like a second-degree burn. Appropriate resuscitation and wound care may help prevent conversion to a deeper wound, but infection or suboptimal perfusion may result in an increase in burn depth. This is clinically relevant because many superficial partialthickness burns will heal with expectant management, and the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 230 3 PART I BASIC CONSIDERATIONS majority of deep partial-thickness burns require excision and skin grafting. The last area of a burn is called the zone of hyperemia, which will heal with minimal or no scarring and is most like a superficial or first-degree burn. Unfortunately, even experienced burn surgeons have limited ability to accurately predict the healing potential of partialthickness burns soon after injury; one reason is that burn wounds evolve over the 48 to 72 hours after injury. Numerous techniques have been developed with the idea that better early prediction of burn depth will expedite appropriate surgical decision making. One of the most effective ways to determine burn depth is fullthickness biopsy, but this has several limitations; not only is the procedure painful and potentially scarring, but accurate interpretation of the histopathology requires a specialized pathologist and may have slow turnaround times.24 Laser Doppler can measure skin perfusion to predict burn depth with a positive predictive value of up to 80% in some studies.25,26 Noncontact ultrasound has been postulated as a painless modality to predict nonhealing wounds and has the advantage of easily performed serial measurements.27 Unfortunately, none of these newer therapies have proven adequately superior to justify their cost and as yet have not substituted serial examination by experienced burn surgeons. PROGNOSIS The Baux score (mortality risk equals age plus %TBSA) was used for many years to predict mortality in burns. Analysis of multiple risk factors for burn mortality has validated age and %TBSA as the strongest predictors of mortality.28 Advancements in burn care have lowered overall mortality to the point that the Baux score may no longer be accurate. However, age and burn size, as well as inhalation injury, continue to be the most robust indicators for burn mortality.29 Age even as a single variable strongly predicts mortality in burns,30 and in-hospital mortality in elderly burn patients is a function of age regardless of other comorbidities.31 In nonelderly patients, comorbidities such as preinjury human immunodeficiency virus (HIV), metastatic cancer, and kidney or liver disease may influence mortality and length of stay.32 A recent large database study of 68,661 burn patients found that the variables with the highest predictive value for mortality were age, %TBSA, inhalation injury, coexistent trauma, and pneumonia.33 RESUSCITATION A myriad of formulas exist for calculating fluid needs during burn resuscitation, suggesting that no one formula benefits all patients. The most commonly used formula, the Parkland or Baxter formula, consists of 3 to 4 mL/kg/% burn of lactated Ringer’s, of which half is given during the first 8 hours after burn and the remaining half is given over the subsequent 16 hours. The concept behind continuous fluid requirements is simple. The burn (and/or inhalation injury) drives an inflammatory response that leads to capillary leak; as plasma leaks into the extravascular space, crystalloid administration maintains the intravascular volume. Therefore, if a patient receives a large fluid bolus in a prehospital setting or emergency department, that fluid has likely leaked into the interstitium and the patient still requires ongoing burn resuscitation according to the estimates. Continuation of fluid volumes should depend on the time since injury, urine output, and mean arterial pressure (MAP). As the leak closes, the patient will require less volume to maintain these two resuscitation endpoints. Children under 20 kg have the additional requirement that they do not have sufficient glycogen stores to maintain an adequate glucose level in response to the inflammatory response. Specific pediatric formulas have been described, but the simplest approach is to deliver a weight-based maintenance IV fluid with glucose supplementation in addition to the calculated resuscitation fluid with lactated Ringer’s. It is important to remember that any formula for burn resuscitation is merely a guideline, and fluid must be titrated based on appropriate measures of adequate resuscitation. A number of parameters are widely used to gauge burn resuscitation, but the most common remain the simple outcomes of blood pressure and urine output. As in any critically ill patient, a target MAP of 60 mmHg ensures optimal end-organ perfusion. 4 Goals for urine output should be 30 mL/h in adults and 1 to 1.5 mL/kg/h in pediatric patients. Because blood pressure and urine output may not correlate perfectly with true tissue perfusion, the search continues for other adjunctive parameters that may more accurately reflect adequate resuscitation. Some centers have found serum lactate to be a better predictor of mortality in severe burns,34,35 and others have found that base deficit predicts eventual organ dysfunction and mortality.36,37 Because burned patients with normal blood pressure and serum lactate levels may have compromised gastric mucosal perfusion, continuous measurement of mucosal pH with its logistical difficulties has garnered limited popularity.38,39 Invasive monitoring with pulmonary artery catheters typically results in significant excessive fluid administration without improved cardiac output or preload measurements; use of invasive monitoring seems to have variable effects on long-term outcomes.40 Actual administrated fluid volumes typically exceed volumes predicted by standard formulas.41 One survey of burn centers showed that 58% of patients end up getting more fluids than would be predicted by Baxter’s formula.42 Comparison of modernday patients with historical controls shows that over-resuscitation may be a relatively recent trend.43 One theory is that increased opioid analgesic use results in peripheral vasodilation and hypotension and the need for greater volumes of bloused resuscitative fluids.44 A classic study by Navar et al showed that burned patients with inhalation injury required an average of 5.76 mL/ kg/% burn, vs. 3.98 mL/kg/% burn for patients without inhalation injury, and this has been corroborated by subsequent studies.45,46 Prolonged mechanical ventilation may also play a role in increased fluid needs.47 A recent multicenter study found that age, weight, %TBSA, and intubation on admission were significant predictors of more fluid delivery during the resuscitation period. Those patients receiving higher fluid volumes were at increased risk of complications and death.48 Common complications include abdominal compartment syndrome, extremity compartment syndrome, intraocular compartment syndrome, and pleural effusions. Monitoring bladder pressures can provide valuable information about development of intra-abdominal hypertension. The use of colloid as part of the burn resuscitation has generated much interest over the years. In late resuscitation when the capillary leak has closed, colloid administration may decrease overall fluid volumes and potentially may decrease associated complications such as intra-abdominal hypertension.49 However, albumin use has never been shown to improve outcomes in burn patients and has controversial effects on mortality in critically ill patients.50,51 Attempts to minimize fluid volumes in burn resuscitation have included study of hypertonic solutions, which appear to transiently decrease initial resuscitation volumes, with the downside of causing hyperchloremic acidosis.52 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ The role of blood transfusion in critically injured patients has undergone a reevaluation in recent years.58,59 Blood transfusions are considered to be immunosuppressive, which is one explanation for the common responses seen to blood transfusions, such as increased infection and shorter time to recurrence after oncologic surgery.60 A large multicenter study of blood transfusions in burn patients found that increased numbers of transfusions were associated with increased infections and higher mortality in burn patients, even when correcting for burn severity.61 A follow-up study implanting a restrictive transfusion policy in burned children showed that a hemoglobin threshold of 7 g/dL had no more adverse outcomes vs. a traditional transfusion trigger of 10 g/dL. In addition, costs incurred to the institution were significantly less.62 These data, in concert with other reported complications such as transfusion-related lung injury,63 have led to recommendations that blood transfusions be used only when there is an apparent physiologic need. Attempts to minimize blood transfusion in nonburned critically ill patients have led to use of erythropoietin by some centers. However, burn patients often have elevated erythropoietin levels, and a randomized study in burn patients showed that recombinant human erythropoietin did not effectively prevent anemia or decrease the number of transfusions given.64 INHALATION INJURY AND VENTILATOR MANAGEMENT Inhalation injuries are commonly seen in tandem with burn injuries and are known to increase mortality in burned patients.65 Smoke inhalation is present in as many as 35% of hospitalized burn patients and may triple the hospital stay compared to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 231 BURNS TRANSFUSION isolated burn injuries.66 The combination of burns, inhalation injury, and pneumonia increases mortality by up to 60% over burns alone.67 Subsequent development of the adult respiratory distress syndrome (ARDS) is common in these patients and may be caused in part by recruitment of alveolar leukocytes with an enhanced endotoxin-activated cytokine response.68 When ARDS complicates burns and inhalation injury, mortality approaches 66%; in one study, patients with burns ≥60% TBSA in combination with inhalation injury and ARDS had 100% mortality.69 Smoke inhalation causes injury in two ways: by direct heat injury to the upper airways and inhalation of combustion products into the lower airways. Direct injury to the upper airway causes airway swelling that typically leads to maximal edema in the first 24 to 48 hours after injury and often requires a short course of endotracheal intubation for airway protection. Combustion products found in smoke, most commonly from synthetic substances in structural fires, cause lower airway injury. These irritants cause direct mucosal injury, which in turn leads to mucosal sloughing, edema, reactive bronchoconstriction, and finally obstruction of the lower airways. Injury to both the epithelium and pulmonary alveolar macrophages causes release of prostaglandins, chemokines, and other inflammatory mediators; neutrophil migration; increased tracheobronchial blood flow; and finally increased capillary permeability. All of these components of acute lung injury increase the risk of pneumonia and ARDS following an inhalation injury. The physiologic effects of smoke inhalation are numerous. Inhalation injury decreases lung compliance70 and increases airway resistance work of breathing.71 Inhalation injury in the presence of burns also increases overall metabolic demands.72 The most common physiologic derangement seen with inhalation injury is increased fluid requirement during resuscitation. Since severe inhalation injury may result in mucosal sloughing with obstruction of smaller airways, bronchoscopy findings including carbon deposits, erythema, edema, bronchorrhea, and a hemorrhagic appearance may be useful for staging inhalation injury. Furthermore, bronchoalveolar lavage within 24 hours after an inhalation injury demonstrates a high rate of positive quantitative cultures,73 suggesting that pneumonia develops soon after the acute lung injury. Because bronchoscopy is an invasive test, attempts have been made to utilize other diagnostic modalities, such as thoracic computed tomography (CT) scans74 and xenon ventilation-perfusion scanning.75 Decreased Pao2:Fio2 ratio (<200) on admission may not only predict inhalation injury but also indicate increased fluid needs more accurately than bronchoscopic grading of the severity of inhalation.76 Treatment of inhalation injury consists primarily of supportive care. Aggressive pulmonary toilet and routine use of nebulized bronchodilators such as albuterol are recommended. Nebulized N-acetylcysteine is an antioxidant free radical scavenger designed to decrease the toxicity of high oxygen concentrations. Aerosolized heparin aims to prevent formation of fibrin plugs and decrease the formation of airway casts. These agents seem to improve pulmonary toilet but have no demonstrated effect on mortality.77 Aerosolized tissue plasminogen activator78 and recombinant human antithrombin79 have shown promise in sheep models, but have not yet seen widespread clinical use. Administration of intrabronchial surfactant has been used as a salvage therapy in patients with severe burns and inhalation injury.80 Inhaled nitric oxide may also be useful as a last effort in burn patients with severe lung injury who are failing other means of ventilatory support.81 The use of steroids has traditionally CHAPTER 8 Other adjuncts are being increasingly used during initial burn resuscitation. High-dose ascorbic acid (vitamin C) may decrease fluid volume requirements and ameliorate respiratory embarrassment during resuscitation.53 Plasmapheresis may also decrease fluid requirements in patients who require higher volumes than predicted to maintain adequate urine output and MAP. It is postulated that plasmapheresis may filter out inflammatory mediators, thus decreasing ongoing vasodilation and capillary leak.54 One recent adjunct that has found increasing utility in other surgical ICUs has been the application of bedside thoracic ultrasound.55 Ultrasound offers the potential to make rapid, noninvasive assessments during acute changes in clinical condition. For burn patients, bedside ultrasonography may be indicated for evaluation of volume status, gross assessment of cardiac function, and diagnosis of pneumothorax. Determining patient cardiac function and volume status may guide fluid resuscitation. Cardiac function can be evaluated with three common heart views: the parasternal long axis, parasternal short axis, and apical four-chamber views.56 Volume status can be estimated by examination of cardiac function, evaluation of the inferior vena cava (IVC) diameter, and changes with respiration. Ultrasound also allows timely diagnosis of pneumothorax.57 A high-frequency probe with an adequate window between ribs permits identification of lung parenchyma against the chest well. A pneumothorax appears as a transition on ultrasound between lung parenchyma, which has a heterogeneous appearance, and air, which has a hypoechoic appearance. Further studies are warranted to identify indications for the use of ultrasound in burned patients. 232 PART I BASIC CONSIDERATIONS been avoided due to worse outcomes in burn patients,82 but new promising data in late ARDS have prompted scientific review of steroid use.83 New ventilator strategies have contributed to the improved mortality with ARDS. Although ARDS still contributes to mortality in burn patients, treatments have improved so that mortality is primarily from multisystem organ failure rather than isolated respiratory causes.84 The ARDS Network Study finding that low tidal volume (6 cc/kg) or “lung-protective ventilation” had a 22% lower mortality than patients with traditional tidal volumes (12 cc/kg)85 has dramatically changed the management of patients with acute lung injury. A similar approach had previously been shown to improve outcomes in pediatric burn patients.86 In patients with refractory hypoxemia despite lung-protective ventilation, prone positioning may improve oxygenation but has not shown a definitive effect on mortality.87 No specific studies have examined prone positioning in burned patients, and caution must be used in patients with facial burns who are already at risk for loss of the endotracheal tube. High-frequency percussive ventilation (HFPV) has shown early promise in patients with inhalation injury.88 One study showed notable decreases in both morbidity and mortality with HFPV, especially in patients with burns less than 40% TBSA and inhalation injury.89 A related technique is high-frequency oscillatory ventilation, which has been used primarily as a salvage modality in patients refractory to more conventional measures.90 Extracorporeal membrane oxygenation (ECMO) is typically reserved for salvage situations, and experience with this modality is limited to small numbers of patients.91 A promising area of future study may be arteriovenous carbon dioxide removal, a technique that has proven superior to both low tidal volume ventilation and HFPV in a sheep model but has not yet transitioned from bench to bedside.92 TREATMENT OF THE BURN WOUND Multitudes of topical therapies exist for the treatment of burn wounds. Silver sulfadiazine is one of the most widely used in clinical practice. Silver sulfadiazine has a wide range of antimicrobial activity, primarily as prophylaxis against burn wound infections rather than treatment of existing infections. It has the added benefits of being inexpensive and easily applied and has soothing qualities. It is not significantly absorbed systemically and thus has minimal metabolic derangements. Silver sulfadiazine has a reputation for causing neutropenia, but this association is more likely due to neutrophil margination from the inflammatory response. True allergic reactions to the sulfa component of silver sulfadiazine are rare, and at-risk patients can have a small test patch applied to identify a burning sensation or rash. Silver sulfadiazine destroys skin grafts and is contraindicated on burns or donor sites in proximity to newly grafted areas. Also, silver sulfadiazine may retard epithelial migration in healing partial-thickness wounds. Mafenide acetate, either in cream or solution form, is an effective topical antimicrobial. It is effective even in the presence of eschar and can be used in both treating and preventing wound infections; the solution formulation is an excellent antimicrobial for fresh skin grafts. Use of mafenide acetate may be limited by pain with application to partial-thickness burns. Mafenide is absorbed systemically, and a major side effect is metabolic acidosis resulting from carbonic anhydrase inhibition. Silver nitrate has broad-spectrum antimicrobial activity as a topical solution. The solution used must be dilute (0.5%), and prolonged topical application leads to electrolyte extravasation with resulting hyponatremia. A rare complication is methemoglobinemia. Although inexpensive, silver nitrate solution causes black stains, and laundry costs may offset any fiscal benefit to the hospital. Increasingly, Dakin’s solution (0.5% sodium hypochlorite solution) is being used as an inexpensive topical antimicrobial. For smaller burns or larger burns that are nearly healed, topical ointments such as bacitracin, neomycin, and polymyxin B can be used. These are also useful for superficial partialthickness facial burns as they can be applied and left open to air without dressing coverage. Meshed skin grafts in which the interstices are nearly closed are another indication for use of these agents, preferably with greasy gauze to help retain the ointment in the affected area. All three have been reported to cause nephrotoxicity and should be used sparingly in large burns. The recent media fascination with methicillin-resistant Staphylococcus aureus (MRSA) has led to widespread use by community practitioners of mupirocin for new burns. Unless the patient has known risk factors for MRSA, mupirocin should only be used in culture-positive burn wound infections to prevent emergence of further resistance. Silver-impregnated dressings such as Acticoat (Smith & Nephew, London, United Kingdom), Aquacel Ag (Convatec, Princeton, NJ), and Mepilex Ag (Mölnlycke Health Care US, LLC, Norcross, GA) are increasingly being used for donor sites, skin grafts, and partial-thickness burns. These may be more comfortable for the patient, reduce the number of dressing changes, and shorten hospital length of stay, but they do limit serial wound examinations. Biologic membranes such as Biobrane (DowHickham, Sugarland, TX) provide a prolonged barrier under which wounds may heal. Because of the occlusive nature of these dressings, these are typically used only on fresh superficial partial-thickness burns that are clearly not contaminated. NUTRITION Nutritional support may be more important in patients with large burns than in any other patient population. Not only does adequate nutrition play a role in acute issues such as immune responsiveness, but the hypermetabolic response in burn injury may raise baseline metabolic rates by as much as 200%.93 This can lead to catabolism of muscle proteins and decreased lean body mass that may delay functional recovery.94 Early enteral feeding for patients with burns larger than 20% TBSA is safe and may reduce loss of lean body mass,95 slow the hypermetabolic response,96 and result in more efficient protein metabolism.97 If the enteral feeds are started within the first few hours after admission, gastric ileus can be avoided. Adjuncts such as metoclopramide promote gastrointestinal motility; if other measures for gastric feeding are unsuccessful, advancing the tube into the small bowel with nasojejunal feeding can be attempted.98 In endotracheally intubated patients, trips to the operating room do not necessitate holding enteral feedings.99 Immune-modulating supplements such as glutamine may decrease infectious complications and mortality in burn patients,100 likely via prevention of T-cell suppression in mesenteric lymph nodes.101 Calculating the appropriate caloric needs of the burn patient can be challenging. A commonly used formula in nonburned patients is the Harris-Benedict equation, which calculates caloric needs using factors such as gender, age, height, and weight. This formula uses an activity factor for specific injuries, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ There are several complications commonly associated with treatment of burn patients. Though not always avoidable, maintaining vigilance for typical complications and using appropriate techniques for prevention may limit the frequency and severity of complications. Ventilator-associated pneumonia, as in all critically ill patients, is a significant problem in burned patients. However, it is so common in patients with inhalation injury that a better nomenclature may be postinjury pneumonia. Unfortunately, commonly used scores in critical illness such as the Clinical Pulmonary Infection Score (CPIS) have not been shown to be reliable in burn patients. Quantitative bronchoscopic cultures in the setting of clinical suspicion of pneumonia should guide treatment of pneumonia.113 Simple measures such as elevating the head of the bed and maintaining excellent oral hygiene and pulmonary toilet are recommended to help decrease the risk of postinjury pneumonia. There is some question as to whether early tracheostomy decreases infectious morbidity in burn patients and whether it improves long-term outcomes. There do not seem to be any major differences in the rates of pneumonia with early tracheostomy, though there may be reduced development of subglottic stenosis compared with prolonged endotracheal intubation.114,115 Practical considerations such as protection of facial skin grafts may influence the decision for tracheostomy placement. One major consideration in deciding whether to perform a tracheostomy has been the presence of eschar at the insertion site, which complicates SURGERY Full-thickness burns with a rigid eschar can form a tourniquet effect as the edema progresses, leading to compromised venous outflow and eventually arterial inflow. The resulting compartment syndrome is most common in circumferential extremity burns, but abdominal and thoracic compartment syndromes also occur. Warning signs of impending compartment syndrome may include paresthesias, pain, decreased capillary refill, and progression to loss of distal pulses; in an intubated patient, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 233 BURNS COMPLICATIONS IN BURN CARE tracheostomy site care and increases the risk of airway infection. Bedside percutaneous dilatational tracheostomy is a facile method for performing tracheostomy and is reported to be as safe as open tracheostomy in the burn population.116 Massive resuscitation of burned patients may lead to an abdominal compartment syndrome characterized by increased airway pressures with hypoventilation, and decreased urine output and hemodynamic compromise. Decompressive laparotomy is the standard of care for refractory abdominal compartment syndrome but carries an especially poor prognosis in burn patients.117 Adjunctive measures such as minimizing fluid, performing torso escharotomies, decreasing tidal volumes, and chemical paralysis should be initiated before resorting to decompressive laparotomy. Patients undergoing massive resuscitation also develop elevated intraocular pressures and may require lateral canthotomy.118 Deep vein thrombosis (DVT) has been commonly believed to be a rare phenomenon in burned patients, and there is a paucity of controlled studies regarding heparin prophylaxis in this population.119 However, recent data show that up to 25% of burn patients develop DVT, and fatal pulmonary emboli have been reported in burn patients.120,121 A large retrospective study in patients with routine prophylaxis found DVT in only 0.25% of patients and reported no bleeding complications.122 Thus, it appears that heparin prophylaxis is safe in burn patients and may help prevent thrombotic complications. Unfortunately, the use of both prophylactic and therapeutic heparin may be associated with heparin-associated thrombocytopenia (HIT). One study of HIT in burn patients showed an incidence of 1.6% in heparinized burn patients. Thrombotic complications included DVT, pulmonary embolus, and even arterial thrombosis requiring limb amputation. Nonheparin anticoagulation for HIT commonly caused bleeding complications requiring transfusion.123 Although rare, a high index of suspicion for HIT should be maintained in thrombocytopenic burn patients, particularly if the platelet counts drop at hospital days 7 to 10. Burn patients often require central venous access for fluid resuscitation and hemodynamic monitoring. Because of the anatomic relation of their burns to commonly used access sites, burn patients may be at higher risk for catheter-related bloodstream infections. The 2009 Centers for Disease Control and Prevention National Healthcare Safety Network report (http:// www.cdc.gov/nhsn/dataStat.html) indicates that American burn centers have higher infectious complication rates than any other ICUs. Because burn patients may commonly exhibit leukocytosis with a documented bloodstream infection, practice has been to rewire lines over a guide wire and to culture the catheter tip. However, this may increase the risk of catheter-related infections in burned patients, and a new site should be used if at all possible.124 CHAPTER 8 and for burns, the basal energy expenditure is multiplied by two. The Harris-Benedict equation may be inaccurate in burns of less than 40% TBSA, and in these patients, the Curreri formula may be more appropriate. This formula estimates caloric needs to be 25 kcal/kg/d plus 40 kcal/%TBSA/d. Indirect calorimetry can also used to calculate resting energy expenditure, but in burn patients, a “metabolic cart” has not been documented to be more beneficial than the predictive equations.102 Titrating caloric needs closely is important, because overfeeding patients will lead to storage of fat instead of muscle anabolism.103 Modifying the hypermetabolic response is an area of intense study with several recent findings. β-Blocker use in pediatric patients decreases heart rate and resting energy expenditure and abrogates protein catabolism, even in long-term use.104 There may be benefits to β-blockade in adult patients,105 and many centers use β-blockers routinely in the adult population with limited safety and efficacy data. The anabolic steroid oxandrolone has been extensively studied in pediatric patients as well, and has demonstrated improvements in lean body mass and bone density in severely burned children.106 The weight gain and functional improvements seen with oxandrolone may persist even after stopping administration of the drug.107 A recent double-blind, randomized study of oxandrolone showed decreased length of stay, improved hepatic protein synthesis, and no adverse effects on endocrine function, although the authors noted a rise in transaminases with unclear clinical significance.108 Intensive insulin therapy in critically ill patients has shown benefit, presumably from avoidance of hyperglycemia.109 However, in burn patients, the insulin itself may have a metabolic benefit, with improvements in lean body mass and amelioration of the inflammatory response to burn injury.110,111 Oral hypoglycemic agents such as metformin also help to avoid hyperglycemia and may contribute to prevention of muscle catabolism.112 234 PART I BASIC CONSIDERATIONS the surgeon should anticipate the compartment syndrome and perform frequent neurovascular evaluations. Abdominal compartment syndrome should be suspected with decreased urine output, increased ventilator airway pressures, and hypotension. Hypoventilation, increased airway pressures, and hypotension may also characterize thoracic compartment syndrome. Escharotomies are rarely needed within the first 8 hours following injury and should not be performed unless indicated because of the terrible aesthetic sequelae. When indicated, they are usually performed at the bedside, preferably with electrocautery to minimize blood loss. Extremity incisions are made on the lateral and medial aspects of the limbs in an anatomic position and may extend onto thenar and hypothenar eminences of the hand. Digital escharotomies do not usually result in any meaningful salvage of functional tissue and are not recommended. Inadequate perfusion despite proper escharotomies may indicate the need for fasciotomy, but this procedure should not be routinely performed as part of the eschar release. Thoracic escharotomies should be placed along the anterior axillary lines with bilateral subcostal and subclavicular extensions. Extension of the anterior axillary incisions down the lateral abdomen typically will allow adequate release of abdominal eschar. The strategy of early excision and grafting in burned patients revolutionized survival outcomes in burn care. Not only did it improve mortality, but early excision also decreased reconstruction surgery, hospital length of stay, and costs of care.125,126 Once the initial resuscitation is complete and the patient is hemodynamically stable, attention should be turned to excising the burn wound. Burn excision and wound coverage should ideally start within the first several days, and in larger burns, serial excisions can be performed as patient condition allows. Excision is performed with repeated tangential slices using a Watson or Goulian blade until viable, diffusely bleeding tissue remains. It is appropriate to leave healthy dermis, which will appear white with punctate areas of bleeding. Excision to fat or fascia may be necessary in deeper burns. The downside of tangential excision is a high blood loss, though this may be ameliorated using techniques such as instillation of an epinephrine tumescence solution underneath the burn. Pneumatic tourniquets are helpful in extremity burns, and compresses soaked in a dilute epinephrine solution are necessary adjuncts after excision. A fibrinogen and thrombin spray sealant (Tisseel Fibrin Sealant; Baxter, Deerfield, IL) also has beneficial effects on both hemostasis and graft adherence to the wound bed. The use of these techniques has markedly decreased the number of blood transfusions given during burn surgery.127 For patients with clearly deep burns and concern for excessive blood loss, fascial excision may be employed. In this technique, electrocautery is used to excise the burned tissue and the underlying subcutaneous tissue down to muscle fascia. This technique markedly decreases blood loss but results in a cosmetically inferior appearance due to the loss of subcutaneous tissue. For excision of burns in difficult anatomic areas such as the face, eyelids, or hands, a pressurized water dissector may offer more precision but is time consuming, has a steep learning curve, and is expensive.128 WOUND COVERAGE Since full-thickness burns are impractical for most burn wounds, split-thickness sheet autografts harvested with a power dermatome make the most durable wound coverings and have a decent cosmetic appearance. In larger burns, meshed a­ utografted skin provides a larger area of wound coverage. This also allows drainage of blood and serous fluid to prevent accumulation under the skin graft with subsequent graft loss. Areas of cosmetic importance such as the face, neck, and hands should be grafted with nonmeshed sheet grafts to ensure optimal appearance and function. Unfortunately, even extensive meshing of skin grafts in patients with limited donor sites may not provide adequate amounts of skin. Options for temporary wound coverage include human cadaveric allograft, which is incorporated into the wound but is rejected by the immune system and must be eventually replaced. This allows temporary biologic wound coverage until donor sites heal enough so that they may be reharvested. Xenograft appears to function as well as allograft for temporary wound coverage and is considerably less ­expensive. The search for a perfect permanent synthetic skin substitute remains elusive. Integra (Integra LifeSciences Corporation, Plainsboro, NJ) is a bilayer product with a porous collagenchondroitin 6-sulphate inner layer that is attached to an outer silastic sheet, which helps prevent fluid loss and infection as the inner layer becomes vascularized, creating an artificial neodermis. At approximately 2 weeks after placement, the silastic layer can be removed and a thin autograft can be placed over the neodermis. This results in faster healing of the more superficial donor sites and seems to be associated with hypertrophic scarring and improved joint function.129 Alloderm (LifeCell Corporation, The Woodlands, TX) is another dermal substitute consisting of cryopreserved acellular human dermis. This must also be used in combination with thin split-thickness skin grafts.130 Epidermal skin substitutes such as cultured epithelial autografts are an option in patients with massive burns and very limited donor sites.131 Their clinical use has been limited by a long turnaround time for culturing, as well as the fragility of the cultured skin, which creates great difficulty with intraoperative handling and graft take. There are promising developments in skin culturing techniques and engineered skin development, but no other products are Food and Drug Administration approved and commercially available.132 Thighs make convenient anatomic donor sites; they are easily harvested and relatively hidden from an aesthetic standpoint. The thicker skin of the back is useful in older patients, who have thinner skin elsewhere and may have difficulty with healing of donor sites. The buttocks are an excellent donor site in infants and toddlers; silver sulfadiazine can be applied to the donor site with a diaper as coverage. The scalp is also an excellent donor site; the skin is thick and the many hair follicles allow rapid healing, with the added advantage of being completely hidden once hair regrows. Epinephrine tumescence is necessary for harvesting the scalp, for both hemostasis of this hypervascular area and also to create a smooth contoured surface for harvesting. The list of commonly used donor site dressings is long and includes simple transparent films to hydrocolloids, petrolatum gauzes, and silver-impregnated dressings. Donor sites close to fresh grafts may be dressed with a porous nonadherent gauze, and both the donors and grafts are soaked with an antimicrobial solution. Principals behind choosing a dressing should balance ease of care, comfort, infection control, and cost. The choice of donor site dressing is largely institution dependent, and few data support the clear superiority of any single treatment plan. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ REHABILITATION Despite many areas of progress in prevention, burns continue to be a common source of injury. Some successful initiatives have included community-based interventions targeting simple home safety measures. Smoke alarms are known to decrease mortality from structural fires, but not all homes are equipped with proper smoke alarms, particularly in low-income households. Mandatory smoke alarm installation via community initiatives can be successful, but seems to be contingent on close long-term follow-up to ensure proper maintenance and function.137,138 Regulation of hot water heater temperatures has had some success and may be even more effective in conjunction with community-based programs emphasizing education and in-home inspections.139,140 RADIATION BURNS Interest in mass burn casualty disaster planning invariably includes a discussion of radiation burns. The 1945 nuclear bombing on Hiroshima and Nagasaki provided several important lessons for healthcare providers. First, the proximity to the detonated bomb directly impacted mortality. The fatality rate at 0.6 miles from ground zero was 86%, decreased to 27% at 0.6 to 1.6 miles, and was 2% for patients 1.6 to 3.1 miles away. Over 122,338 individuals died in Hiroshima, and 68,000 of these deaths occurred in the first 20 days. Of the survivors, 79,130 people were injured and 118,613 remain uninjured. Estimates of the injuries at Hiroshima suggest that 90% of patients had burns, 83% sustained traumatic injuries, and 37% had radiation injuries.141,142 The mechanism of the explosion explains how radioactive material is distributed. A 20-kiloton nuclear device generates 180 mph winds 0.8 miles from the epicenter. The explosion results in a direct pressure wave and an indirect wind drag. The direct pressure can destroy windows and buildings, rupture eardrums, and cause pulmonary contusions, pneumothoraces, and hemothoraces. Radiation travels linearly, resulting in varying degree of burns depending on the distance from ground zero and time of exposure. A fireball at detonation sends radioactive material into the air and follows wind patterns settling to the ground in a predictable pattern. Thermal injuries near ground zero result in 100% fatalities due to incineration.141,142 Radioactive material results in both acute injury from immediate exposure and more prolonged injury from delayed exposure to radioactive fallout or contamination. When a 10-kiloton nuclear bomb is detonated, people at a distance 0.7 miles from ground zero absorb 4.5 Gy. At 60 days, the medial lethal radiation dose (LD50) is 3.5 Sv; with aggressive medical VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ BURNS PREVENTION 235 CHAPTER 8 Rehabilitation is an integral part of the clinical care plan for the burn patient and should be initiated on admission. Immediate and ongoing physical and occupational therapy is mandatory to prevent functional loss. Patients who are unable to actively participate should have passive range of motion done at least twice a day. This includes patients with burns over joints, such as with hand burns. Patients should be taught exercises they can do themselves to maintain full range of motion. Patients with foot and extremity burns should be instructed to walk independently without crutches or other assistive devices to prevent extremity swelling, desensitize the burned areas, and prevent disuse atrophy; when patients are not ambulating, they must elevate the affected extremity to minimize swelling. If postoperative immobilization is used for graft protection, the graft should be evaluated early and at frequent intervals so that active exercise can be resumed at the earliest possible occasion. The transition to outpatient care should also include physical and occupational therapy, with introduction of exercises designed to accelerate return to activities of daily living as well as specific job-related tasks. Tight-fitting pressure garments provide vascular support in burns that are further along in the healing process. Whether they prevent hypertrophic scar formation has been long debated. However, they do provide vascular support that many patients find more comfortable. Once patients have recovered from their acute burns, many face management of the hypertrophic burn scars. In patients with healed burns or donor sites, hypertrophic scar-related morbidity includes pruritus, erythema, pain, thickened tight skin, and even contractures. Within these scars, there is believed to be an increased inflammatory response that has increased neovascularization, abundant collagen production, and abnormal extracellular matrix structure. Treatment for these scars has included nonsurgical therapies such as compression garments, silicone gel sheeting, massage, physical therapy, and corticosteroid. Surgical excision and scar revision represent more invasive scar management approaches that are often necessary for functional and aesthetic recovery. Laser-based therapies provide addition treatment options for symptomatic hypertrophic scars. Two of the most common ones are the pulsed dye laser (PDL) and the ablative carbon dioxide (CO2) laser. The PDL causes photothermolysis of hemoglobin, resulting in coagulative necrosis.133 It obliterates small capillaries close to the skin and has had success treating congenital, cutaneous vascular malformations. The CO2 laser has been used for treatment of acne and recently has been gaining increasing acceptance for its use to treat hypertrophic burn scars.134 It works by ablating microscopic columns of tissue to flatten scars and is also believed to stimulate matrix metalloproteinases and other signaling pathways to induce collagen reorganization. Lasers are believed to help with scar remodeling and collagen reorganization. Outpatient and office-based treatment sessions are tolerated well by most patients. There is wide practice variation on when to start therapy and the number of treatments, but the literature has general support for starting treatment at 6 to 12 months and offering three treatments. More research is needed to determine the full potential of laser therapy to provide burn survivors a less invasive treatment of hypertrophic scars with improved symptoms and quality of life. Psychological rehabilitation is equally important in the burn patient. Depression, posttraumatic stress disorder, concerns about image, and anxiety about returning to society constitute predictable barriers to progress in both the inpatient and outpatient setting. Psychological distress occurs in as many as 34% of burn patients and persists in severity long after discharge.135 Despite this, many patients will be able to quickly return to work or school, and goals should be set accordingly. The return to school for pediatric patients is actually very prompt, averaging about 10 days after discharge. However, further study is needed to determine whether attendance and performance suffer despite early re-entry to school.136 The involvement of clinical psychologists and psychiatrists is invaluable in providing guidance and coping techniques to lessen the significant psychological burden of burn injury. 236 PART I BASIC CONSIDERATIONS care, this dose might be doubled to nearly 7 Sv. To put this in context, radiation exposure from a diagnostic CT of the chest or abdomen is 5 mSv, and the average annual background absorbed radiation dose is 3.6 mSv. Radiation is known to impact several organ systems and result in several syndromes based on increasing exposure doses. These syndromes include hematologic (1–8 Sv exposure), gastrointestinal (8–30 Sv exposure), and cardiovascular/neurologic syndromes (>30 Sv exposure), with the latter two being nonsurvivable.141-143 After initial evaluation and decontamination by removing clothing, a useful way to estimate exposure is by determining the time to emesis. Patients who do not experience emesis within 4 hours of exposure are unlikely to have severe clinical effects. Emesis within 2 hours suggests a dose of at least 3 Sv, and emesis within 1 hour suggests at least 4 Sv. The hematologic system follows a similar dose-dependent temporal pattern for predicting radiation exposure, mortality, and treatment. These have been determined based on the Armed Forces Radiobiology Research Institute’s Biodosimetry Assessment Tool, which can be downloaded from www.afrri.usuhs.mil. The combination of radiation exposure and burn wounds has the potential to increase mortality compared with traditional burns. Early closure of wounds before radiation depletes circulating lymphocytes may be needed for wound healing (which occurs within 48 hours). Also, in radiation injuries combined with burn or trauma, laboratory lymphocyte counts may be unreliable.141-144 A significant difference between burn/traumatic injuries and radiation injures is that burn/traumatic injuries can result in higher mortality when not treated within hours. Decontamination and triage are vital to maximize the number of survivors. Initial decontamination requires removal of clothing and washing wounds with water. Irrigation fluid should be collected to prevent radiation spread into the water supply. Work by many professional organizations, including the ABA, has focused on nationwide triage for disasters and will be vital to save as many lives as possible. Yet, it is likely that expectant or comfort care could be offered to more patients than typically seen in civilian hospitals, due to resource availability after the disaster. FUTURE AREAS OF STUDY It has long been anecdotally noted that two patients of similar ages and burn size may have very divergent responses to their burn injuries. Attention is being increasingly turned to identifying genetic differences among burn patients and how they affect response to injury. Specific allele variants have been linked with increased mortality in burned patients.145 It may be that genetic differences may predispose burn patients to severe sepsis,146 perhaps by downregulating the immune response.147 The Inflammation and the Host Response to Injury trial was a prospective, multicenter, federally funded study that aimed to define specific genetic pathways that differ in the response to both burns and traumatic injury.148 Blood and tissue samples from a strictly defined patient population were analyzed using gene arrays to determine whether differential expression in certain genetic pathways affects clinical outcomes.149 Although data from this study are still being analyzed, some interesting findings suggest that sepsis, trauma, and burn patients share common gene expression patterns, starting early after injury. These genes can upregulate proinflammatory pathways as well as disrupt antigen presentation pathways. A better understanding of these common genomic responses may allow for the targeted treatment of immunologic and signal pathways to help improve patient survival from burn injuries. With the dramatic progress in improving survival following a major burn injury during the twentieth century, understanding and addressing functional and psychological outcomes is critical to the well-being of burn survivors. Since 1993, the National Institute of Disability and Rehabilitation Research has funded four burn model systems to identify long-term sequelae of burn injuries and to develop ways to improve outcomes for survivors. Ongoing outcome studies are crucial for dismantling barriers that our patients face in returning to their communities and to the workplace or to school. REFERENCES Entries highlighted in bright blue are key references. 1. Baxter CR, Shires T. Physiological response to crystalloid resuscitation of severe burns. Ann N Y Acad Sci. 1968;150:874. 2. Janzekovic Z. 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Ramzy PI, Barret JP, Herndon DN. Thermal injury. Crit Care Clin. 1999;15(2):333-352. 78. Enkhbaatar P, Murakami K, Cox R, et al. Aerosolized tissue plasminogen inhibitor improves pulmonary function in sheep with burn and smoke inhalation. Shock. 2004;22(1):70-75. 79. Murakami K, McGuire R, Cox RA, et al. Recombinant antithrombin attenuates pulmonary inflammation following smoke inhalation and pneumonia in sheep. Crit Care Med. 2003; 31(2):577-583. 80. Pallua N, Warbanow K, Noah EM, et al. Intrabronchial surfactant application in cases of inhalation injury: first results from patients with severe burns and ARDS. Burns. 1998;24(3):197-206. 81. Sheridan RL, Zapol WM, Ritz RH, et al. Low-dose inhaled nitric oxide in acutely burned children with profound respiratory failure. Surgery. 1999;126:856. 82. Moylan JA, Alexander LG Jr. Diagnosis and treatment of inhalation injury. World J Surg. 1978;2:185-191. 83. Thompson BT. Glucocorticoids and acute lung injury. Crit Care Med. 2003;31:S253. 84. Hollingsed TC, Saffle JR, Barton RG, et al. Etiology and consequences of respiratory failure in thermally injured patients. Am J Surg. 1993;166:592. 85. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301. 86. Sheridan RL, Kacmarek RM, McEttrick MM, et al. Permissive hypercapnia as a ventilatory strategy in burned children: effect on barotrauma, pneumonia, and mortality. J Trauma. 1995;39:854. 87. Venet C, Guyomarch S, Migeot C, et al. The oxygenation variations related to prone positioning during mechanical ventilation: a clinical comparison between ARDS and non-ARDS hypoxemic patients. Intensive Care Med. 2001;27:1352. 88. Reper P, Van Bos R, Van Loey K, et al. High frequency percussive ventilation in burn patients: hemodynamics and gas exchange. Burns. 2003;29:603. 89. Hall JJ, Hunt JL, Arnoldo BD, et al. Use of high-frequency percussive ventilation in inhalation injuries. J Burn Care Res. 2007;28(3):396-400. 90. Cartotto R, Ellis S, Gomez M, et al. High frequency oscillatory ventilation in burn patients with the acute respiratory distress syndrome. Burns. 2004;30:453-463. 91. Patton ML, Simone MR, Kraut JD, et al. Successful utilization of ECMO to treat an adult burn patient with ARDS. Burns. 1998;24:566. 92. Schmalstieg FC, Keeney SE, Rudloff HE, et al. Arteriovenous CO2 removal improves survival compared to high frequency percussive and low tidal volume ventilation in a smoke/burn sheep acute respiratory distress syndrome model. Ann Surg. 2007;246(3):512-521; discussion 521-523. 93. Hart DW, Wolf SE, Mlcak R, et al. Persistence of muscle catabolism after severe burn. Surgery. 2000;128(2):312-319. 94. Hart DW, Wolf SE, Chinkes DL, et al. Determinants of skeletal muscle catabolism after severe burn. Ann Surg. 2000;232(4):455-465. 95. Gottschlich MM, Jenkins ME, Mayes T, et al. The 2002 clinical research award: an evaluation of the safety of early vs. delayed enteral support and effects on clinical, nutritional, and endocrine outcomes after severe burns. J Burn Care Rehabil. 2002;23(6):401-415. 96. Hart DW, Wolf SE, Chinkes DL, et al. Effects of early excision and aggressive enteral feeding on hypermetabolism, catabolism, and sepsis after severe burn. J Trauma. 2003; 54(4):755-764. 97. Jeschke MG, Herndon DN, Ebener C, et al. Nutritional intervention high in vitamins, protein, amino acids, and (omega)3 fatty acids improves protein metabolism during the hypermetabolic state after thermal injury. Arch Surg. 2001;136(11):1301-1306. 98. Sefton EJ, Boulton-Jones JR, Anderton D, et al. Enteral feeding in patients with major burn injury: the use of nasojejunal feeding after the failure of nasogastric feeding. Burns. 2002;28(4):386-390. 99. Jenkins ME, Gottschlich MM, Warden GD. Enteral feeding during operative procedures in thermal injuries. J Burn Care Rehabil. 1994;15:199. 100. Garrel D, Patenaude J, Nedelec B, et al. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med. 2003;31(10):2444-2449. 101. Choudry MA, Haque F, Khan M, et al. Enteral nutritional supplementation prevents mesenteric lymph node T-cell suppression in burn injury. Crit Care Med. 2003;31(6): 1764-1770. 102. Liusuwan RA, Palmieri TL, Kinoshita L, et al. Comparison of measured resting energy expenditure vs. predictive equations in pediatric burn patients. J Burn Care Rehabil. 2005;26(6):464-470. 103. Hart DW, Wolf SE, Herndon DN, et al. Energy expenditure and caloric balance after burn: increased feeding leads to fat rather than lean mass accretion. Ann Surg. 2002;235(1):152-161. 104. Herndon DN, Hart DW, Wolf SE, et al. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med. 2001; 345(17):1223-1229. 105. Arbabi S, Ahrns KS, Wahl WL, et al. Beta-blocker use is associated with improved outcomes in adult burn patients. J Trauma. 2004;56(2):265-269; discussion 269-271. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 239 BURNS 129. Jones I, Currie L, Martin R. A guide to biological skin substitutes. Br J Plast Surg. 2002;55(3):185-193. 130. Kearney JN. Clinical evaluation of skin substitutes. Burns. 2001;27(5):545-551. 131. Compton CC, Gill JM, Bradford DA, et al. Skin regenerated from cultured epithelial autografts on full-thickness burn wounds from 6 days to 5 years after grafting. A light, electron microscopic and immunohistochemical study. Lab Invest. 1989;60(5):600-612. 132. Boyce ST, Kagan RJ, Yakuboff KP, et al. Cultured skin substitutes reduce donor skin harvesting for closure of excised, full-thickness burns. Ann Surg. 2002;235(2):269-279. 133. Parrett BM, Donelan MB. Pulsed dye laser in burn scars: current concepts and future directions. Burns. 2010;36(4): 443-449. 134. Cho SB, Lee SJ, Chung WS, et al. Treatment of burn scar using a carbon dioxide fractional laser. J Drugs Dermatol. 2010;9(2):173-175. 135. Carniol PJ, Meshkov L, Grunebaum LD. Laser treatment of facial scars. Curr Opin Otolaryngol Head Neck Surg. 2011; 19(4):283-288. 136. Christiansen M, Carrougher GJ, Engrav LH, et al. Time to school re-entry after burn injury is quite short. J Burn Care Res. 2007;28(3):478-481; discussion 482-483. 137. Ballesteros MF, Jackson ML, Martin MW. Working toward the elimination of residential fire deaths: The Centers for Disease Control and Prevention’s Smoke Alarm Installation and Fire Safety Education (SAIFE) Program. J Burn Care Rehabil. 2005;26(5):434-439. 138. DiGuiseppi C, Roberts I, Wade A, et al. Incidence of fires and related injuries after giving out free smoke alarms: cluster randomised controlled trial. Br Med J. 2002;325:995-998. 139. Fallat ME, Rengers SJ. The effect of education and safety devices on scald burn prevention. J Trauma. 1993;34:560-564. 140. Cagle KM, Davis JW, Dominic W, et al. Results of a focused scald-prevention program. J Burn Care Res. 2006;27:859-863. 141. Wolbarst AB, Wiley AL Jr, Nemhauser JB, et al. Medical response to a major radiologic emergency: a primer for medical and public health practitioners. Radiology. 2010;254(3):660-677. 142. Flynn DF, Goans RE. Nuclear terrorism: triage and medical management of radiation and combined-injury casualties. Surg Clin North Am. 2006;86(3):601-636. 143. DiCarlo AL, Maher C, Hick JL, et al. Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation. Disaster Med Public Health Prep. 2011;5(Suppl 1):S32-S44. 144. Palmer JL, Deburghgraeve CR, Bird MD, et al. Development of a combined radiation and burn injury model. J Burn Care Res. 2011;32(2):317-323. 145. Barber RC, Aragaki CC, Chang LY, et al. CD14-159 C allele is associated with increased risk of mortality after burn injury. Shock. 2007;27(3):232-237. 146. Barber RC, Chang LY, Arnoldo BD, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res. 2006;4(4):250-255. 147. Moore CB, Medina MA, van Deventer HW, et al. Downregulation of immune signaling genes in patients with large surface burn injury. J Burn Care Res. 2007;28(6):879-887. 148. Xiao W, Mindrinos MN, Seok J, et al. Inflammation and host response to injury large-scale collaborative research program. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581-2590. 149. Klein MB, Silver G, Gamelli RL, et al. Inflammation and the Host Response to Injury Investigators. Inflammation and the host response to injury: an overview of the multicenter study of the genomic and proteomic response to burn injury. J Burn Care Res. 2006;27(4):448-451. CHAPTER 8 106. Murphy KD, Thomas S, Mlcak RP, et al. Effects of longterm oxandrolone administration in severely burned children. ­Surgery. 2004;136(2):219-224. 107. Demling RH, DeSanti L. Oxandrolone induced lean mass gain during recovery from severe burns is maintained after discontinuation of the anabolic steroid. Burns. 2003;29:793. 108. Jeschke MG, Finnerty CC, Suman OE, et al. The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. Ann Surg. 2007;246(3):351-360; discussion 360-362. 109. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367. 110. Thomas SJ, Morimoto K, Herndon DN, et al. The effect of prolonged euglycemic hyperinsulinemia on lean body mass after severe burn. Surgery. 2002;132(2):341-347. 111. Jeschke MG, Klein D, Herndon DN. Insulin treatment improves the systemic inflammatory reaction to severe trauma. Ann Surg. 2004;239(4):553-560. 112. Gore DC, Wolf SE, Sanford A, et al. Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury. Ann Surg. 2005;241(2):334-342. 113. Pham TN, Neff MJ, Simmons JM, et al. The clinical pulmonary infection score poorly predicts pneumonia in patients with burns. J Burn Care Res. 2007;28(1):76-79. 114. Barret JP, Desai MH, Herndon DN. Effects of tracheostomies on infection and airway complications in pediatric burn patients. Burns. 2000;26:190. 115. Saffle JR, Morris SE, Edelman L. Early tracheostomy does not improve outcome in burn patients. J Burn Care Rehabil. 2002;23:431. 116. Gravvanis AI, Tsoutsos DA, Iconomou TG, et al. Percutaneous vs. conventional tracheostomy in burned patients with inhalation injury. World J Surg. 2005;29(12):1571-1575. 117. Hershberger RC, Hunt JL, Arnoldo BD, Purdue GF. Abdominal compartment syndrome in the severely burned patient. J Burn Care Res. 2007;28(5):708-714. 118. Sullivan SR, Ahmadi AJ, Singh CN, et al. Elevated orbital pressure: another untoward effect of massive resuscitation after burn injury. J Trauma. 2006;60(1):72-76. 119. Faucher LD, Conlon KM. Practice guidelines for deep venous thrombosis prophylaxis in burns. J Burn Care Res. 2007;28(5):661-663. 120. Wibbenmeyer LA, Hoballah JJ, Amelon MJ, et al. The prevalence of venous thromboembolism of the lower extremity among thermally injured patients determined by duplex sonography. J Trauma. 2003;55:1162-1167. 121. Wahl WL, Brandt MM, Ahrns KS, et al. Venous thrombosis incidence in burn patients: preliminary results of a prospective study. J Burn Care Rehabil. 2002;23:97. 122. Fecher AM, O’Mara MS, Goldfarb IW, et al. Analysis of deep vein thrombosis in burn patients. Burns. 2004;30(6):591-593. 123. Scott JR, Klein MB, Gernsheimer T, et al. Arterial and venous complications of heparin-induced thrombocytopenia in burn patients. J Burn Care Res. 2007;28(1):71-75. 124. O’Mara MS, Reed NL, Palmieri TL, et al. Central venous catheter infections in burn patients with scheduled catheter exchange and replacement. J Surg Res. 2007;142(2):341-350. 125. Engrav LH, Heimbach DM, Reus JL, et al. Early excision and grafting vs. nonoperative treatment of burns of indeterminant depth: a randomized prospective study. J Trauma. 1983;23:1001-1004. 126. Thompson P, Herndon DN, Abston S, et al. Effect of early excision on patients with major thermal injury. J Trauma. 1987;27(2):205-207. 127. Sheridan RL, Tompkins RG. What’s new in burns and metabolism. J Am Coll Surg. 2004;198(2):243-263. 128. Klein MB, Hunter S, Heimbach DM, et al. The Versajet water dissector: a new tool for tangential excision. J Burn Care Rehabil. 2005;26(6):483-487. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 9 chapter History of Wound Healing Phases of Wound Healing 241 241 Hemostasis and Inflammation / 242 Proliferation / 244 Matrix Synthesis / 244 Maturation and Remodeling / 245 Epithelialization / 245 Role of Growth Factors in Normal Healing / 246 Wound Contraction / 246 Wound Healing Adrian Barbul, David T. Efron, and Sandra L. Kavalukas Heritable Diseases of Connective Tissue 246 Nerve / 251 Fetal Wound Healing / 251 Ehlers-Danlos Syndrome / 246 Marfan’s Syndrome / 246 Osteogenesis Imperfecta / 248 Epidermolysis Bullosa / 248 Acrodermatitis Enteropathica / 249 Classification of Wounds Healing in Specific Tissues Gastrointestinal Tract / 249 Bone / 249 Cartilage / 251 Tendon / 251 HISTORY OF WOUND HEALING The earliest accounts of wound healing date back to about 2000 b.c., when the Sumerians employed two modes of treatment: a spiritual method consisting of incantations, and a physical method of applying poultice-like materials to the wound. The Egyptians were the first to differentiate between infected and diseased wounds compared to noninfected wounds. The 1650 b.c. Edwin Smith Surgical Papyrus, a copy of a much older document, describes at least 48 different types of wounds. A later document (Ebers Papyrus, 1550 b.c.) relates the use of concoctions containing honey (antibacterial properties), lint (absorbent properties), and grease (barrier) for treating wounds. These same properties are still considered essential in contemporary daily wound management. The Greeks, equipped with the knowledge bequeathed by the Egyptians, went even further and classified wounds as acute or chronic in nature. Galen of Pergamum (120–201 a.d.), appointed as the doctor to the Roman gladiators, had an enormous number of wounds to deal with following gladiatorial combats. He emphasized the importance of maintaining a moist environment to ensure adequate healing. It took almost 19 centuries for this important concept to be proven scientifically, when it was shown that the epithelialization rate increases by 50% in a moist wound environment when compared to a dry wound environment.1 The next major stride in the history of wound healing was the discovery of antiseptics and their importance in reducing wound infections. Ignaz Philipp Semmelweis, a Hungarian obstetrician (1818–1865), noted that the incidence of puerperal fever was much lower if medical students, following cadaverdissection class and prior to attending childbirth, washed their hands with soap and hypochlorite. Louis Pasteur (1822–1895) was instrumental in dispelling the theory of spontaneous 252 Factors Affecting Wound Healing / 252 Chronic Wounds / 259 249 Excess Healing Treatment of Wounds 261 264 Local Care / 264 Antibiotics / 265 Dressings / 265 Skin Replacements / 266 generation of germs and proving that germs existed in and were always introduced from the environment. Joseph Lister probably made one of the most significant contributions to wound healing. On a visit to Glasgow, Scotland, Lister noted that some areas of the city’s sewer system were less murky than the rest. He discovered that the water from pipes that were dumping waste containing carbolic acid (phenol) was clear. In 1865, Lister began soaking his surgical instruments in phenol and spraying the operating rooms, reducing the postoperative mortality rates from 50% to 15%. After attending an impressive lecture by Lister in 1876, Robert Wood Johnson left the meeting and began 10 years of research that would ultimately result in the production of an antiseptic dressing in the form of cotton gauze impregnated with iodoform. Since then, several other materials have been used to impregnate cotton gauze to achieve antisepsis. The 1960s and 1970s led to the development of polymeric dressings. These polymeric dressings can be custom made to specific parameters, such as permeability to gases (occlusive vs. semiocclusive), varying degrees of absorbency, and different physical forms. Due to the ability to customize, the available range of materials that aid in wound care has grown exponentially to include an ever-expanding variety. Currently, the practice of wound healing encompasses manipulation and/or use of, among others, inflammatory cytokines, growth factors, and bioengineered tissue. It is the combination of all these modali1 ties that enables optimal wound healing. PHASES OF WOUND HEALING As noted by John Hunter (1728–1793), a keen observer of biologic phenomena, “. . . the injury alone has in all cases a tendency to produce the disposition and the means of a cure.”2 Normal wound healing follows a predictable pattern that can be divided into overlapping phases defined by characteristic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 Wound healing is a complex cellular and biochemical cascade that leads to restitution of integrity and function. Although individual tissues may have unique healing characteristics, all tissues heal by similar mechanisms, and the process undergoes phases of inflammation, cellular migration, proliferation, matrix deposition, and remodeling. Factors that impede normal healing include local, systemic, and technical conditions that the surgeon must take into account. 5 cellular populations and biochemical activities: (a) hemostasis and inflammation, (b) proliferation, and (c) maturation and remodeling. An approximate timeline of these events is 2 depicted in Fig. 9-1. This sequence of events is fluid and overlapping, and in most circumstances spans the time from injury to resolution of acute wounds. All wounds need to progress through this series of cellular and biochemical events that Clinically, excess healing can be as significant a problem as impaired healing; genetic, technical, and local factors play a major role. Optimal outcome of acute wounds relies on complete evaluation of the patient and of the wound and application of best practices and techniques. characterizes the phases of healing in order to successfully re-establish tissue integrity. Hemostasis and Inflammation Hemostasis precedes and initiates inflammation with the ensuing release of chemotactic factors from the wound site (Fig. 9-2A). Wounding by definition disrupts tissue integrity, leading to Phases of healing Maturation Proliferation Inflammation 2 4 6 8 10 12 14 16 Relative number of cells 0 months Neutrophils Macrophages Fibroblasts Lymphocytes 2 4 6 8 10 12 14 16 Relative amount of matrix synthesis 0 Collagen I Fibronectin Collagen III Wound-breaking strength 0 242 2 4 6 8 10 Days postwounding 12 14 16 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 9-1. The cellular, biochemical, and mechanical phases of wound healing. Fibrin Epidermis Platelets Clot Epidermis Neutrophils Dermis Lymphocytes B Scab Epidermis Fibroblast Dermis Endothelial buds Collagen Macrophage C Figure 9-2. The phases of wound healing viewed histologically. A. The hemostatic/inflammatory phase. B. Latter inflammatory phases reflecting infiltration by mononuclear cells and lymphocytes. C. The proliferative phase, with associated angiogenesis and collagen synthesis. division of blood vessels and direct exposure of extracellular matrix to platelets. Exposure of subendothelial collagen to platelets results in platelet aggregation, degranulation, and activation of the coagulation cascade. Platelet α granules release a number of wound-active substances, such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), plateletactivating factor (PAF), fibronectin, and serotonin. In addition to achieving hemostasis, the fibrin clot serves as scaffolding for the migration into the wound of inflammatory cells such as polymorphonuclear leukocytes (PMNs, neutrophils) and monocytes. Cellular infiltration after injury follows a characteristic, predetermined sequence (see Fig. 9-1). PMNs are the first infiltrating cells to enter the wound site, peaking at 24 to 48 hours. Increased vascular permeability, local prostaglandin release, and the presence of chemotactic substances such as complement factors, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), TGF-β, platelet factor 4, or bacterial products all stimulate neutrophil migration. The postulated primary role of neutrophils is phagocytosis of bacteria and tissue debris. PMNs are also a major source of cytokines early during inflammation, especially TNF-α3 which may have a significant influence on subsequent angiogenesis and Table 9-1 Macrophage activities during wound healing Activity Mediators Phagocytosis Reactive oxygen species Nitric oxide Débridement Collagenase, elastase Cell recruitment and activation Growth factors: PDGF, TGF-β, EGF, IGF Cytokines: TNF-α, IL-1, IL-6 Fibronectin Matrix synthesis Growth factors: TGF-β, EGF, PDGF Cytokines: TNF-α, IL-1, IFN-γ Enzymes: arginase, collagenase Prostaglandins Nitric oxide Angiogenesis Growth factors: FGF, VEGF Cytokines: TNF-α Nitric oxide EGF = epithelial growth factor; FGF = fibroblast growth factor; IGF = insulin-like growth factor; IFN-γ = interferon-γ; IL = interleukin; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Wound Healing A Disrupted blood vessel 243 CHAPTER 9 Red blood cells Dermis collagen synthesis (see Fig. 9-2B). PMNs also release proteases such as collagenases, which participate in matrix and ground substance degradation in the early phase of wound healing. Other than their role in limiting infections, these cells do not appear to play a role in collagen deposition or acquisition of mechanical wound strength. On the contrary, neutrophil factors have been implicated in delaying the epithelial closure of wounds.4 The second population of inflammatory cells that invades the wound consists of macrophages, which are recognized as being essential to successful healing.5 Derived from circulating monocytes, macrophages achieve significant numbers in the wound by 48 to 96 hours postinjury and remain present until wound healing is complete. Macrophages, like neutrophils, participate in wound débridement via phagocytosis and contribute to microbial stasis via oxygen radical and nitric oxide synthesis (see Fig. 9-2B,C). The macrophage’s most pivotal function is activation and recruitment of other cells via mediators such as cytokines and growth factors, as well as directly by cell-cell interaction and intercellular adhesion molecules (ICAM). By releasing such mediators as TGF-β, vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), epithelial growth factor (EGF), and lactate, macrophages regulate cell proliferation, matrix synthesis, and angiogenesis.6,7 Macrophages also play a significant role in regulating angiogenesis and matrix deposition and remodeling (Table 9-1). T lymphocytes comprise another population of inflammatory/immune cells that routinely invades the wound. Less numerous than macrophages, T-lymphocyte numbers peak at about 1 week postinjury and truly bridge the transition from the inflammatory to the proliferative phase of healing. Though known to be essential to wound healing, the role of lymphocytes in wound healing is not fully defined.8 A significant body of 244 PART I BASIC CONSIDERATIONS data supports the hypothesis that T lymphocytes play an active role in the modulation of the wound environment. Depletion of most wound T lymphocytes decreases wound strength and collagen content,9 while selective depletion of the CD8+ suppressor subset of T lymphocytes enhances wound healing. However, depletion of the CD4+ helper subset has no effect.10 Lymphocytes also exert a downregulating effect on fibroblast collagen synthesis by cell-associated interferon (IFN)-γ, TNF-α, and IL-1. This effect is lost if the cells are physically separated, suggesting that extracellular matrix synthesis is regulated not only via soluble factors but also by direct cell-cell contact between lymphocytes and fibroblasts.11 reticulum results in the hydroxylation of proline to hydroxyproline and of lysine to hydroxylysine by specific hydroxylases (Fig. 9-3). Prolyl hydroxylase requires oxygen and iron as cofactors, α-ketoglutarate as co-substrate, and ascorbic acid (vitamin C) as an electron donor. In the endoplasmic reticulum, the protocollagen chain is also glycosylated by the linking of galactose and glucose at specific hydroxylysine residues. These steps of hydroxylation and glycosylation alter the hydrogen bonding forces within the chain, imposing steric changes that force the protocollagen chain to assume an α-helical configuration. Proliferation Collagen genes The proliferative phase is the second phase of wound healing and roughly spans days 4 through 12 (see Fig. 9-2C). It is during this phase that tissue continuity is re-established. Fibroblasts and endothelial cells are the last cell populations to infiltrate the healing wound, and the strongest chemotactic factor for fibroblasts is PDGF.12,13 Upon entering the wound environment, recruited fibroblasts first need to proliferate, and then become activated, to carry out their primary function of matrix synthesis remodeling. This activation is mediated mainly by the cytokines and growth factors released from wound macrophages. Fibroblasts isolated from wounds synthesize more collagen than nonwound fibroblasts, they proliferate less, and they actively carry out matrix contraction. Although it is clear that the cytokine-rich wound environment plays a significant role in this phenotypic alteration and activation, the exact mediators are only partially characterized.14,15 Additionally, lactate, which accumulates in significant amounts in the wound environment over time (~10 mmol), is a potent regulator of collagen synthesis through a mechanism involving adenosine diphosphate (ADP)-ribosylation.16,17 Endothelial cells also proliferate extensively during this phase of healing. These cells participate in the formation of new capillaries (angiogenesis), a process essential to successful wound healing. Endothelial cells migrate from intact venules close to the wound. Their migration, replication, and new capillary tubule formation is under the influence of such cytokines and growth factors as TNF-α, TGF-β, and VEGF. Although many cells produce VEGF, macrophages represent a major source in the healing wound, and VEGF receptors are located specifically on endothelial cells.18,19 mRNA transcription Pre-mRNA mRNA processing Collagen mRNA Ribosome on rough endoplasmic reticulum Proline and Lysine hydroxylation OH OH Triple helix formation α-1 α-1 α-2 Golgi Secretory vesicle Cell membrane Procollagen peptidase Matrix Synthesis Extracellular space Biochemistry of Collagen. Collagen, the most abundant protein in the body, plays a critical role in the successful completion of adult wound healing. Its deposition, maturation, and subsequent remodeling are essential to the functional integrity of the wound. Although there are at least 18 types of collagen described, the main ones of interest to wound repair are types I and III. Type I collagen is the major component of extracellular matrix in skin. Type III, which is also normally present in skin, becomes more prominent and important during the repair process. Biochemically, each chain of collagen is composed of a glycine residue in every third position. The second position in the triplet is made up of proline or lysine during the translation process. The polypeptide chain that is translated from mRNA contains approximately 1000 amino acid residues and is called protocollagen. Release of protocollagen into the endoplasmic mRNA translation Lysyl oxidase C H ALDOL condensation C O H O Nonenzymatic C H C O H NH2 Syndesine C C O HO HO Aldimine Figure 9-3. The steps of collagen synthesis. mRNA = messenger RNA. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Epithelialization While tissue integrity and strength are being re-established, the external barrier must also be restored. This process is characterized primarily by proliferation and migration of epithelial cells adjacent to the wound (Fig. 9-4). The process begins within 1 day of injury and is seen as thickening of the epidermis at the wound edge. Marginal basal cells at the edge of the wound lose their firm attachment to the underlying dermis, enlarge, and begin to migrate across the surface of the provisional matrix. Fixed basal cells in a zone near the cut edge undergo a series of rapid mitotic divisions, and these cells appear to migrate by moving over one another in a leapfrog fashion until the defect is covered.22 Epidermis Wound Dermis Hair follicle Sweat gland Blood vessels Maturation and Remodeling The maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by a reorganization of previously synthesized collagen. Collagen is broken down by matrix metalloproteinases (MMPs), and the net wound collagen content is the result of a balance between collagenolysis and collagen synthesis. There is a net shift toward collagen synthesis and eventually the re-establishment of extracellular matrix composed of a relatively acellular collagen-rich scar. Wound strength and mechanical integrity in the fresh wound are determined by both the quantity and quality of the newly deposited collagen. The deposition of matrix at the wound site follows a characteristic pattern: fibronectin and collagen type III constitute the early matrix scaffolding; glycosaminoglycans and proteoglycans represent the next significant matrix components; and collagen type I is the final matrix. By several weeks postinjury, the amount of collagen in the wound reaches a plateau, but the tensile strength continues to increase for several more months.20 Fibril formation and fibril cross-linking result in decreased collagen solubility, increased strength, and increased resistance to enzymatic degradation of the collagen matrix. Fibrillin, a glycoprotein secreted by fibroblasts, is essential for the formation of elastic fibers found in connective tissue. Regenerating epithelium Epithelial island Epidermis Dermis Epidermis Dermis Hair follicle Sweat gland Blood vessels Figure 9-4. The healing by epithelialization of superficial cutaneous wounds. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 245 Wound Healing Proteoglycan Synthesis. Glycosaminoglycans comprise a large portion of the “ground substance” that makes up granulation tissue. Rarely found free, they couple with proteins to form proteoglycans. The polysaccharide chain is made up of repeating disaccharide units composed of glucuronic or iduronic acid and a hexosamine, which is usually sulfated. The disaccharide composition of proteoglycans varies from about 10 units in the case of heparan sulfate to as much as 2000 units in the case of hyaluronic acid. The major glycosaminoglycans present in wounds are dermatan and chondroitin sulfate. Fibroblasts synthesize these compounds, increasing their concentration greatly during the first 3 weeks of healing. The interaction between collagen and proteoglycans is being actively studied. It is thought that the assembly of collagen subunits into fibrils and fibers is dependent upon the lattice provided by the sulfated proteoglycans. Furthermore, it appears that the extent of sulfation is critical in determining the configuration of the collagen fibrils. As scar collagen is deposited, the proteoglycans are incorporated into the collagen scaffolding. However, with scar maturation and collagen remodeling, the content of proteoglycans gradually diminishes. Scar remodeling continues for many (6 to 12) months postinjury, gradually resulting in a mature, avascular, and acellular scar. The mechanical strength of the scar never achieves that of the uninjured tissue. There is a constant turnover of collagen in the extracellular matrix, both in the healing wound as well as during normal tissue homeostasis. Collagenolysis is the result of collagenase activity, a class of MMPs that require activation. Both collagen synthesis and lysis are strictly controlled by cytokines and growth factors. Some factors affect both aspects of collagen remodeling. For example, TGF-β increases new collagen transcription and also decreases collagen breakdown by stimulating synthesis of tissue inhibitors of metalloproteinase.21 This balance of collagen deposition and degradation is the ultimate determinant of wound strength and integrity. CHAPTER 9 Three α-helical chains entwine to form a right-handed superhelical structure called procollagen. At both ends, this structure contains nonhelical peptide domains called registration peptides. Although initially joined by weak, ionic bonds, the procollagen molecule becomes much stronger by the covalent cross-linking of lysine residues. Extracellularly, the nonhelical registration peptides are cleaved by a procollagen peptidase, and the procollagen strands undergo further polymerization and cross-linking. The resulting collagen monomer is further polymerized and cross-linked by the formation of intra- and intermolecular covalent bonds. Collagen synthesis, as well as posttranslational modifications, are highly dependent on systemic factors such as an adequate oxygen supply; the presence of sufficient nutrients (amino acids and carbohydrates) and cofactors (vitamins and trace metals); and the local wound environment (vascular supply and lack of infection). Addressing these factors and reversing nutritional deficiencies can optimize collagen synthesis and deposition. 246 PART I BASIC CONSIDERATIONS Once the defect is bridged, the migrating epithelial cells lose their flattened appearance, become more columnar in shape, and increase their mitotic activity. Layering of the epithelium is re-established, and the surface layer eventually keratinizes.23 Re-epithelialization is complete in less than 48 hours in the case of approximated incised wounds, but may take substantially longer in the case of larger wounds, where there is a significant epidermal/dermal defect. If only the epithelium and superficial dermis are damaged, such as occurs in split-thickness skin graft donor sites or in superficial second-degree burns, then repair consists primarily of re-epithelialization with minimal or no fibroplasia and granulation tissue formation. The stimuli for re-epithelialization remain incompletely defined; however, it appears that the process is mediated by a combination of a loss of contact inhibition; exposure to constituents of the extracellular matrix, particularly fibronectin; and cytokines produced by immune mononuclear cells.24,25 In particular EGF, TGF-β, basic fibroblast growth factor (bFGF), PDGF, and IGF-1 have been shown to promote epithelialization. Role of Growth Factors in Normal Healing Growth factors and cytokines are polypeptides produced in normal and wounded tissue that stimulate cellular migration, proliferation, and function. They often are named for the cells from which they were first derived (e.g., platelet-derived growth factor, PDGF) or for their initially identified function (e.g., fibroblast growth factor, FGF). These names are often misleading because growth factors have been demonstrated to have multiple functions. Most growth factors are extremely potent and produce significant effects in nanomolar concentrations. They may act in an autocrine manner (where the growth factor acts on the cell producing it), a paracrine manner (by release into the extracellular environment, where it acts on the immediately neighboring cells), or in an endocrine manner (where the effect of the substance is distant to the site of release, and the substance is carried to the effector site through the blood stream). The timing of release may be as important as concentration in determining the effectiveness of growth factors. As these polypeptides exert their effects by cell-surface receptor binding, the appropriate receptor on the responding cells must be present at the time of release in order for the biologic effect to occur. Table 9-2 summarizes the principal growth factors found in healing wounds and their known effects on cells participating in the healing process. Growth factors have divergent actions on different cells; they can be chemoattractive to one cell type while stimulating replication of a different cell type. Little is known about the ratio of growth factor concentrations, which may be as important as the absolute concentration of individual growth factors. Growth factors act on cells via surface receptor binding. Various receptor types have been described, such as ion channels, G-protein linked, or enzyme linked. The response elicited in the cell is usually one of phosphorylation or dephosphorylation of second-messenger molecules through the action of phosphatases or kinases, resulting in activation or deactivation of proteins in the cytosol or nucleus of the target cell. Phosphorylation of nuclear proteins is followed by the initiation of transcription of target genes.26 The signal is stopped by internalization of the receptor-ligand complex. Wound Contraction All wounds undergo some degree of contraction. For wounds that do not have surgically approximated edges, the area of the wound will be decreased by this action (healing by secondary intention); the shortening of the scar itself results in contracture. The myofibroblast has been postulated as being the major cell responsible for contraction, and it differs from the normal fibroblast in that it possesses a cytoskeletal structure. Typically this cell contains α-smooth muscle actin in thick bundles called stress fibers, giving myofibroblasts contractile capability.27 The α-smooth muscle actin is undetectable until day 6, and then is increasingly expressed for the next 15 days of wound healing.28 After 4 weeks, this expression fades and the cells are believed to undergo apoptosis.29 A puzzling point is that the identification of myofibroblasts in the wound does not correspond directly to the initiation of wound contraction, which starts almost immediately after injury. Fibroblasts placed in a collagen lattice in vitro actively move in the lattice and contract it without expressing stress fibers. It is postulated that the movement of cells with concomitant reorganization of the cytoskeleton is responsible for contraction.30 HERITABLE DISEASES OF CONNECTIVE TISSUE Heritable diseases of connective tissue consist of a group of generalized, genetically determined, primary disorders of one of the elements of connective tissue: collagen, elastin, or mucopolysaccharide. Five major types, Ehlers-Danlos syndrome, Marfan’s syndrome, osteogenesis imperfecta, epidermolysis bullosa, and acrodermatitis enteropathica, will be discussed, as each provides unique challenges to the surgeon. Ehlers-Danlos Syndrome Ehlers-Danlos syndrome (EDS) is a group of 10 disorders that present as a defect in collagen formation. Over half of the affected patients manifest genetic defects encoding alpha chains of collagen type V, causing it to be either quantitatively or structurally defective. These changes lead to “classic” EDS with phenotypic findings that include thin, friable skin with prominent veins, easy bruising, poor wound healing, atrophic scar formation, recurrent hernias, and hyperextensible joints. Gastrointestinal problems include bleeding, hiatal hernia, intestinal diverticulae, and rectal prolapse. Small blood vessels are fragile, making suturing difficult during surgery. Large vessels may develop aneurysms, varicosities, or arteriovenous fistulas or may spontaneously rupture.31–33 Table 9-3 presents a description of EDS subtypes including a recently recognized autosomal recessive form characterized by tenascin-X deficiency. The defect is a quantitative loss of protein, resulting in phenotypic changes similar to those observed in other types of EDS. EDS must be considered in every child with recurrent hernias and coagulopathy, especially when accompanied by platelet abnormalities and low coagulation factor levels. Inguinal hernias in these children resemble those seen in adults. Great care should be taken to avoid tearing the skin and fascia. The transversalis fascia is thin, and the internal ring is greatly dilated. An adult-type repair with the use of mesh or felt may result in a lower incidence of recurrence.34 The biochemical changes and phenotypic manifestation of the disease represent a major challenge to the surgeon. Dermal wounds should be closed in two layers, approximated with the sutures under tension, and the stitches should be left in place twice as long as usual. In addition, external fixation with adhesive tape can help reinforce the scar and prevent stretching.35 Marfan’s Syndrome Patients with Marfan’s syndrome have tall stature, arachnodactyly, lax ligaments, myopia, scoliosis, pectus excavatum, and aneurysm VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 247 Table 9-2 Growth factors participating in wound healing Cellular and Biologic Effects PDGF Platelets, macrophages, monocytes, smooth muscle cells, endothelial cells Chemotaxis: fibroblasts, smooth muscle, monocytes, neutrophils Mitogenesis: fibroblasts, smooth muscle cells Stimulation of angiogenesis Stimulation of collagen synthesis Enhance re-epithelization Modulate tissue remodeling FGF Fibroblasts, endothelial cells, keratinocytes, smooth muscle cells, chondrocytes Stimulation of angiogenesis (by stimulation of endothelial cell proliferation and migration) Mitogenesis: mesoderm and neuroectoderm HGF Fibroblasts Stimulates fibroblasts, keratinocytes, chondrocytes, myoblasts Suppresses inflammation, granulation tissue formation, angiogenesis, re-epithelialization Keratinocyte growth factor Keratinocytes, fibroblasts Significant homology with FGF; stimulates keratinocytes EGF Platelets, macrophages, monocytes (also identified in salivary glands, duodenal glands, kidney, and lacrimal glands) Stimulates proliferation and migration of all epithelial cell types TGF-α Keratinocytes, platelets, macrophages Homology with EGF; binds to EGF receptor Mitogenic and chemotactic for epidermal and endothelial cells TGF-β (three isoforms: β1, β2, β3) Platelets, T lymphocytes, macrophages, monocytes, neutrophils, fibroblasts, keratinocytes Stimulates angiogenesis Stimulates leukocyte chemotaxis TGF-β1 stimulates wound matrix production (fibronectin, collagen glycosaminoglycans); regulation of inflammation TGF-β3 inhibits scar formation Insulin-like growth Platelets (IGF-1 in high concentrations in factors (IGF-1, IGF-2) liver; IGF-2 in high concentrations in fetal growth); likely the effector of growth hormone action Promote protein/extracellular matrix synthesis Increase membrane glucose transport Vascular endothelial growth factor Macrophages, fibroblasts, endothelial cells, keratinocytes Mitogen for endothelial cells (not fibroblasts) Stimulates angiogenesis Proinflammatory IL-1 Macrophages, leukocytes, keratinocytes, fibroblasts IL-4 IL-6 Activin Leukocytes Fibroblasts, endothelial cells, macrophages, keratinocytes Keratinocytes, fibroblasts Angiopoitein-1/-2 CX3CL1 Endothelial cells Macrophages, endothelial cells Proinflammatory Stimulates angiogenesis, re-epithelialization, tissue remodeling Enhances collagen synthesis Stimulates inflammation, angiogenesis, re-epithelialization, collagen deposition, tissue remodeling Stimulates granulation tissue formation, keratinocyte differentiation, re-epithelialization Stimulates angiogenesis Stimulates inflammation, angiogenesis, collagen deposition Granulocytemacrophage colonystimulating factor Macrophage/monocytes, endothelial cells, fibroblasts Stimulates macrophage differentiation/proliferation CX3CL1 = chemokine (C-X3-C motif) ligand; EGF = epidermal growth factor; FGF = fibroblast growth factor; HGF = hepatocyte growth factor; IL = interleukin; PDGF = platelet-derived growth factor; TGF = transforming growth factor. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Wound Healing Wound Cell Origin CHAPTER 9 Growth Factor 248 Table 9-3 Clinical, genetic, and biochemical aspects of Ehlers-Danlos subtypes PART I BASIC CONSIDERATIONS Type Clinical Features Inheritance Biochemical Defect I Skin: soft, hyperextensible, easy bruising, fragile, atrophic scars; hypermobile joints; varicose veins; premature births AD Not known II Similar to type I, except less severe AD Not known III Skin: soft, not hyperextensible, normal scars; small and large joint hypermobility AD Not known IV Skin: thin, translucent, visible veins, normal scarring, no hyperextensibility; no joint hypermobility; arterial, bowel, and uterine rupture AD Type III collagen defect V Similar to type II XLR Not known VI Skin: hyperextensible, fragile, easy bruising; hypermobile joints; hypotonia; kyphoscoliosis AR Lysyl hydroxylase deficiency VII Skin: soft, mild hyperextensibility, no increased fragility; extremely lax joints with dislocations AD Type I collagen gene defect VIII Skin: soft, hyperextensible, easy bruising, abnormal scars with purple discoloration; hypermobile joints; generalized periodontitis AD Not known IX Skin: soft, lax; bladder diverticula and rupture; limited pronation and supination; broad clavicle; occipital horns XLR Lysyl oxidase defect with abnormal copper use X Similar to type II with abnormal clotting studies AR Fibronectin defect TNx Hypermobile joints, skin fragility AR Absence of tenascin X protein AD = autosomal dominant; AR = autosomal recessive; XLR = X-linked recessive. Source: Reproduced and updated with permission from Phillips et al.31 Copyright © Elsevier. of the ascending aorta. Patients who suffer from this syndrome also are prone to hernias. Surgical repair of a dissecting aneurysm is difficult, as the soft connective tissue fails to hold sutures. Skin may be hyperextensible but shows no delay in wound healing.36,37 The genetic defect associated with Marfan’s syndrome is a mutation in the FBN1 gene, which encodes for fibrillin. Previously, it was thought that structural alteration of the microfibrillar system was responsible for the phenotypic changes seen with the disease. However, recent research indicates an intricate role that FBN1 gene products play in TGF-β signaling. These extracellular matrix molecules normally bind and regulate TGF-β signaling; abnormal FBN1 gene function may cause an increase in TGF-β signaling, particularly in the aortic wall.38 Table 9-4 Osteogenesis Imperfecta Patients with osteogenesis imperfecta (OI) have brittle bones, osteopenia, low muscle mass, hernias, and ligament and joint laxity. OI is a result of a mutation in type I collagen. Mutations in prolidase, an enzyme responsible for cleaving c-terminal proline and hydroxyproline, may have a role in the disease. There are four major OI subtypes with mild to lethal manifestations. Patients experience dermal thinning and increased bruisability. Scarring is normal, and the skin is not hyperextensible. Surgery can be successful but difficult in these patients, as the bones fracture easily under minimal stress.31,34 Table 9-4 lists the various features associated with the clinical subtypes of OI. Epidermolysis Bullosa skin layers; the last can present as multiple blisters throughout different layers of skin. There are identified genetic defects for each subtype, but the overall phenotype is remarkably similar. The disease manifestations include impairment in tissue adhesion within the epidermis, basement membrane, or dermis, resulting in tissue separation and blistering with minimal trauma. Characteristic features of EB are blistering and ulceration. The recessively inherited dystrophic type is characterized by defects in the COL7A1 gene, encoding type 7 collagen, important for connecting the epidermis to the dermis, and therefore phenotypically resulting in blistering.39 Management of nonhealing Epidermolysis bullosa (EB) is classified into four major subtypes: EB simplex, junctional EB, dystrophic EB, and Kindler’s syndrome. The first three are determined by location in various Osteogenesis imperfecta: clinical and genetic features Type Clinical Features Inheritance I Mild bone fragility, blue sclera Dominant II “Prenatal lethal”; crumpled long Dominant bones, thin ribs, dark blue sclera III Progressively deforming; multiple fractures; early loss of ambulation Dominant/ recessive IV Mild to moderate bone fragility; normal or gray sclera; mild short stature Dominant Source: Reproduced with permission from Phillips et al.31 Copyright © Elsevier. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Acrodermatitis Enteropathica HEALING IN SPECIFIC TISSUES Gastrointestinal Tract Technical Considerations. Traditional teaching holds that in Healing of full-thickness injury to the gastrointestinal (GI) tract remains an unresolved clinical issue. Healing of full-thickness GI wounds begins with a surgical or mechanical reapposition of the bowel ends, which is most often the initial step in the repair process. Sutures or staples are principally used, although various other means such as buttons, plastic tubes, and various wrappings have been attempted with variable success. Failure of healing results in dehiscence, leaks, and fistulas, which carry significant morbidity and mortality. Conversely, excessive healing can be just as troublesome, resulting in stricture formation and stenosis of the lumen. Repair of the GI tract is vital to restoring the integrity of the luminal structure and to the resumption of motor, absorptive, and barrier functions. The gross anatomic features of the GI tract are remarkably constant throughout most of its length. Within the lumen, the epithelium is supported by the lamina propria and underlying muscularis mucosa. The submucosa lies radially and circumferentially outside of these layers, is comprised of abundant collagenous and elastic fibers, and supports neural and vascular structures. Further toward the peritoneal surface of the bowel are the inner and outer muscle layers and ultimately a peritoneal extension, the serosa. The submucosa is the layer that imparts the greatest tensile strength and greatest suture-holding capacity, a characteristic that should be kept in mind during surgical repair of the GI tract. Additionally, serosal healing is essential for quickly achieving a watertight seal from the luminal side of the bowel. The importance of the serosa is underscored by the significantly higher rates of anastomotic failure observed clinically in segments of bowel that are extraperitoneal and lack serosa (i.e., the esophagus and rectum). order for an anastomosis to heal without complications it must be tension-free, have an adequate blood supply, receive adequate nutrition, and be free of sepsis. Although sound principles for all wound healing, there are several considerations unique to anastomotic healing. From a technical viewpoint, the ideal method of suturing two ends of bowel together has not yet been identified. Although debate exists concerning methods of creating an anastomosis, clinically there has been no convincing evidence that a given technique has any advantage over another (i.e., handsutured vs. stapled, continuous vs. interrupted sutures, absorbable vs. nonabsorbable sutures, or single- vs. two-layer closure). A recent meta-analysis revealed that stapled ileocolic anastomoses have fewer leak rates than hand-constructed ones, but no data on colo-colic or small bowel anastomoses have been offered yet.46 It is known, however, that hand-sutured everting anastomoses are at greater risk of leakage and cause greater adhesion formation, but have a lower incidence of stenosis. Because no overall definite superiority of any one method exists, it is recommended that surgeons be familiar with several techniques and apply them as circumstances dictate. The amount of intravenous fluid administered perioperatively affects many aspects of recovery from colonic surgery; experimental and clinical data show that anastomotic healing may be adversely affected by overzealous fluid administration, which results in fluid accumulation in the third space, increased abdominal pressure, and tissue edema, all of which can compromise blood flow in the small vessels at the healing edge.47,48 Bone Following any type of injury to bone, several changes take place at the site of injury to restore structural and functional integrity. Most of the phases of healing resemble those observed VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 249 Wound Healing Acrodermatitis enteropathica (AE) is an autosomal recessive disease of children that causes an inability to absorb sufficient zinc from breast milk or food. The AE mutation affects zinc uptake in the intestine by preventing zinc from binding to the cell surface and its translocation into the cell. Recently, the genetic defect has been localized on chromosome 8q24.3 identified as the SLC39A4 gene, expressed in the intestinal lumen and upregulated based on zinc stores.41 Zinc deficiency is associated with impaired granulation tissue formation, as zinc is a necessary cofactor for DNA polymerase and reverse transcriptase, and its deficiency may impair healing due to inhibition of cell proliferation. AE is characterized by impaired wound healing as well as erythematous pustular dermatitis involving the extremities and the areas around the bodily orifices. Diagnosis is confirmed by the presence of an abnormally low blood zinc level (>100 mg/dL). Oral supplementation with 100 to 400 mg zinc sulfate orally per day is curative for impaired healing.42,43 Injuries to all parts of the GI tract undergo the same sequence of healing as cutaneous wounds. However, there are some significant differences (Table 9-5). Mesothelial (serosal) and mucosal healing can occur without scarring. The early integrity of the anastomosis is dependent on formation of a fibrin seal on the serosal side, which achieves watertightness, and on the suture-holding capacity of the intestinal wall, particularly the submucosal layer. There is a significant decrease in marginal strength during the first week due to an early and marked collagenolysis. The lysis of collagen is carried out by collagenase derived from neutrophils, macrophages, and intraluminal bacteria. Recently, it has been shown that strains of Pseudomonas aeruginosa undergo phenotypic shifts characterized by higher collagenase secretion in an injured/anastomosed bowel environment.44 Collagenase activity occurs early in the healing process, and during the first 3 to 5 days, collagen breakdown far exceeds collagen synthesis. The integrity of the anastomosis represents equilibrium between collagen lysis, which occurs early, and collagen synthesis, which takes a few days to initiate (Fig. 9-5). Collagenase is expressed postinjury in all segments of the GI tract, but it is much more marked in the colon compared to the small bowel. Collagen synthesis in the GI tract is carried out by both fibroblasts and smooth muscle cells. Colon fibroblasts produce greater amounts of collagen than skin fibroblasts, reflecting different phenotypic features, as well as different responses to cytokines and growth factors among these different fibroblast populations. Ultimate anastomotic strength is not always related to the absolute amount of collagen, and the structure and arrangement of the collagen matrix may be more important.45 CHAPTER 9 wounds in patients with EB is a challenge, as their nutritional status is compromised because of oral erosions and esophageal obstruction. Surgical interventions include esophageal dilatation and gastrostomy tube placement. Dermal incisions must be meticulously placed to avoid further trauma to skin.34,40 The skin requires nonadhesive pads covered by a “bulky” dressing to avoid blistering. 250 Table 9-5 Comparison of wound healing in the gastrointestinal tract and skin pH Skin Varies throughout GI tract in accordance with local exocrine secretions Usually constant except during sepsis or local infection BASIC CONSIDERATIONS Microorganisms Aerobic and anaerobic, especially in the colon and Skin commensals rarely cause problems; rectum; problematic if they contaminate the infection usually results from exogenous peritoneal cavity contamination or hematogenous spread Shear stress Intraluminal bulk transit and peristalsis exert distracting forces on the anastomosis Skeletal movements may stress the suture line but pain usually acts as a protective mechanism preventing excess movement Tissue oxygenation Dependent on intact vascular supply and neocapillary formation Circulatory transport of oxygen as well as diffusion Cell type Fibroblasts and smooth muscle cells Fibroblasts Lathyrogens d-Penicillamine has no effect on collagen cross-linking Significant inhibition of cross-linking with decreased wound strength Steroids Contradictory evidence exists concerning their Significant decrease in collagen negative effect on GI healing; increased abscess in accumulation the anastomotic line may play a significant role Collagenase activity — Increased presence throughout GI tract after transection and reanastomosis; during sepsis excess enzyme may promote dehiscence by decreasing suture-holding capacity of tissue Not as significant a role in cutaneous wounds Wound strength — Rapid recovery to preoperative level. Less rapid than GI tissue Definite scarring seen in fetal wound sites Usually heals without scar formation in the fetus Collagen synthesis Scar formation Age Resultant curve Strength of new collagen increases with synthesis Tensile strength PART I Wound environment GI Tract Strength of collagen decreases due to lysis Days Figure 9-5. Diagrammatic representation of the concept of GI wound healing as a fine balance between collagen synthesis and collagenolysis. The “weak” period when collagenolysis exceeds collagen synthesis can be prolonged or exacerbated by any factors that upset the equilibrium. (Reproduced with permission from Hunt TK, Van Winkle W Jr. Wound healing: normal repair. In: Dunphy JE, ed. Fundamentals of Wound Management in Surgery. New York: Chirurgecom, Inc.; 1976:29.) in dermal healing, but some notable individual characteristics apply to bone injuries. The initial stage of hematoma formation consists of an accumulation of blood at the fracture site, which also contains devitalized soft tissue, dead bone, and necrotic marrow. The next stage accomplishes the liquefaction and degradation of nonviable products at the fracture site. The normal bone adjacent to the injury site can then undergo revascularization, with new blood vessels growing into the fracture site. This is similar to the formation of granulation tissue in soft tissue. The symptoms associated with this stage are characteristic of inflammation, with clinical evidence of swelling and erythema. Three to 4 days following injury, soft tissue forms a bridge between the fractured bone segments in the next stage (soft callus stage). This soft tissue is deposited where neovascularization has taken place and serves as an internal splint, preventing damage to the newly laid blood vessels and achieving a fibrocartilaginous union. The soft callus is formed externally along the bone shaft and internally within the marrow cavity. Clinically, this phase is characterized by the end of pain and inflammatory signs. The next phase (hard callus stage) consists of mineralization of the soft callus and conversion to bone. This may take up to 2 to 3 months and leads to complete bony union. The bone is now considered strong enough to allow weight bearing and will appear healed on radiographs. This stage is followed by the remodeling phase, in which the excessive callus is reabsorbed and the marrow cavity is recanalized. This remodeling allows for the correct transmission of forces and restores the contours of the bone. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Cartilage consists of cells (chondrocytes) surrounded by an extracellular matrix made up of several proteoglycans, collagen fibers, and water. Unlike bone, cartilage is very avascular and depends on diffusion for transmittal of nutrients across the matrix. Additionally, the hypervascular perichondrium contributes substantially to the nutrition of the cartilage. Therefore, injuries to cartilage may be associated with permanent defects due to the meager and tenuous blood supply. The healing response of cartilage depends on the depth of injury. In a superficial injury, there is disruption of the proteoglycan matrix and injury to the chondrocytes. There is no inflammatory response, but an increase in synthesis of proteoglycan and collagen dependent entirely on the chondrocyte. Unfortunately, the healing power of cartilage is often inadequate, and overall regeneration is incomplete. Therefore, superficial cartilage injuries are slow to heal and often result in persistent structural defects. In contrast to superficial injuries, deep injuries involve the underlying bone and soft tissue. This leads to the exposure of vascular channels of the surrounding damaged tissue that may help in the formation of granulation tissue. Hemorrhage allows for the initiation of the inflammatory response and the subsequent mediator activation of cellular function for repair. As the granulation tissue is laid down, fibroblasts migrate toward the wound and synthesize fibrous tissue that undergoes chondrification. Gradually, hyaline cartilage is formed, which restores the structural and functional integrity of the injured site. Tendon Tendons and ligaments are specialized structures that link muscle and bone, and bone and bone, respectively. They consist of parallel bundles of collagen interspersed with spindle cells. Tendons and ligaments can be subjected to a variety of injuries, such as laceration, rupture, and contusion. Due to the mobility of the underlying bone or muscles, the damaged ends usually separate. Tendon and ligament healing progresses in a similar fashion as in other areas of the body (i.e., through hematoma formation, organization, laying down of reparative tissue, and scar formation). Matrix is characterized by accumulation of type I and III collagen along with increased water, DNA, and glycosaminoglycan content. As the collagen fibers are organized, transmission of forces across the damaged portion can occur. Restoration of the mechanical integrity may never be equal to that of the undamaged tendon. Tendon vasculature has a clear effect on healing. Hypovascular tendons tend to heal with less motion and more scar formation than tendons with better blood supply. The specialized cells, tenocytes, are metabolically very active and retain a large regenerative potential, even in the absence of vascularity. Cells on the tendon surface are identical to those within the sheath and play a role in tendon healing as well. Nerve injuries are very common, with an estimated 200,000 repairs performed every year in the United States. Peripheral nerves are a complex arrangement of axons, nonneuronal cells, and extracellular elements. There are three types of nerve injuries: neurapraxia (focal demyelination), axonotmesis (interruption of axonal continuity but preservation of Schwann cell basal lamina), and neurotmesis (complete transection). Following all types of injury, the nerve ends progress through a predictable pattern of changes involving three crucial steps: (a) survival of axonal cell bodies; (b) regeneration of axons that grow across the transected nerve to reach the distal stump; and (c) migration and connection of the regenerating nerve ends to the appropriate nerve ends or organ targets. Phagocytes remove the degenerating axons and myelin sheath from the distal stump (Wallerian degeneration). Regenerating axonal sprouts extend from the proximal stump and probe the distal stump and the surrounding tissues. Schwann cells ensheathe and help in remyelinating the regenerating axons. Functional units are formed when the regenerating axons connect with the appropriate end targets. Several factors play a role in nerve healing, such as growth factors, cell adhesion molecules, and nonneuronal cells and receptors. Growth factors include nerve growth factor, brain-derived neurotrophic factor, basic and acidic fibroblastic growth factors, and neuroleukin. Cell adhesion molecules involved in nerve healing include nerve adhesion molecule, neuron-glia adhesion molecule, myelin adhesion glycoprotein, and N-cadherin. This complex interplay of growth factors and adhesion molecules helps in nerve regeneration. Fetal Wound Healing The main characteristic that distinguishes the healing of fetal wounds from that of adult wounds is the lack of scar formation. Understanding how fetal wounds achieve integrity without evidence of scarring holds promise for the possible manipulation of unwanted fibrosis or excessive scar formation in adults. Although early fetal healing is characterized by the absence of scarring and resembles tissue regeneration, there is a phase of transition during gestational life when a more adultlike healing pattern emerges. This so-called “transition wound” occurs at the beginning of the third trimester, and during this period, there is scarless healing; however, there is a loss of the ability to regenerate skin appendages.49 Eventually a classic, adult-patterned healing with scar formation occurs exclusively, although overall healing continues to be faster than in adults. There are a number of characteristics that may influence the differences between fetal and adult wounds. These include wound environment, inflammatory responses, differential growth factor profiles, and wound matrix. Wound Environment. The fetus is bathed in a sterile, temperature-stable fluid environment, although this alone does not explain the observed differences. Experiments have demonstrated that scarless healing may occur outside of the amniotic fluid environment, and conversely, scars can form in utero.50,51 Inflammation. The extent and robustness of the inflammatory response correlates directly with the amount of scar formation in all healing wounds. Reduced fetal inflammation due to the immaturity of the fetal immune system may partially explain the lack of scarring observed. Not only is the fetus neutropenic, but fetal wounds contain lower numbers of PMNs and macrophages.52 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 251 Wound Healing Cartilage Nerve CHAPTER 9 As in dermal healing, the process of osseous union is mediated by soluble growth factors and cytokines. The most extensively studied group is the bone morphogenic proteins (BMPs), which belong to the TGF-β superfamily. By stimulating the differentiation of mesenchymal cells into chondroblasts and osteoblasts, BMPs directly affect bone and cartilage repair. Other growth factors such as PDGF, TGF-β, TNF-α, and bFGF also participate in bony repair by mediating the inflammatory and proliferative phases of healing. PART I Growth Factors. Fetal wounds are notable for the absence of TGF-β, which may have a significant role in scarring. Conversely, blocking TGF-β1 or TGF-β2 using neutralizing antibodies considerably reduces scar formation in adult wounds. Exogenous application of TGF-β3 downregulates TGF-β1 and TGF-β2 levels at the wound site with a resultant reduction in scarring.53 Thus, the balance between the concentration and/or activity of TGF-β isoforms may be important for regulating scar production. Primary Intention Epithelialization Connective Tissue Repair BASIC CONSIDERATIONS Wound Matrix. The fetal wound is characterized by excessive and extended hyaluronic acid production, a high-molecularweight glycosaminoglycan that is produced primarily by fibroblasts. Although adult wounds also produce hyaluronic acid, its synthesis is sustained only in the fetal wound. Components of amniotic fluid, most specifically fetal urine, have a unique ability to stimulate hyaluronic acid production.54 Fetal fibroblasts produce more collagen than adult fibroblasts, and the increased level of hyaluronic acid may aid in the orderly organization of collagen. As a result of these findings, hyaluronic acid is used topically to enhance healing and to inhibit postoperative adhesion formation.55 The collagen pattern of fetal wounds is reticular in nature and resembles surrounding tissue, while adult patterns express large bundles of parallel collagen fibrils oriented perpendicular to the surface.56 Secondary Intention Contraction Epithelialization Tertiary Intention Contraction Connective Tissue Repair CLASSIFICATION OF WOUNDS Wounds are classified as either acute or chronic. Acute wounds heal in a predictable manner and time frame. The process occurs with few, if any, complications, and the end result is a well-healed wound. Surgical wounds can heal in several ways. An incised wound that is clean and closed by sutures is said to heal by primary intention. Often, because of bacterial contamination or tissue loss, a wound will be left open to heal by granulation tissue formation and contraction; this constitutes healing by secondary intention. Delayed primary closure, or healing by tertiary intention, represents a combination of the first two, consisting of the placement of sutures, allowing the wound to stay open for a few days, and the subsequent closure of the sutures (Fig. 9-6). The healing spectrum of acute wounds is broad (Fig. 9-7). In examining the acquisition of mechanical integrity and strength during healing, the normal process is characterized by a constant and continual increase that reaches a plateau at some point postinjury. Wounds with delayed healing are characterized by decreased wound-breaking strength in comparison to wounds that heal at a normal rate; however, they eventually achieve the same integrity and strength as wounds that heal normally. Conditions such as nutritional deficiencies, infections, or severe trauma cause delayed healing, which reverts to normal with correction of the underlying pathophysiology. Impaired healing is characterized by a failure to achieve mechanical strength equivalent to normally healed wounds. Patients with compromised immune systems such as those with diabetes, chronic steroid usage, or tissues damaged by radiotherapy are prone to this type of impaired healing. The surgeon must be aware of these situations and exercise great care in the placement of incision and suture selection, postoperative care, and adjunctive therapy to maximize the chances of healing without supervening complications. Normal healing is affected by both systemic and local factors (Table 9-6). The clinician must be familiar with these factors and should attempt to counteract their deleterious effects. Complications occurring in wounds with higher risk can lead to failure of 3 healing or the development of chronic, nonhealing wounds. Figure 9-6. Different clinical approaches to the closure and healing of acute wounds. Factors Affecting Wound Healing Advanced Age. Most surgeons believe that aging produces intrinsic physiologic changes that result in delayed or impaired wound healing. Clinical experience with elderly patients tends to support this belief. Studies of hospitalized surgical patients show a direct correlation between older age and poor wound healing outcomes such as dehiscence and incisional hernia.57,58 Normal healing Wound mechanical strength 252 Delayed healing Impaired healing chronic Time Figure 9-7. The acquisition of wound mechanical strength over time in normal, delayed, and impaired healing. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Factors affecting wound healing Steroids and Chemotherapeutic Drugs. Large doses or Local Mechanical injury Infection Edema Ischemia/necrotic tissue Topical agents Ionizing radiation Low oxygen tension Foreign bodies However, these statistics fail to take into account underlying illnesses or diseases as a possible source of impaired wound healing in the elderly. The increased incidence of cardiovascular disease, metabolic diseases (diabetes mellitus, malnutrition, and vitamin deficiencies), and cancer, and the widespread use of drugs that impair wound healing may all contribute to the higher incidence of wound problems in the elderly. However, more recent clinical experience suggests that major operative interventions can be accomplished safely in the elderly. The results of animal studies regarding the effects of aging on wound healing have yielded contradictory results. In healthy human volunteers, there was a significant delay of 1.9 days in the epithelialization of superficial skin defects in those older than 70 years of age when compared to younger volunteers.59 In the same volunteers, using a micro-model of fibroplasia, no difference in DNA or hydroxyproline wound accumulation could be demonstrated between the young and elderly groups; however, the young volunteers had a significantly higher amount of total α-amino nitrogen in their wounds, a reflection of total protein content of the wound. Thus, although wound collagen synthesis does not seem to be impaired with advanced age, noncollagenous protein accumulation at wounded sites is decreased with aging, which may impair the mechanical properties of scarring in elderly patients. Hypoxia, Anemia, and Hypoperfusion. Low oxygen tension has a profoundly deleterious effect on all aspects of wound healing. Fibroplasia, although stimulated initially by the hypoxic wound environment, is significantly impaired by local hypoxia. Optimal collagen synthesis requires oxygen as a cofactor, particularly for the hydroxylation steps. Increasing subcutaneous oxygen tension levels by increasing the fraction of inspired oxygen (Fio2) of inspired air for brief periods during and immediately following surgery results in enhanced collagen deposition and in decreased rates of wound infection after elective surgery.60–62 Major factors affecting local oxygen delivery include hypoperfusion either for systemic reasons (low volume or cardiac failure) or due to local causes (arterial insufficiency, local vasoconstriction, or excessive tension on tissues). The level of vasoconstriction of the subcutaneous capillary bed is exquisitely chronic usage of glucocorticoids reduce collagen synthesis and wound strength.64 The major effect of steroids is to inhibit the inflammatory phase of wound healing (angiogenesis, neutrophil and macrophage migration, and fibroblast proliferation) and the release of lysosomal enzymes. The stronger the anti-inflammatory effect of the steroid compound used, the greater the inhibitory effect on wound healing. Steroids used after the first 3 to 4 days postinjury do not affect wound healing as severely as when they are used in the immediate postoperative period. Therefore, if possible, their use should be delayed, or alternatively, forms with lesser anti-inflammatory effects should be administered. In addition to their effect on collagen synthesis, steroids also inhibit epithelialization and contraction and contribute to increased rates of wound infection, regardless of the time of administration.64 Steroid-delayed healing of cutaneous wounds can be stimulated to epithelialize by topical application of vitamin A.64,65 Collagen synthesis of steroid-treated wounds also can be stimulated by vitamin A. All chemotherapeutic antimetabolite drugs adversely affect wound healing by inhibiting early cell proliferation and wound DNA and protein synthesis, all of which are critical to successful repair. Delay in the use of such drugs for about 2 weeks postinjury appears to lessen the wound healing impairment.66 Extravasation of most chemotherapeutic agents is associated with tissue necrosis, marked ulceration, and protracted healing at the affected site.67 Metabolic Disorders. Diabetes mellitus is the best known of the metabolic disorders contributing to increased rates of wound infection and failure.68 Uncontrolled diabetes results in reduced inflammation, angiogenesis, and collagen synthesis. Additionally, the large- and small-vessel disease that is the hallmark of advanced diabetes contributes to local hypoxemia. Defects in granulocyte function, capillary ingrowth, and fibroblast proliferation all have been described in diabetes. Obesity, insulin resistance, hyperglycemia, and diabetic renal failure contribute significantly and independently to the impaired wound healing observed in diabetics.69 In wound studies on experimental diabetic animals, insulin restores collagen synthesis and granulation tissue formation to normal levels if given during the early phases of healing.70 In clean, noninfected, and well-perfused experimental wounds in human diabetic volunteers, type 1 diabetes mellitus was noted to decrease wound collagen accumulation in the wound, independent of the degree of glycemic control. Type 2 diabetic patients showed no effect on collagen accretion when compared to healthy, age-matched controls.71 Furthermore, the diabetic wound appears to be lacking in sufficient growth factor levels, which signal normal healing. It remains unclear whether decreased collagen synthesis or an increased breakdown due to an abnormally high proteolytic wound environment is responsible. Careful preoperative correction of blood sugar levels improves the outcome of wounds in diabetic patients. Increasing the inspired oxygen tension, judicious use of antibiotics, and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Wound Healing Systemic Age Nutrition Trauma Metabolic diseases Immunosuppression Connective tissue disorders Smoking 253 CHAPTER 9 responsive to fluid status, temperature, and hyperactive sympathetic tone as is often induced by postoperative pain. Correction of these factors can have a remarkable influence on wound outcome, particularly on decreasing wound infection rates.61–63 Mild to moderate normovolemic anemia does not appear to adversely affect wound oxygen tension and collagen synthesis, unless the hematocrit falls below 15%.63 Table 9-6 1.5 OHP (µg/cm) PART I BASIC CONSIDERATIONS correction of other coexisting metabolic abnormalities all can result in improved wound healing. Uremia also has been associated with disordered wound healing. Experimentally, uremic animals demonstrate decreased wound collagen synthesis and breaking strength. The contribution of uremia alone to this impairment, rather than that of associated malnutrition, is difficult to assess.69 The clinical use of dialysis to correct the metabolic abnormalities and nutritional restoration should impact greatly on the wound outcome of such patients. Obesity is the largest growing public health problem in the United States and the world. Over 60% of Americans are overweight or obese. Uncomplicated obesity (i.e., in the absence of comorbid conditions such as cardiovascular disease, diabetes, or respiratory insufficiency) has by itself significant deleterious effects on wound healing. Visceral adiposity is active metabolically and immunologically and, through generation of proinflammatory cytokines and adipokines, leads to the development of the metabolic syndrome. Many of these molecules have effects on cells participating in the healing response. In nondiabetic obese rodents, wounds are mechanically weaker, and there is less dermal and reparative scar collagen. Pre-adipocytes infiltrate the dermis, and although they can evolve into fibroblasts, their regulatory mechanisms appear different from those of dermal or wound fibroblasts. Many studies indicate that obese patients have high rates of perioperative complications, with estimates as high as 30% for wound dehiscence, 17% for surgical site infections, 30% for incisional hernias, 19% for seromas, 13% for hematomas, and 10% for fat necrosis.72–74 Increased subcutaneous fat was associated with a 10-fold increased risk of surgery-related complications including anastomotic leaks, abdominal collection, and wound infections.75 In many studies, obesity is a constant and major risk factor for hernia formation and recurrence after repair. The mechanism by which obesity impairs wound healing awaits complete delineation. Nutrition. The importance of nutrition in the recovery from traumatic or surgical injury has been recognized by clinicians since the time of Hippocrates. Poor nutritional intake or lack of individual nutrients significantly alters many aspects of wound healing. The clinician must pay close attention to the nutritional status of patients with wounds, since wound failure or wound infections may be no more than a reflection of poor nutrition. Although the full interaction of nutrition and wound healing is still not fully understood, efforts are being made to develop wound-specific nutritional interventions and institute the pharmacologic use of individual nutrients as modulators of wound outcomes. Experimental rodents fed either a 0% or 4% protein diet have impaired collagen deposition with a secondary decrease in skin and fascial wound-breaking strength and increased wound infection rates. Induction of energy-deficient states by providing only 50% of the normal caloric requirement leads to decreased granulation tissue formation and matrix protein deposition in rats. Acute fasting in rats markedly impairs collagen synthesis while decreasing procollagen mRNA.76 Clinically, it is extremely rare to encounter pure energy or protein malnutrition, and the vast majority of patients exhibit combined protein-energy malnutrition. Such patients have diminished hydroxyproline accumulation (an index of collagen deposition) into subcutaneously implanted polytetrafluoroethylene tubes when compared to normally nourished patients (Fig. 9-8). Furthermore, malnutrition correlates clinically with enhanced rates of wound complications and increased wound failure 1.0 0.5 0.0 2.0 Well nourished Malnourished Adequate food intake 1.5 OHP (nmol/mg) 254 Inadequate food intake 1.0 0.5 0.0 Figure 9-8. Effect of malnutrition on collagen deposition in experimental human wounds. OHP = hydroxyproline. following diverse surgical procedures. This reflects impaired healing response as well as reduced cell-mediated immunity, phagocytosis, and intracellular killing of bacteria by macrophages and neutrophils during protein-calorie malnutrition.76 Two additional nutrition-related factors warrant discussion. First, the degree of nutritional impairment need not be long-standing in humans, as opposed to the experimental situation. Thus patients with brief preoperative illnesses or reduced nutrient intake in the period immediately preceding the injury or operative intervention will demonstrate impaired fibroplasias.77,78 Second, brief and not necessarily intensive nutritional intervention, either via the parenteral or enteral route, can reverse or prevent the decreased collagen deposition noted with malnutrition or with postoperative starvation.79 The possible role of single amino acids in enhanced wound healing has been studied for the last several decades. Arginine appears most active in terms of enhancing wound fibroplasia. Arginine deficiency results in decreased woundbreaking strength and wound-collagen accumulation in chowfed rats. Rats that are given 1% arginine HCl supplementation, and therefore are not arginine-deficient, have enhanced woundbreaking strength and collagen synthesis when compared to chow-fed controls.80 Studies have been carried out in healthy human volunteers to examine the effect of arginine supplementation on collagen accumulation. Young, healthy, human volunteers (aged 25–35 years) were found to have significantly increased wound-collagen deposition following oral supplementation with either 30 g of arginine aspartate (17 g of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Experimental Control 4 3 2 1 ASP LYS OHP αAN Figure 9-9. Ratios of 14-day to 7-day values for aspartate (ASP), hydroxyproline (OHP), lysine (LYS), and α-amino nitrogen (αAN) in volunteers given dietary supplements of arginine, β-hydroxyβ-methylbutyrate, and glutamine. *P < .05. (Reproduced with permission from Williams JZ, Abumrad NN, Barbul A. Effect of a specialized amino acid mixture on human collagen deposition. Ann Surg. 2002;236:369.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 255 Wound Healing 5 healthy nonsmokers. In severely injured or extensively burned patients, this requirement may increase to as high as 2 g daily. There is no evidence that excess vitamin C is toxic; however, there is no evidence that supertherapeutic doses of vitamin C are of any benefit.84 Vitamin A deficiency impairs wound healing, while supplemental vitamin A benefits wound healing in nondeficient humans and animals. Vitamin A increases the inflammatory response in wound healing, probably by increasing the lability of lysosomal membranes. There is an increased influx of macrophages, with an increase in their activation and increased collagen synthesis. Vitamin A directly increases collagen production and epidermal growth factor receptors when it is added in vitro to cultured fibroblasts. As mentioned before, supplemental vitamin A can reverse the inhibitory effects of corticosteroids on wound healing. Vitamin A also can restore wound healing that has been impaired by diabetes, tumor formation, cyclophosphamide, and radiation. Serious injury or stress leads to increased vitamin A requirements. In the severely injured patient, supplemental doses of vitamin A have been recommended. Doses ranging from 25,000 to 100,000 IU per day have been advocated. The connections between specific minerals and trace elements and deficits in wound healing are complex. Frequently, deficiencies are multiple and include macronutrient deficiencies. As with some of the vitamins described earlier, the specific trace element may function as a cofactor or part of an enzyme that is essential for homeostasis and wound healing. Clinically, preventing deficiencies is often easier to accomplish than diagnosing them. Zinc is the most well-known element in wound healing and has been used empirically in dermatologic conditions for centuries. It is essential for wound healing in animals and humans. There are over 150 known enzymes for which zinc is either an integral part or an essential cofactor, and many of these enzymes are critical to wound healing.85 With zinc deficiency, there is decreased fibroblast proliferation, decreased collagen synthesis, impaired overall wound strength, and delayed epithelialization. These defects are reversed by zinc supplementation. To date, no study has shown improved wound healing with zinc supplementation in patients who are not zinc deficient.86 Infections. Wound infections continue to represent a major medical problem, both in terms of how they affect the outcome of surgical procedures (surgical site infections), and for their impact on the length of hospital stay and medical costs.87 Many otherwise successful surgical operations fail because of the development of wound infections. The occurrence of infections is of major concern when implants are used, and their occurrence may lead to the removal of the prosthetic material, thus subjecting the patient to further operations and severe risk of morbidity and mortality. Infections can weaken an abdominal closure or hernia repair and result in wound dehiscence or recurrence of the hernia. Cosmetically, infections can lead to disfiguring, unsightly, or delayed closures. Exhaustive studies have been undertaken that examine the appropriate prophylactic treatment of operative wounds. Bacterial contaminants normally present on skin are prevented from entry into deep tissues by intact epithelium. Surgery breaches the intact epithelium, allowing bacteria access to these tissues and the bloodstream. Antibiotic prophylaxis is most effective when adequate concentrations of antibiotic are present in the tissues at the time of incision, and assurance of adequate preoperative antibiotic dosing and timing has become a significant CHAPTER 9 free arginine) or 30 g of arginine HCl (24.8 g of free arginine) daily for 14 days.81 In a study of healthy older humans (aged 67–82 years), daily supplements of 30 g of arginine aspartate for 14 days resulted in significantly enhanced collagen and total protein deposition at the wound site when compared to controls given placebos. There was no enhanced DNA synthesis present in the wounds of the arginine-supplemented subjects, suggesting that the effect of arginine is not mediated by an inflammatory mode of action.82 In this and later studies, arginine supplementation, whether administered orally or parenterally, had no effect on the rate of epithelialization of a superficial skin defect. This further suggests that the main effect of arginine on wound healing is to enhance wound collagen deposition. Recently, a dietary supplemental regimen of arginine, β-hydroxy-β-methyl butyrate, and glutamine was found to significantly and specifically enhance collagen deposition in elderly, healthy human volunteers when compared to an isocaloric, isonitrogenous supplement (Fig. 9-9).83 As increases in breaking strength during the first weeks of healing are directly related to new collagen synthesis, arginine supplementation may result in an improvement in wound strength as a consequence of enhanced collagen deposition. The vitamins most closely involved with wound healing are vitamin C and vitamin A. Scurvy or vitamin C deficiency leads to a defect in wound healing, particularly via a failure in collagen synthesis and cross-linking. Biochemically, vitamin C is required for the conversion of proline and lysine to hydroxyproline and hydroxylysine, respectively. Vitamin C deficiency has also been associated with an increased incidence of wound infection, and if wound infection does occur, it tends to be more severe. These effects are believed to be due to an associated impairment in neutrophil function, decreased complement activity, and decreased walling-off of bacteria secondary to insufficient collagen deposition. The recommended dietary allowance is 60 mg daily. This provides a considerable safety margin for most 256 PART I BASIC CONSIDERATIONS hospital performance measure.88 Addition of antibiotics after operative contamination has occurred clearly is ineffective in preventing postoperative wound infections. Studies that compare operations performed with and without antibiotic prophylaxis demonstrate that class II, III, and IV procedures (see below) treated with appropriate prophylactic antibiotics have only one third the wound infection rate of previously reported untreated series.89 More recently, repeat dosing of antibiotics has been shown to be essential in decreasing postoperative wound infections in operations with durations exceeding the biochemical half-life (t1/2) of the antibiotic or in which there is large-volume blood loss and fluid replacement.90,91 In lengthy cases, those in which prosthetic implants are used, or when unexpected contamination is encountered, additional doses of antibiotic may be administered for 24 hours postoperatively. Selection of antibiotics for use in prophylaxis should be tailored to the type of surgery to be performed, operative contaminants that might be encountered during the procedure, and the profile of resistant organisms present at the institution where the surgery is performed. The continuing widespread appearance of methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE) has significantly restricted the selection of these agents for routine use. Surgery-specific treatment guidelines are provided in Table 9-7.90 Patients with prosthetic heart valves or any implanted vascular or orthopedic prostheses should receive antibiotic prophylaxis prior to any procedure in which significant bacteremia is anticipated. Dental procedures require prophylaxis with broadspectrum penicillins or amoxicillin, while urologic instrumentation should be pretreated with a second-generation cephalosporin. Patients with prostheses who undergo gastrointestinal surgery should receive anaerobic coverage combined with a cephalosporin. Nasal screening and decolonization for Staphylococcus aureus carriers is recommended for selected procedures (i.e., cardiac, orthopedic, neurosurgical procedures with implants). The incidence of wound infection is about 5% to 10% nationwide and has not changed during the last few decades. Quantitatively, it has been shown that if the wound is contaminated with >105 microorganisms, the risk of wound infection is markedly increased, but this threshold may be much lower in the presence of foreign materials. The source of pathogens for the infection is usually the endogenous flora of the patient’s skin, mucous membranes, or from hollow organs. The most common organisms responsible for wound infections in order of frequency are Staphylococcus species, coagulase-negative Streptococcus, enterococci, and Escherichia coli. The incidence of wound infection bears a direct relationship to the degree of contamination that occurs during the operation from the disease process itself (clean—class I, clean contaminated—class II, contaminated—class III, and dirty—class IV). Many factors contribute to the development of postoperative wound infections. Most surgical wound infections become apparent within 7 to 10 days postoperatively, although a small number manifest years after the original operative intervention. With the hospital stay becoming shorter and shorter, many infections are detected in the outpatient setting, leading to underreporting of the true incidence of wound infections absent intensive surveillance. There has been much debate about the actual definition of wound infection. The narrowest definition would include wounds that drain purulent material with bacteria identified on culture. The more broad definition would include all wounds draining pus, whether or not the bacteriologic studies are positive; wounds that are opened by the surgeon; and wounds that the surgeon considers infected.92 Anatomically, wound infections can be classified as superficial incisional, deep incisional, and organ/space wound infections, involving fascia, muscle, or the abdominal cavity. About three fourths of all wound infections are superficial, involving skin and subcutaneous tissue only. Clinical diagnosis is easy when a postoperative wound looks edematous and erythematous and is tender. Often the presentation is more subtle, and development of postoperative fever, usually low-grade; development of a mild and unexplained leukocytosis; or the presence of undue incisional pain should direct attention to the wound. Inspection of the wound is most useful in detecting subtle edema around the suture or staple line, manifested as a waxy appearance of the skin, which characterizes the early phase of infection. If a wound infection is suspected, several stitches or staples around the most suspicious area should be removed with insertion of a cottontipped applicator into the subcutaneous area to open a small segment of the incision. This causes minimal if any discomfort to the patient. Presence of pus mandates further opening of the subcutaneous and skin layers to the full extent of the infected pocket. Samples should be taken for aerobic and anaerobic cultures, with very few patients requiring antibiotic therapy. Patients who are immunosuppressed (diabetics and those on steroids or chemotherapeutic agents), who have evidence of tissue penetration or systemic toxicity, or who have had prosthetic devices inserted (vascular grafts, heart valves, artificial joints, or mesh) should be treated with systemic antibiotics.92 Deep wound infections arise immediately adjacent to the fascia, either above or below it, and often have an intraabdominal component. Most intra-abdominal infections do not, however, communicate with the wound. Deep infections present with fever and leukocytosis. The incision may drain pus spontaneously, or the intra-abdominal extension may be recognized following the drainage of what was thought to be a superficial wound infection, but pus draining between the fascial sutures will be noted. Sometimes wound dehiscence will occur. The most dangerous of the deep infections is necrotizing fasciitis. It results in high mortality, particularly in the elderly. This is an invasive process that involves the fascia and leads to secondary skin necrosis. Pathophysiologically, it is a septic thrombosis of the vessels between the skin and the deep layers. The skin demonstrates hemorrhagic bullae and subsequent frank necrosis, with surrounding areas of inflammation and edema. The fascial necrosis is usually wider than the skin involvement or than the surgeon estimates on clinical grounds. The patient is toxic and has high fever, tachycardia, and marked hypovolemia, which if uncorrected, progresses to cardiovascular collapse. Bacteriologically, this is a mixed infection, and samples should be obtained for Gram stain smears and cultures to aid in diagnosis and treatment. As soon as bacteriologic studies have been obtained, highdose penicillin treatment needs to be started (20–40 million U/d intravenously) due to concern over the presence of Clostridia perfringens and other related species; broad-spectrum antibiotics should be added and the regimen modified based on culture results. Cardiovascular resuscitation with electrolyte solutions, blood, and/or plasma is carried out as expeditiously as possible prior to induction of anesthesia. The aim of surgical treatment is thorough removal of all necrosed skin and fascia. If viable skin overlies necrotic fascia, multiple longitudinal skin incisions can be made to allow for excision of the devitalized fascia. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 257 Table 9-7 Antimicrobial prophylaxis for surgery Cardiac Staphylococcus aureus, S. epidermidis Cefazolin or Cefuroxime or Vancomycin4 1–2 g IV2,3 1.5 g IV3 1 g IV esophageal/gastroduodenal Enteric gram-negative bacilli, gram-positive cocci High risk5 only: cefazolin6 1–2 g IV2 Biliary tract Enteric gram-negative bacilli, enterococci, clostridia High risk7 only: cefazolin6,8 1–2 g IV2 Colorectal Enteric gram-negative bacilli, anaerobes, enterococci Oral: neomycin + erythromycin base9 or metronidazole9 Parenteral: cefoxitin6 or Cefotetan6or —see note 9 Gastrointestinal Cefazolin + Metronidazole6 or Ampicillin/sulbactam Appendectomy, nonperforated11 1–2 g IV 1–2 g IV 1–2 g IV2 0.5 g IV 3 g IV Same as for colorectal Cefoxitin6 or cefotetan6 or Cefazolin6 + Metronidazole 1–2 g IV 1–2 g IV2 0.5 g IV Enteric gram-negative bacilli, enterococci High risk only12: ciprofloxacin10 or 500 mg PO or 400 mg IV 1 DS tablet Genitourinary Cystoscopy alone Trimethoprim-sulfamethoxazole Cystoscopy with manipulation Enteric gram-negative bacilli, enterococci or upper tract instrumentation13 Ciprofloxacin10or Trimethoprim-sulfamethoxazole 500 mg PO or 400 mg IV 1 DS tablet Enteric gram-negative bacilli, enterococci Cefazolin6 1–2 g IV2 Enteric gram-negative bacilli, anaerobes, group B streptococci, enterococci Cefazolin6 or cefoxitin6 or cefotetan6 1–2 g IV2 3 g IV or Ampicillin/sulbactam6,10 Cesarean section Same as for hysterectomy Cefazolin6 1–2 g IV2 Abortion, surgical Same as for hysterectomy Doxycycline 300 mg PO15 Anaerobes, enteric gram-negative bacilli, S. aureus Clindamycin or Cefazolin + Metronidazole or Ampicillin/sulbactam10 600–900 mg IV 1–2 g IV2 0.5 g IV 3 g IV Neurosurgery S. aureus, S. epidermidis Cefazolin 1–2 g IV2 Ophthalmic S. epidermidis, S. aureus, streptococci, Gentamicin, tobramycin, ciproenteric gram-negative bacilli, floxacin, gatifloxacin, levofloxacin, Pseudomonas spp. moxifloxacin, ofloxacin or neomycingramicidin-polymyxin B OR cefazolin Orthopedic S aureus, S. epidermidis Thoracic (noncardiac) S. aureus, S. epidermidis, streptococci, Cefazolin or enteric gram-negative bacilli Ampicillin/sulbactam10 or Vancomycin4 Open or laparoscopic surgery14 Gynecologic and obstetric  Vaginal, abdominal, or laparoscopic hysterectomy Head and neck surgery Incisions through oral or pharyngeal mucosa Cefazolin16 or Vancomycin2,16 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Multiple drops topically over 2 to 24 hours 100 mg subconjuctivally 1–2 g IV2, 1 g IV 1–2 g IV2 3 g IV 1 g IV Wound Healing Common Pathogens CHAPTER 9 Recommended Antimicrobials Adult Dosage before Surgery1 Nature of Operation 258 Table 9-7 Antimicrobial prophylaxis for surgery PART I BASIC CONSIDERATIONS Nature of Operation Common Pathogens Recommended Antimicrobials Adult Dosage before Surgery1 Vascular  Arterial surgery involving a prosthesis, the abdominal aorta, or a groin incision S. aureus, S. epidermidis, enteric gram-negative bacilli Cefazolin or Vancomycin4 1–2 g IV2 1 g IV Lower extremity amputation S. aureus, S. epidermidis, enteric for ischemia gram-negative bacilli, clostridia Cefazolin or Vancomycin4 1–2 g IV2 1 g IV Parenteral prophylactic antimicrobials can be given as a single IV dose begun within 60 min before the operation. For prolonged operations (>3 h) or those with major blood loss, or in patients with extensive burns, additional intraoperative doses should be given at intervals 1–2 times the half-life of the drug (ampicillin/sulbactam q2 h, cefazolin q4 h, cefuroxime q4 h, cefoxitin q2 h, clindamycin q6 h, vancomycin q12 h) for the duration of the procedure in a patient with normal renal function. If vancomycin or a fluoroquinolone is used, the infusion should be started 60–120 min before the initial incision to minimize the possibility of an infusion reaction close to the time of induction of anesthesia and to have adequate tissue levels at the time of incision. 2 The recommended dose of cefazolin is 1 g for patients who weigh 80 kg and 2 g for those >80 kg. Morbidly obese patients may need higher doses. 3 Some experts recommend an additional dose when patients are removed from bypass during open heart surgery. 4 Vancomycin can be used in hospitals in which methicillin-resistant Staphylococcus aureus (MRSA) and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillin or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 min, hypotension may occur; treatment with diphenhydramine (Benadryl and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of vancomycin to patients weighing more than 75 kg up to a maximum of 1.5 g with a slower infusion rate (90 min for 1.5 g). For procedures in which gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (gentamicin, tobramycin, or amikacin), aztreonam, or a fluoroquinolone. 5 Morbid obesity, GI obstruction, decreased gastric acidity or gastrointestinal motility, gastric bleeding, malignancy or perforation, or immunosuppression. 6 For patients allergic to penicillin and cephalosporins, clindamycin or vancomycin with either gentamicin, ciprofloxacin, levofloxacin, or aztreonam is a reasonable alternative. Fluoroquinolones should not be used for prophylaxis in cesarean section. 7 Age >70 y, acute cholecystitis, nonfunctioning gallbladder, obstructive jaundice, or common duct stones. 8 Cefotetan, cefoxitin, and ampicillin/sulbactam are reasonable alternatives. 9 In addition to mechanical bowel preparation, 1 g of neomycin plus 1 g of erythromycin at 1 p.m., 2 p.m., and 11 p.m. or 2 g of neomycin plus 2 g of metronidazole at 7 p.m. and 11 p.m. the day before an 8 a.m. operation. 10 Due to increasing resistance of E. coli to fluoroquinolones and ampicillin/sulbactam, local sensitivity profiles should be reviewed prior to use. 11 For a ruptured viscous, therapy is often continued for about 5 d. 12 Urine culture positive or unavailable, preoperative catheter, transrectal prostate biopsy, or placement of prosthetic material. 13 Shock wave lithotripsy, ureteroscopy. 14 Including percutaneous renal surgery, procedures with entry into the urinary tract, and those involving implantation of a prosthesis. If manipulation of bowel is involved, prophylaxis is given according to colorectal guidelines. 15 Divided into 100 mg before procedure and 200 mg after. 16 If a tourniquet is to be used in the procedure, the entire dose of antibiotic must be infused prior to its inflation. Source: Reprinted with special permission from Treatment Guidelines from The Medical Letter, October 2012; Vol. 10(122):73. www.medicalletter.org. 1 Although removal of all necrotic tissue is the goal of the first surgical intervention, the distinction between necrotic and simply edematous tissue often is difficult. Careful inspection every 12 to 24 hours will reveal any new necrotic areas, and these need further débridement and excision. When all necrotic tissue has been removed and the infection has been controlled, the wounds may be covered with homo- or xenografts until definitive reconstruction and autografting can take place. The mere presence of bacteria in an open wound, either acute or chronic, does not constitute an infection, because large numbers of bacteria can be present in the normal situation. In addition, the bacteria identified by cultures may not be representative of the bacteria causing the actual wound infection. There seems to be confusion as to what exactly constitutes wound infection. For purposes of clarity, we have to differentiate between contamination, colonization, and infection. Contamination is the presence of bacteria without multiplication, colonization is multiplication without host response, and infection is the presence of host response in reaction to deposition and multiplication of bacteria. The presence of a host response helps to differentiate between infection and colonization as seen in chronic wounds. The host response that helps in diagnosing wound infection comprises cellulitis, abnormal discharge, delayed healing, change in pain, abnormal granulation tissue, bridging, and abnormal color and odor. As discussed previously, neutrophils play a major role in preventing wound infections. Chronic granulomatous disease (CGD) comprises a genetically heterogeneous group of diseases in which the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxide enzyme is deficient. This defect impairs the intracellular killing of microorganisms, leaving the patient liable to infection by bacteria and fungi. Afflicted patients have recurrent infections and form granulomas, which can lead to obstruction of the gastric antrum and genitourinary tracts and poor wound healing. Surgeons become involved when the patient develops infectious or obstructive complications. The nitroblue tetrazolium (NBT) reduction test is used to diagnose CGD. Normal neutrophils can reduce this compound, while neutrophils from affected patients do not, facilitating the diagnosis via a colorimetric test. Clinically, patients develop recurrent infections such as pneumonia, lymphadenitis, hepatic abscess, and osteomyelitis. Organisms most commonly responsible are Staphylococcus aureus, Aspergillus, Klebsiella, Serratia, or Candida. When CGD patients require surgery, a preoperative pulmonary function test should be considered since they are VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Ischemic Arterial Ulcers. These wounds occur due to a lack of blood supply and are painful at presentation. They usually are associated with other symptoms of peripheral vascular disease, such as intermittent claudication, rest pain, night pain, and color or trophic changes. These wounds commonly are present at the most distal portions of the extremities such as the interdigital clefts, although more proximal locations are also encountered. On examination, there may be diminished or absent pulses with decreased ankle-brachial index and poor formation of granulation tissue. Other signs of peripheral ischemia, such as dryness of skin, hair loss, scaling, and pallor can be present. The wound itself usually is shallow with smooth margins, and a pale base and surrounding skin may be present. The management of these wounds is two-pronged and includes revascularization and wound care.107 Nonhealing of these wounds is the norm unless successful revascularization is performed. After establishing adequate blood supply, most such wounds progress to heal satisfactorily. A strategy of prevention is extremely important in the approach to patients with limb ischemia. In bedridden patients, especially those who are sedated (in the intensive care unit), demented, or with peripheral neural compromise (neuropathy or paraplegia), pressure ulcers develop rapidly and often unecessarily. Removal of restrictive stockings (in patients with critical ischemia), frequent repositioning, and surveillence are vital to preventing these ulcers.108 Venous Stasis Ulcers. Although there is unanimous agree- Chronic wounds are defined as wounds that have failed to proceed through the orderly process that produces satisfactory anatomic and functional integrity or that have proceeded through the repair process without producing an adequate anatomic and functional result. The majority of wounds that have not healed in 3 months are considered chronic. Skin ulcers, which usually occur in traumatized or vascular compromised soft tissue, are also considered chronic in nature, and proportionately are the major component of chronic wounds. In addition to the factors discussed earlier that can delay wound healing, other causative mechanisms may also play a role in the etiology of chronic wounds. Repeated trauma, poor perfusion or oxygenation, and/ or excessive inflammation contribute to the causation and the perpetuation of the chronicity of wounds. Unresponsiveness to normal regulatory signals also has been implicated as a predictive factor of chronic wounds. This may come about as a failure of normal growth factor synthesis,103 and thus an increased breakdown of growth factors within a wound environment that is markedly proteolytic because of overexpression of protease activity or a failure of the normal antiprotease inhibitor mechanisms.104 Fibroblasts from chronic wounds also have been found to have decreased proliferative potential, perhaps because of senescence105 or decreased expression of growth factor receptors.106 Chronic wounds occur due to various etiologic factors, and several of the most common are discussed later. Malignant transformation of chronic ulcers can occur in any long-standing wound (Marjolin’s ulcer). Any wound that does not heal for a prolonged period of time is prone to malignant transformation. Malignant wounds are differentiated clinically from nonmalignant wounds by the presence of overturned ment that venous ulcers are due to venous stasis and hydrostatic back pressure, there is less consensus as to what are the exact pathophysiologic pathways that lead to ulceration and impaired healing. On the microvascular level, there is alteration and distention of the dermal capillaries with leakage of fibrinogen into the tissues; polymerization of fibrinogen into fibrin cuffs leads to perivascular cuffing that can impede oxygen exchange, thus contributing to ulceration. These same fibrin cuffs and the leakage of macromolecules such as fibrinogen and α2-macroglobulin trap growth factors and impede wound healing.103 Another hypothesis suggests that neutrophils adhere to the capillary endothelium and cause plugging with diminished dermal blood flow. Venous hypertension and capillary damage lead to extravasation of hemoglobin. The products of this breakdown are irritating and cause pruritus and skin damage. The resulting brownish pigmentation of skin combined with the loss of subcutaneous fat produces characteristic changes called lipodermatosclerosis. Regardless of the pathophysiologic mechanisms, the clinically characteristic picture is that of an ulcer that fails to re-epithelialize despite the presence of adequate granulation tissue. Venous stasis occurs due to the incompetence of either the superficial or deep venous systems. Chronic venous ulcers usually are due to the incompetence of the deep venous system and are commonly painless. Stasis ulcers tend to occur at the sites of incompetent perforators, the most common being above the medial malleolus, over Cockett’s perforator. Upon examination, the typical location combined with a history of venous incompetence and other skin changes is diagnostic. The wound usually is shallow with irregular margins and pigmented surrounding skin. The cornerstone of treatment of venous ulcers is compression therapy, although the best method to achieve it remains VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 259 Wound Healing Chronic Wounds wound edges (Fig. 9-10). In patients with suspected malignant transformations, biopsy of the wound edges must be performed to rule out malignancy. Cancers arising de novo in chronic wounds include both squamous and basal cell carcinomas. CHAPTER 9 predisposed to obstructive and restrictive lung disease. Wound complications, mainly infection, are common. Sutures should be removed as late as possible since the wounds heal slowly. Abscess drains should be left in place for a prolonged period until the infection is completely resolved.93 Hyperglycemia has been shown to be a significant risk factor of postoperative infections.94 Tight blood glucose control, beginning preoperatively and continued into the operating room and beyond, has been associated with significant reduction in infectious complications, in particular following cardiac surgery.95,96 Too tight of a glycemic control (80–100 mg/dL) appears to be associated with more complications and is as effective, if not less than, moderate control (120–180 mg/dL).97,98 Another host factor that has been implicated in the development of superficial surgical site infection relates to the state of the subcutaneous capillary bed. Thomas K. Hunt had shown through several decades of work that this capillary bed is exquisitely sensitive to hypovolemia,99 hypothermia,100 and stress, leading to rapid vasoconstriction with secondary impaired oxygen delivery and increased rates of infection.61 Maintenance of euvolemia, core temperature above 36 to 36.5°C, and pain control have all been shown singly and additively to reduce rates of wound infections.63 Another suggestion has been to increase inspired Fio2 to 0.8 for the duration of the operation and in the immediate postoperative period, as a means of increasing subcutaneous tissue oxygen delivery. Although successful in most studies,62,101 there have also been negative results from such a single approach102; this suggests that addressing volume, temperature, pain control, and oxygen delivery in concert may be the more fruitful approach to reduce surgical wound infections. 260 PART I BASIC CONSIDERATIONS Figure 9-10. Typical appearance of the malignant transformation of a long-standing chronic wound. (Photos used with permission by Dr. Robert S. Kirsner, University of Miami.) controversial. Compression can be accomplished via rigid or flexible means. The most commonly used method is the rigid, zinc oxide–impregnated, nonelastic bandage. Others have proposed a four-layered bandage approach as a more optimal method of obtaining graduated compression.109 Wound care in these patients focuses on maintaining a moist wound environment, which can be achieved with hydrocolloids. Other, more modern approaches include use of vasoactive substances and growth factor application, as well as the use of skin substitutes. Recently, sprayed allogeneic keratinocytes and fibroblasts plus four-layer bandages have been shown to hasten healing when compared to compression alone.110 Most venous ulcers can be healed with perseverance and by addressing the venous hypertension.109 Unfortunately, recurrences are frequent despite preventative measures, largely because of patients’ lack of compliance.111 Diabetic Wounds. Ten percent to 25% of diabetic patients run the risk of developing ulcers. There are approximately 50,000 to 60,000 amputations performed in diabetic patients each year in the United States. The major contributors to the formation of diabetic ulcers include neuropathy, foot deformity, and ischemia. It is estimated that 60% to 70% of diabetic ulcers are due to neuropathy, 15% to 20% are due to ischemia, and another 15% to 20% are due to a combination of both. The neuropathy is both sensory and motor and is secondary to persistently elevated glucose levels. The loss of sensory function allows unrecognized injury to occur from ill-fitting shoes, foreign bodies, or other trauma. The motor neuropathy or Charcot’s foot leads to collapse or dislocation of the interphalangeal or metatarsophalangeal joints, causing pressure on areas with little protection. There is also severe micro- and macrovascular circulatory impairment. Once ulceration occurs, the chances of healing are poor. The treatment of diabetic wounds involves local and systemic measures.112 Achievement of adequate blood sugar levels is very important. Most diabetic wounds are infected, and eradication of the infectious source is paramount to the success of healing. Treatment should address the possible presence of osteomyelitis and should employ antibiotics that achieve adequate levels both in soft tissue and bone. Wide débridement of all necrotic or infected tissue is another cornerstone of treatment. Off-loading of the ulcerated area by using specialized orthotic shoes or casts allows for ambulation while protecting the fragile wound environment. Topical application of PDGF and granulocyte-macrophage colony-stimulating factor has met with limited but significant success in achieving closure.113 The application of engineered skin allograft substitutes, although expensive, also has shown some significant success.114 Prevention and specifically foot care play an important role in the management of diabetics.115 Decubitus or Pressure Ulcers. The incidence of pressure ulcers ranges from 2.7% to 9% in the acute care setting, in comparison to 2.4% to 23% in long-term care facilities. A pressure ulcer is a localized area of tissue necrosis that develops when soft tissue is compressed between a bony prominence and an external surface. Excessive pressure causes capillary collapse and impedes the delivery of nutrients to body tissues. Pressure ulcer formation is accelerated in the presence of friction, shear forces, and moisture. Other contributory factors in the pathogenesis of pressure ulcers include immobility, altered activity VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ levels, altered mental status, chronic conditions, and altered nutritional status. The four stages of pressure ulcer formation are as follows: stage I, nonblanching erythema of intact skin; stage II, partial-thickness skin loss involving epidermis or dermis or both; stage III, full-thickness skin loss, but not through the fascia; and stage IV, full-thickness skin loss with extensive involvement of muscle and bone. The treatment of established pressure ulcers is most successful when carried out in a multidisciplinary manner by involving wound care teams consisting of physicians, nurses, dietitians, physical therapists, and nutritionists. Care of the ulcer itself comprises débridement of all necrotic tissue, maintenance of a favorable moist wound environment that will facilitate healing, relief of pressure, and addressing host issues such as nutritional, metabolic, and circulatory status. Débridement is most efficiently carried out surgically, but enzymatic proteolytic preparations and hydrotherapy also are used. The wound bed should be kept moist by employing dressings that absorb secretions but do not desiccate the wound.116 Operative repair, usually involving flap rotation, has been found to be useful in obtaining closure. Unfortunately, recurrence rates are extremely high, owing to the population at risk and the inability to fully address the causative mechanisms.117 261 CHAPTER 9 Wound Healing EXCESS HEALING Clinically, excess healing can be as significant as wound failure. It is likely that more operative interventions are required for correction of the morbidity associated with excessive 4 healing than are required for wound failure. The clinical manifestations of exuberant healing are protean and differ in the skin (mutilating or debilitating scars, burn contractions), tendons (frozen repairs), the GI tract (strictures or stenoses), solid organs (cirrhosis, pulmonary fibrosis), or the peritoneal cavity (adhesive disease). Hypertrophic scars (HTSs) and keloids represent an overabundance of fibroplasia in the dermal healing process. HTSs rise above the skin level but stay within the confines of the original wound and often regress over time. Keloids rise above the skin level as well, but extend beyond the border of the original wound and rarely regress spontaneously (Fig. 9-11). Both HTSs and keloids occur after trauma to the skin and may be tender, pruritic, and cause a burning sensation. Keloids are 15 times more common in darker-pigmented ethnicities, with individuals of African, Spanish, and Asian ethnicities being especially susceptible. Men and women are equally affected. Genetically, the predilection to keloid formation appears to be autosomal dominant with incomplete penetration and variable expression.117,118 HTSs usually develop within 4 weeks after trauma. The risk of HTS increases if epithelialization takes longer than 21 days, independent of site, age, and race. Rarely elevated more than 4 mm above the skin level, HTSs stay within the boundaries of the wound. They usually occur across areas of tension and flexor surfaces, which tend to be at right angles to joints or skin creases. The lesions are initially erythematous and raised and over time may evolve into pale, flatter scars. Keloids can result from surgery, burns, skin inflammation, acne, chickenpox, zoster, folliculitis, lacerations, abrasions, tattoos, vaccinations, injections, insect bites, or ear piercing, or may arise spontaneously. Keloids tend to occur 3 months to years after the initial insult, and even minor injuries can result in large lesions. They vary in size from a few millimeters to large, Figure 9-11. Recurrent keloid on the neck of a 17-year-old patient that had been revised several times. (Reproduced with permission from Murray JC, Pinnell SR. Keloids and excessive dermal scarring. In: Cohen IK, Diegelmann RF, Lindblad WJ, eds. Wound Healing: Biochemical and Clinical Aspects. Philadelphia: WB Saunders; 1993. Copyright Elsevier.) pedunculated lesions with a soft to rubbery or hard consistency. While they project above surrounding skin, they rarely extend into underlying subcutaneous tissues. Certain body sites have a higher incidence of keloid formation, including the skin of the earlobe as well as the deltoid, presternal, and upper back regions. They rarely occur on eyelids, genitalia, palms, soles, or across joints. Keloids rarely involute spontaneously, and surgical intervention can lead to recurrence, often with a worse result (Table 9-8). Histologically, both HTSs and keloids demonstrate increased thickness of the epidermis with an absence of rete ridges. There is an abundance of collagen and glycoprotein deposition. Normal skin has distinct collagen bundles, mostly parallel to the epithelial surface, with random connections between bundles by fine fibrillar strands of collagen. In HTS, the collagen bundles are flatter and more random, and the fibers are in a wavy pattern. In keloids, the collagen bundles are virtually nonexistent, and the fibers are connected haphazardly in loose sheets with a random orientation to the epithelium. The collagen fibers are larger and thicker, and myofibroblasts are generally absent.119 Keloidal fibroblasts have normal proliferation parameters but synthesize collagen at a rate 20 times greater than that observed in normal dermal fibroblasts, and 3 times higher than fibroblasts derived from HTS. Abnormal amounts of extracellular matrix such as fibronectin, elastin, and proteoglycans also are produced. The synthesis of fibronectin, which promotes clot generation, granulation tissue formation, and re-epithelialization, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 262 TABLE 9-8 Characteristics of keloids and hypertrophic scars PART I Incidence Keloid Hypertrophic Scar Rare Frequent Ethnic groups African American, Asian, Hispanic No predilection Prior injury Yes Yes BASIC CONSIDERATIONS Site predilection Neck, chest, ear lobes, shoulders, upper back Anywhere Genetics Autosomal dominant with incomplete penetration No Timing Symptom-free interval; may appear years after injury 4–6 weeks postinjury Symptoms Pain, pruritus, hyperesthesia, growth beyond wound margins Raised, some pruritus, respects wound confines Regression No Frequent spontaneous Contracture Rare Frequent Histology Hypocellular, thick, wavy collagen fibers in random orientation Parallel orientation of collagen fibers decreases during the normal healing process; however, production continues at high levels for months to years in HTSs and keloids. This perturbed synthetic activity is mediated by altered growth factor expression. TGF-β expression is higher in HTS, and both HTS- and keloid-derived fibroblasts respond to lower concentrations of TGF-β than do normal dermal fibroblasts. HTSs also express increased levels of insulin-like growth factor-1, which reduces collagenase mRNA activity and increases mRNA for types I and II procollagen.120 Keloid fibroblasts have enhanced expression of TGF-β1 and TGF-β2, VEGF, and plasminogen activator inhibitor-1 and an increased number of PDGF receptors; they also have upregulated antiapoptotic gene expression, which can be differentially expressed within different areas of the same scar. The underlying mechanisms that cause HTSs and keloids are not known. The immune system appears to be involved in the formation of both HTSs and keloids, although the exact relationship is unknown. Much is inferred from the presence of various immune cells in HTSs and keloids. For example, in both HTSs and keloids, keratinocytes express human leukocyte antigen (HLA)-2 and ICAM-1 receptors, which are absent in normal scar keratinocytes. Keloids also have increased deposition of immunoglobulins IgG, IgA, and IgM, and their formation correlates with serum levels of IgE. Antinuclear antibodies against fibroblasts, epithelial cells, and endothelial cells are found in keloids, but not HTSs. HTSs have higher T lymphocyte and Langerhans cell contents. There is also a larger number of mast cells present in both HTSs and keloids compared to normal scars. Another recently described cell population is the fibrocyte, a leukocyte subpopulation derived from peripheral mononuclear cells. Present in large numbers at the site of excess scarring, fibrocytes can stimulate fibroblast numbers and collagen synthesis. They also generate large numbers of cytokines, growth factors, and extracellular matrix proteins, which are characteristically upregulated in keloid tissue. Other mechanisms that may cause abnormal scarring include mechanical tension (although keloids often occur in areas of minimal tension) and prolonged irritation and/ or inflammation that may lead to the generation of abnormal concentrations of profibrotic cytokines. Treatment goals include restoration of function to the area, relief of symptoms, and prevention of recurrence. Many patients seek intervention due to cosmetic concerns. Because the underlying mechanisms causing keloids and HTSs remain unknown, many different modalities of treatment have been used without consistent success.121 Excision alone of keloids is subject to a high recurrence rate, ranging from 45% to 100%. Inclusion of the dermal advancing edge that characterizes keloids, use of incisions in skin tension lines, and tension-free closure all have been proposed to decrease recurrence rates. There are fewer recurrences when surgical excision is combined with other modalities such as intralesional corticosteroid injection, topical application of silicone sheets, or the use of radiation or pressure. Surgery is recommended for debulking large lesions or as second-line therapy when other modalities have failed. Silicone application is relatively painless and should be maintained for 24 hours a day for about 3 months to prevent rebound hypertrophy. It may be secured with tape or worn beneath a pressure garment. The mechanism of action is not understood, but increased hydration of the skin, which decreases capillary activity, inflammation, hyperemia, and collagen deposition, may be involved. Silicone is more effective than other occlusive dressings and is an especially good treatment for children and others who cannot tolerate the pain involved in other modalities.102 Intralesional corticosteroid injections decrease fibroblast proliferation, collagen and glycosaminoglycan synthesis, the inflammatory process, and TGF-β levels. When used alone, however, there is a variable rate of response and recurrence; therefore, steroids are recommended as first-line treatment for keloids and second-line treatment for HTSs if topical therapies have failed. Intralesional injections are more effective on younger scars. They may soften, flatten, and give symptomatic relief to keloids, but they cannot make the lesions disappear and they cannot narrow wide HTSs. Success is enhanced when used in combination with surgical excision. Serial injections every 2 to 3 weeks are required. Complications include skin atrophy, hypopigmentation, telangiectasias, necrosis, and ulceration. Although radiation destroys fibroblasts, it has variable, unreliable results and produces poor results, with 10% to 100% recurrence when used alone. It is more effective when combined with surgical excision. The timing, duration, and dosage for radiation therapy are still controversial, but doses ranging from VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 263 Peritoneal injury Macrophages mesothelium Coagulation TF Peritoneal fluid Thrombin + + Fibrinogen Bleeding Inflammation Fibrin PAI-1, PAI-2 tPA, uPA Fibrin residues Fibrinolysis Fibrinolysis degradation Fibroblasts and capillaries Restitution Fibrous adhesion Figure 9-12. Fibrin formation and degradation in peritoneal tissue repair and adhesion formation. PAI-1, PAI-2 = types 1 and 2 plasminogen activator inhibitor; TF = tissue factor; tPA = tissue plasminogen activator; uPA = urokinase plasminogen activator. within the peritoneal cavity. During normal repair, fibrin is principally degraded by the fibrinolytic protease plasmin, which is derived from inactive plasminogen through the action of two plasminogen activators (PA): tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Fibrinolytic activity in peritoneal fluid is reduced after abdominal surgery due to initial decreases in tPA levels and later to increases in plasminogen activator inhibitor-1 (PAI-1), which are induced by various cytokines, including TNF-α, IL-1, and interleukin-6 (IL-6).123 There are two major strategies for adhesion prevention or reduction. Surgical trauma is minimized within the peritoneum by careful tissue handling, avoiding desiccation and ischemia, and spare use of cautery, laser, and retractors. Fewer adhesions form with laparoscopic surgical techniques due to reduced tissue trauma. The second major advance in adhesion prevention has been the introduction of barrier membranes and gels, which separate and create barriers between damaged mesothelial surfaces, allowing for adhesion-free healing. Currently, only three products are Food and Drug Administration (FDA) approved for reducing adhesion formation: Interceed (oxidized regenerated cellulose, indicated only in pelvic surgery), Seprafilm (a film composed of hyaluronic acid and carboxymethylcellulose) that is usually applied below the incision, and Adept (4% icodextrin, a corn starch derivative in electrolyte solution, also for use mainly in pelvic surgery). However, use of these substances directly over bowel anastomoses is contraindicated due to an elevated risk of leak.124 There have been innumerable studies investigating different molecules in hopes of preventing adhesion formation, but most of the success is limited to animal models, and clinically significant results in humans have yet to be achieved. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Wound Healing Platelets CHAPTER 9 1500 to 2000 rads appear effective. Given the risks of hyperpigmentation, pruritus, erythema, paresthesias, pain, and possible secondary malignancies, radiation should be reserved for adults with scars resistant to other modalities. Pressure aids collagen maturation, flattens scars, and improves thinning and pliability. It reduces the number of cells in a given area, possibly by creating ischemia, which decreases tissue metabolism and increases collagenase activity. External compression is used to treat HTSs, especially after burns. Therapy must begin early, and a pressure between 24 and 30 mmHg must be achieved in order to exceed capillary pressure, yet preserve peripheral blood circulation. Garments should be worn for 23 to 24 hours a day for up to 1 or more years to avoid rebound hypertrophy. Scars older than 6 to 12 months respond poorly. Topical retinoids also have been used as treatment for both HTSs and keloids, with reported responses of 50% to 100%. Intralesional injections of IFN-γ, a cytokine released by T lymphocytes, reduce collagen types I, II, and III by decreasing mRNA and possibly by reducing levels of TGF-β. As monotherapy, IFN-γ has failed because of high recurrence rates due to resistance to repeated injections. More recently, imiquimod, an immunomodulator that induces IFN-γ and other cytokines at the site of application, has been recommended following excision. Intralesional injections of chemotherapeutic agents such as 5-fluorouracil have been used both alone and in combination with steroids. The use of bleomycin or mitomycin C has been reported to achieve some success in older scars resistant to steroids. Peritoneal Scarring. Peritoneal adhesions are fibrous bands of tissues formed between organs that are normally separated and/or between organs and the internal body wall. Most intraabdominal adhesions are a result of peritoneal injury, either by a prior surgical procedure or due to intra-abdominal infection. Postmortem examinations demonstrate adhesions in 67% of patients with prior surgical procedures and in 28% with a history of intra-abdominal infection. Intra-abdominal adhesions are the most common cause (65%–75%) of small bowel obstruction, especially in the ileum. Operations in the lower abdomen have a higher chance of producing small bowel obstruction. Following rectal surgery, left colectomy, or total colectomy, there is an 11% chance of developing small bowel obstruction within 1 year, and this rate increases to 30% by 10 years. Adhesions also are a leading cause of secondary infertility in women and can cause substantial abdominal and pelvic pain. Adhesions account for 2% of all surgical admissions and 3% of all laparotomies in general surgery.122 Adhesions form when the peritoneal surface is damaged due to surgery, thermal or ischemic injury, inflammation, or foreign body reaction. The injury disrupts the protective mesothelial cell layer lining the peritoneal cavity and the underlying connective tissue. The injury elicits an inflammatory response consisting of hyperemia, fluid exudation, release and activation of white blood cells and platelets in the peritoneal cavity, activation of inflammatory cytokines, and the onset of the coagulation and complement cascades. Fibrin deposition occurs between the damaged but opposed serosal surfaces. These filmy adhesions often are transient and degraded by proteases of the fibrinolytic system, with restoration of the normal peritoneal surface. If insufficient fibrinolytic activity is present, permanent fibrous adhesions will form by collagen deposition within 1 week of the injury (Fig. 9-12). Extensive research has been done on the effect of surgery and peritonitis on the fibrinolytic and inflammatory cascades 264 TREATMENT OF WOUNDS Local Care (Fig. 9-13) PART I BASIC CONSIDERATIONS Management of acute wounds begins with obtaining a careful history of the events surrounding the injury. The history is followed by a meticulous examination of the wound. Examination should assess the depth and configuration of the wound, the extent of nonviable tissue, and the presence of foreign bodies and other contaminants. Examination of the wound 5 may require irrigation and débridement of the edges of the wound and is facilitated by use of local anesthesia. Antibiotic administration and tetanus prophylaxis may be needed, and planning the type and timing of wound repair should take place. After completion of the history, examination, and administration of tetanus prophylaxis, the wound should be meticulously anesthetized. Lidocaine (0.5%–1%) or bupivacaine (0.25%–0.5%) combined with a 1:100,000 to 1:200,000 dilution of epinephrine provides satisfactory anesthesia and hemostasis. Epinephrine should not be used in wounds of the fingers, toes, ears, nose, or penis, due to the risk of tissue necrosis secondary to terminal arteriole vasospasm in these structures. Injection of these anesthetics can result in significant initial patient discomfort, and this can be minimized by slow injection, infiltration of the subcutaneous tissues, and buffering the solution with sodium bicarbonate. Care must be observed in calculating the maximum dosages of lidocaine or bupivacaine in order to avoid toxicityrelated side effects. Irrigation to visualize all areas of the wound and remove foreign material is best accomplished with normal saline (without additives). High-pressure wound irrigation is more effective in achieving complete débridement of foreign material and nonviable tissues. Iodine, povidone-iodine, hydrogen peroxide, and organically based antibacterial preparations have all been shown to impair wound healing due to injury to wound neutrophils and macrophages, and thus should not be used. All hematomas present within wounds should be carefully evacuated and any remaining bleeding sources controlled with ligature or cautery. If the injury has resulted in the formation of a marginally viable flap of skin or tissue, this should be resected or revascularized prior to further wound repair and closure. After the wound has been anesthetized, explored, irrigated, and débrided, the area surrounding the wound should be cleaned, inspected, and the surrounding hair clipped. The area surrounding the wound should be prepared with povidone iodine, chlorhexidine, or similar bacteriostatic solutions and draped with sterile towels. Having ensured hemostasis and adequate débridement of nonviable tissues and removal of any remaining foreign bodies, irregular, macerated, or beveled wound edges should be débrided in order to provide a fresh edge for reapproximation. Although plastic surgical techniques such as W- or Z-plasty are seldom recommended for acute wounds, great care must be taken to realign wound edges properly. This is particularly important for wounds that cross the vermilion border, eyebrow, or hairline. Initial sutures that realign the edges of these different tissue types will speed and greatly enhance the aesthetic outcome of the wound repair. In general, the smallest suture required to hold the various layers of the wound in approximation should be selected in order to minimize suture-related inflammation. Nonabsorbable or slowly absorbing monofilament sutures are most suitable for approximating deep fascial layers, particularly in the abdominal wall. Subcutaneous tissues should be closed with braided absorbable sutures, with care to avoid placement of sutures in fat. Although traditional teaching in wound closure has emphasized multiple-layer closures, additional layers of suture closure are associated with increased risk of wound infection, especially when placed in fat. Drains may be placed in areas at risk of forming fluid collections. In areas of significant tissue loss, rotation of adjacent musculocutaneous flaps may be required to provide sufficient tissue mass for closure. These musculocutaneous flaps may be based on intrinsic blood supply or may be moved from distant sites as free flaps and anastomosed into the local vascular bed. In areas with significant superficial tissue loss, split-thickness skin grafting (placed in a delayed manner to assure an adequate tissue bed) may be required and will speed formation of an intact epithelial barrier to fluid loss and infection. Split-thickness skin grafts are readily obtained using manual or mechanical dermatomes, and the grafts may be “meshed” in order to increase the surface area of their coverage. It is essential to ensure hemostasis Management of acute wounds 1. Examination a) Depth? Underlying structures injured b) Configuration? c) Nonviable tissue? 2. Preparation a) Anesthetic -Lidocaine w or w/o epinephrine b) Exploration -Underlying structures injured c) Cleansing -Pulsed irrigation, saline only d) Hemostasis e) Débride nonviable tissue f) Betadine on surrounding skin g) Antibiotics (rare) h) Tetanus 3. Approximation a) Deep layers -Fascial layers only -Absorbable suture b) Superficial layers -Meticulous alignment -Nonabsorbable sutures in skin -Staples -Monofilament -Dermal glues 4. Follow-up a) Cellulitis/drainage? b) Suture removal -4–5 days for face -7–10 days other skin VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 9-13. Algorithm for management of acute wounds. Antibiotics should be used only when there is an obvious wound infection. Most wounds are contaminated or colonized with bacteria. The presence of a host response constitutes an infection and justifies the use of antibiotics. Signs of infection to look for include erythema, cellulitis, swelling, and purulent discharge. Indiscriminate use of antibiotics should be avoided to prevent emergence of multidrug-resistant bacteria. Antibiotic treatment of acute wounds must be based on organisms suspected to be found within the infected wound and the patient’s overall immune status. When a single specific organism is suspected, treatment may be commenced using a single antibiotic. Conversely, when multiple organisms are suspected, as with enteric contamination or when a patient’s immune function is impaired by diabetes, chronic disease, or medication, treatment should commence with a broad-spectrum antibiotic or several agents in combination. Lastly, the location of the wound and the quality of tissue perfusion to that region will significantly impact wound performance after injury. Antibiotics also can be delivered topically as part of irrigations or dressings, although their efficacy is questionable. Dressings The main purpose of wound dressings is to provide the ideal environment for wound healing. The dressing should facilitate the major changes taking place during healing to produce an optimally 265 Desired characteristics of wound dressings Promote wound healing (maintain moist environment) Conformability Pain control Odor control Nonallergenic and nonirritating Permeability to gas Safety Nontraumatic removal Cost-effectiveness Convenience healed wound. Although the ideal dressing still is not a clinical reality, technological advances are promising (Table 9-9). Covering a wound with a dressing mimics the barrier role of epithelium and prevents further damage. In addition, application of compression provides hemostasis and limits edema. Occlusion of a wound with dressing material helps healing by controlling the level of hydration and oxygen tension within the wound. It also allows transfer of gases and water vapor from the wound surface to the atmosphere. Occlusion affects both the dermis and epidermis, and it has been shown that exposed wounds are more inflamed and develop more necrosis than covered wounds. Occlusion also helps in dermal collagen synthesis and epithelial cell migration and limits tissue desiccation. Since it may enhance bacterial growth, occlusion is contraindicated in infected and/or highly exudative wounds. Dressings can be classified as primary or secondary. A primary dressing is placed directly on the wound and may provide absorption of fluids and prevent desiccation, infection, and adhesion of a secondary dressing. A secondary dressing is one that is placed on the primary dressing for further protection, absorption, compression, and occlusion. Many types of dressings exist and are designed to achieve certain clinically desired endpoints. Absorbent Dressings. Accumulation of wound fluid can lead to maceration and bacterial overgrowth. Ideally, the dressing should absorb without getting soaked through, as this would permit bacteria from the outside to enter the wound. The dressing must be designed to match the exudative properties of the wound and may include cotton, wool, and sponge. Nonadherent Dressings. Nonadherent dressings are impregnated with paraffin, petroleum jelly, or water-soluble jelly for use as nonadherent coverage. A secondary dressing must be placed on top to seal the edges and prevent desiccation and infection. Occlusive and Semiocclusive Dressings. Occlusive and semiocclusive dressings provide a good environment for clean, minimally exudative wounds. These film dressings are waterproof and impervious to microbes but permeable to water vapor and oxygen. Hydrophilic and Hydrophobic Dressings. These dressings are components of a composite dressing. Hydrophilic dressing aids in absorption, whereas a hydrophobic dressing is waterproof and prevents absorption. Hydrocolloid and Hydrogel Dressings. Hydrocolloid and hydrogel dressings attempt to combine the benefits of occlusion and absorbency. Hydrocolloids and hydrogels form complex VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Wound Healing Antibiotics Table 9-9 CHAPTER 9 of the underlying tissue bed prior to placement of split-thickness skin grafts, as the presence of a hematoma below the graft will prevent the graft from taking, resulting in sloughing of the graft. In acute, contaminated wounds with skin loss, use of porcine skin xenografts or skin cadaveric allografts is prudent until the danger of infection passes. After closing deep tissues and replacing significant tissue deficits, skin edges should be reapproximated for cosmesis and to aid in rapid wound healing. Skin edges may be quickly reapproximated with stainless steel staples or nonabsorbable monofilament sutures. Care must be taken to remove these from the wound prior to epithelialization of the skin tracts where sutures or staples penetrate the dermal layer. Failure to remove the sutures or staples prior to 7 to 10 days after repair will result in a cosmetically inferior wound. Where wound cosmesis is important, the above problems may be avoided by placement of buried dermal sutures using absorbable braided sutures. This method of wound closure allows for a precise reapproximation of wound edges and may be enhanced by application of wound closure tapes to the surface of the wound. Intradermal absorbable sutures do not require removal. Use of skin tapes alone is only recommended for closure of the smallest superficial wounds. Larger wounds generate sufficient lateral tension that the epithelial edges either separate or curl upward under the tapes, resulting in inadequate epithelial apposition and poor cosmesis. The development of octyl-cyanoacrylate tissue glues have shown new promise for the management of simple, linear wounds with viable skin edges. These new glues are less prone to brittleness and have superior burst-strength characteristics. Studies have shown them to be suitable for use in contaminated situations without significant risk of infection. When used in the above types of wounds, these glues appear to provide superb cosmetic results and result in significantly less trauma than sutured repair, particularly when used in pediatric patients. 266 PART I structures with water, and fluid absorption occurs with particle swelling, which aids in atraumatic removal of the dressing. Absorption of exudates by the hydrocolloid dressing leaves a yellowish-brown gelatinous mass after dressing removal that can be washed off. Hydrogel is a cross-linked polymer that has high water content. Hydrogels allow a high rate of evaporation without compromising wound hydration, which makes them useful in burn wound treatment. Alginates. Alginates are derived from brown algae and conBASIC CONSIDERATIONS tain long chains of polysaccharides containing mannuronic and glucuronic acid. The ratios of these sugars vary with the species of algae used, as well as the season of harvest. Processed as the calcium form, alginates turn into soluble sodium alginate through ion exchange in the presence of wound exudates. The polymers gel, swell, and absorb a great deal of fluid. Alginates are being used when there is skin loss, in open surgical wounds with medium exudation, and on full-thickness chronic wounds. Absorbable Materials. Absorbable materials are mainly used within wounds as hemostats and include collagen, gelatin, oxidized cellulose, and oxidized regenerated cellulose. Medicated Dressings. Medicated dressings have long been used as a drug-delivery system. Agents delivered in the dressings include benzoyl peroxide, zinc oxide, neomycin, and bacitracin-zinc. These agents have been shown to increase epithelialization by 28%. The type of dressing to be used depends on the amount of wound drainage. A nondraining wound can be covered with semiocclusive dressing. Drainage of less than 1 to 2 mL/d may require a semiocclusive or absorbent nonadherent dressing. Moderately draining wounds (3–5 mL/d) can be dressed with a nonadherent primary layer plus an absorbent secondary layer plus an occlusive dressing to protect normal tissue. Heavily draining wounds (>5 mL/d) require a similar dressing as moderately draining wounds, but with the addition of a highly absorbent secondary layer. Mechanical Devices. Mechanical therapy augments and improves on certain functions of dressings, in particular the absorption of exudates and control of odor. The vacuum-assisted closure (VAC) system assists in wound closure by applying localized negative pressure to the surface and margins of the wound. The negative-pressure therapy is applied to a special foam dressing cut to the dimensions of the wound and positioned in the wound cavity or over a flap or graft. The continuous negative pressure is very effective in removing exudates from the wound. This form of therapy has been found to be effective for chronic open wounds (diabetic ulcers and stages III and IV pressure ulcers), acute and traumatic wounds,125 flaps and grafts, and subacute wounds (i.e., dehisced incisions), although more randomized trials need to be carried out to confirm efficacy. Skin Replacements All wounds require coverage in order to prevent evaporative losses and infection and to provide an environment that promotes healing. Both acute and chronic wounds may demand use of skin replacement, and several options are available. Conventional Skin Grafts. Skin grafts have long been used to treat both acute and chronic wounds. Split- (partial-) thickness grafts consist of the epidermis plus part of the dermis, whereas full-thickness grafts retain the entire epidermis and dermis. Autologous grafts (autografts) are transplants from one site on the body to another; allogeneic grafts (allografts, homografts) are transplants from a living nonidentical donor or cadaver to the host; and xenogeneic grafts (heterografts) are taken from another species (e.g., porcine). Split-thickness grafts require less blood supply to restore skin function. The dermal component of full-thickness grafts lends mechanical strength and resists wound contraction better, resulting in improved cosmesis. Allogeneic and xenogeneic grafts require the availability of tissue, are subject to rejection, and may contain pathogens. The use of skin grafts or bioengineered skin substitutes and other innovative treatments (e.g., topically applied growth factors, systemic agents, and gene therapy) cannot be effective unless the wound bed is adequately prepared. This may include débridement to remove necrotic or fibrinous tissue, control of edema, revascularization of the wound bed, decreasing the bacterial burden, and minimizing or eliminating exudate. Temporary placement of allografts or xenografts may be used to prepare the wound bed. Skin Substitutes. Originally devised to provide coverage of extensive wounds with limited availability of autografts, skin substitutes also have gained acceptance as natural dressings. Manufactured by tissue engineering, they combine novel materials with living cells to provide functional skin substitutes, providing a bridge between dressings and skin grafts. Skin substitutes have theoretical advantages of being readily available and not requiring painful harvest, and they may be applied freely or with surgical suturing. In addition, they promote healing, either by stimulating host cytokine generation or by providing cells that may also produce growth factors locally. Their disadvantages include limited survival, high cost, and the need for multiple applications (Table 9-10). Allografting, albeit with a very thin graft, may at times be required to accomplish complete coverage. A variety of skin substitutes are available, each with its own set of advantages and disadvantages; however, the ideal skin substitute has yet to be developed (Table 9-11). The development of the newer composite substitutes, which provide both the dermal and epidermal components essential for permanent skin replacement, may represent an advance toward that goal. The acellular (e.g., native collagen or synthetic material) component acts as a scaffold, promotes cell migration and growth, and activates tissue regeneration and remodeling. The cellular elements re-establish lost tissue and associated function, synthesize extracellular matrix components, produce essential mediators such as cytokines and growth factors, and promote proliferation and migration. Cultured epithelial autografts (CEAs) represent expanded autologous or homologous keratinocytes. CEAs are expanded from a biopsy of the patient’s own skin, will not be rejected, Table 9-10 Desired features of tissue-engineered skin Rapid re-establishment of functional skin (epidermis/dermis) Receptive to body’s own cells (e.g., rapid “take” and integration) Graftable by a single, simple procedure Graftable on chronic or acute wounds Engraftment without use of extraordinary clinical intervention (i.e., immunosuppression) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 267 Table 9-11 Advantages and disadvantages of various bioengineered skin substitutes Disadvantages Cultured allogeneic keratinocyte graft No biopsy needed “Off the shelf” availability Provides wound coverage Promotes healing Unstable Does not prevent wound contracture Inadequate cosmesis Possibility of disease transmission Fragile Bioengineered dermal replacement Prevents contracture Good prep for graft application Limited ability to drive re-epithelialization Largely serves as temporary dressing Cultured bilayer skin equivalent More closely mimics normal anatomy Does not need secondary procedure Easily handled Can be sutured, meshed, etc. Cost Short shelf life True engraftment questionable and can stimulate re-epithelialization as well as the growth of underlying connective tissue. Keratinocytes harvested from a biopsy roughly the size of a postage stamp are cultured with fibroblasts and growth factors and grown into sheets that can cover large areas and give the appearance of normal skin. Until the epithelial sheets are sufficiently expanded, the wound must be covered with an occlusive dressing or a temporary allograft or xenograft. The dermis regenerates very slowly, if at all, for full-thickness wounds, because the sheets are very fragile, are difficult to work with, are susceptible to infection, and do not resist contracture well, leading to poor cosmetic results. CEAs are available from cadavers, unrelated adult donors, or neonatal foreskins. Fresh or cryopreserved cultured allogeneic keratinocytes can be left in place long enough to be superseded by multiplying endogenous skin cells because, unlike allografts containing epidermal Langerhans cells, they do not express major histocompatibility antigens. Cryopreserved CEAs are readily available “off the shelf,” and provide growth factors that may aid healing. However, like autologous keratinocyte sheets, the grafts lack the strength provided by a dermal component and pose a risk of disease transmission. Viable fibroblasts can be grown on bioabsorbable or nonbioabsorbable meshes to yield living dermal tissue that can act as a scaffold for epidermal growth. Fibroblasts stimulated by growth factors can produce type I collagen and glycosaminoglycans (e.g., chondroitin sulfates), which adhere to the wound surface to permit epithelial cell migration, as well as adhesive ligands (e.g., the matrix protein fibronectin), which promote cell adhesion. This approach has the virtue of being less time-consuming and expensive than culturing keratinocyte sheets. There are a number of commercially available, bioengineered dermal replacements approved for use in burn wound treatment as well as other indications. Bioengineered skin substitutes have evolved from keratinocyte monolayers to dermal equivalents to split-thickness products with a pseudo-epidermis, and most recently, to products containing both epidermal and dermal components that resemble the three-dimensional structure and function of normal skin (see Table 9-11). Indicated for use with standard compression therapy in the treatment of venous insufficiency ulcers and for the treatment of neuropathic diabetic foot ulcers, these bilayered skin equivalents also are being used in a variety of wound care settings. Growth Factor Therapy. As discussed previously, it is believed that nonhealing wounds result from insufficient or inadequate growth factors in the wound environment. A simplistic solution would be to flood the wound with single or multiple growth factors in order to “jump-start” healing and re-epithelialization. Although there is a large body of work demonstrating the effects of growth factors in animals, translation of these data into clinical practice has met with limited success. Growth factors for clinical use may be either recombinant or homologous/autologous. Autologous growth factors are harvested from the patient’s own platelets, yielding an unpredictable combination and concentration of factors, which are then applied to the wound. This approach allows treatment with patient-specific factors at an apparently physiologic ratio of growth factor concentrations. Disappointingly, a recent metaanalysis failed to demonstrate any value for autologous plateletrich plasma in the treatment of chronic wounds.126 Recombinant molecular biologic means permit the purification of high concentrations of individual growth factors. Current FDA-approved formulations, as well as those used experimentally, deliver concentrations approximately 103 times higher than those observed physiologically. At present, only platelet-derived growth factor BB (PDGF-BB) is currently approved by the FDA for treatment of diabetic foot ulcers. Application of recombinant human PDGFBB in a gel suspension to these wounds increases the incidence of total healing and decreases healing time. Several other growth factors have been tested clinically and show some promise, but currently none are approved for use. A great deal more needs to be discovered about the concentration, temporal release, and receptor cell population before growth factor therapy is to make a consistent impact on wound healing. Gene or Cell Therapy. Given the disappointing results from the application of purified growth factors onto wounds, the possible therapeutic potential of gene therapy has been recognized and studied. Direct access to the open wound bed, which characterizes almost all chronic wounds, has facilitated this therapy. Gene delivery to wounds includes traditional approaches such as viral vectors and plasmid delivery or, more recently, electroporation and microseeding. Although a variety of genes expressing interleukin-8, PDGF, IGF-1, keratinocyte growth factor, and laminin-5 have VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Wound Healing Advantages CHAPTER 9 Skin Substitute 268 PART I BASIC CONSIDERATIONS been successfully delivered to wounds in both animal and human models, the effects have been modest and specific to unique wound situations. Delivering extra genes into the wound bed presents the challenge of expression of the necessary signals to turn the genes on and off at appropriate times so that dysregulated, hypertrophic, and abnormal healing does not occur. Elaborate systems have been created for topical use as on/off switches for genes. The more important question is which genes to express, in what temporal sequence, and in what regions of the wound bed, as it is unlikely that a single gene coding for one protein can significantly affect overall healing. There is growing consensus that delivery of genes is not going to represent the universal solution. Although gene therapy replaces missing or defective genes, most acute wounds already have and express the necessary genes for successful healing and the wound environment produces signals adequate to the activation of these genes. What, if any, are the deficiencies in gene expression or activity in failed wounds is unknown. Another approach is to deliver multiple genes coding for proteins that can act synergistically and even in a timed sequence, as would occur during normal healing. This would involve the use of activated cells that participate in the healing sequence that could be delivered in an activated state to the wound environment. 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Effects of aggressive versus moderate glycemic control on clinical outcomes in diabetic coronary artery bypass patients. Ann Surg. 2011;254:458-463. 99. Gottrup F, Firmin R, Rabkin J, et al. Directly measured tissue oxygen tension and arterial oxygen tension assess tissue perfusion. Crit Care Med. 1987;15:1030-1036. 100. Sheffield CW, Sessler DI, Hopf HW, et al. Centrally and locally mediated thermoregulatory responses alter subcutaneous oxygen tension. Wound Repair Regen. 1996;4:339-345. 101. Maragakis LL, Cosgrove SE, Martinez EA, et al. Intraoperative fraction of inspired oxygen is a modifiable risk factor for surgical site infection after spinal surgery. Anesthesiology. 2009;110:556-562. 102. Meyhoff C, Weyyerslev J, Jorgensen LN, et al. Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: the PROXI Randomized Clinical Trial. JAMA. 2009;302:1543-1550. 103. Falanga V, Eaglstein WH. The “trap” hypothesis of venous ulceration. Lancet. 1993;341:1006. 104. Lobmann R, Ambrosch A, Schultz G, et al. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia. 2002;45:1011. 105. Stanley A, Osler T. Senescence and the healing rates of venous ulcers. J Vasc Surg. 2001;33:1206. 106. Kim BC, Kim HT, Park SH, et al. Fibroblasts from chronic wounds show altered TGF-β-signaling and decreased TGF-β type II receptor expression. J Cell Physiol. 2003;195:331. 107. Hopf HW, Ueno C, Aslam R, et al. Guidelines for the treatment of arterial insufficiency ulcers. Wound Repair Regen. 2006;14:693. 108. Hopf HW, Ueno C, Aslam R, et al. Guidelines for the prevention of lower extremity arterial ulcers. Wound Repair Regen. 2008;16:175. 109. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the treatment of venous ulcers. Wound Repair Regen. 2006;14:649. 110. Kirsner RS, Marston WA, Snyder RJ, et al. Sprayed-applied cell therapy with human allogeneic fibroblasts and keratinocytes for treatment of chronic venous leg ulcers: a phase 2, multicenter, double-blind, randomized, place-controlled trial. Lancet. 2012;380:977-985. 111. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the prevention of venous ulcers. Wound Repair Regen. 2008;16:147. 112. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for treatment of diabetic ulcers. Wound Repair Regen. 2006;14:680. 113. Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet. 2003;361:1545. 114. Steed DL, Attinger C, Brem H, et al. Guidelines for the prevention of diabetic ulcers. Wound Repair Regen. 2008;16:169. 115. Whitney J, Phillips L, Aslam R, et al. Guidelines for the treatment of pressure ulcers. Wound Repair Regen. 2006;14:663. 116. Stechmiller JK, Cowan L, Whitney J, et al. Guidelines for the prevention of pressure ulcers. Wound Repair Regen. 2008;16:151. 117. Niessen FB, Spauwen PH, Schalkwijk J, et al. On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg. 1999;104:1435. 118. Marneros AG, Norris JE, Olsen BR, et al. Clinical genetics of familial keloids. Arch Dermatol. 2001;137:1429. 119. Gauglitz GG, Korting HC, Pavicic T, et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17:113-125. 120. Butler PD, Longaker MT, Yang GP. Current progress in keloid research and treatment. J Am Coll Surg. 2008;206:731. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 124. Zeng Q, Yu Z, You J, Zhang Q. Efficacy and safety of Seprafilm for preventing postoperative abdominal adhesion: systematic review and meta-analysis. World J Surg. 2007;31:2125. 125. Armstrong DG, Lavery L. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet. 2005;366:1704. 126. Martinez-Zapata MJ, Marti-Carvajal AJ, Sola I, et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2012;10:CD006899. 271 CHAPTER 9 121. Mustoe TA. Evolution of silicone therapy and mechanism of action in scar management. Aesthetic Plast Surg. 2008;32:82. 122. Dijkstra FR, Nieuwenhuijzen M, Reijnen MM, et al. Recent clinical developments in pathophysiology, epidemiology, diagnosis and treatment of intra-abdominal adhesions. Scand J Gastroenterol Suppl. 2000;232:52. 123. Cheong YC, Laird SM, Shellton JB, et al. The correlation of adhesions and peritoneal fluid cytokine concentrations: a pilot study. Hum Reprod. 2002;17:1039. Wound Healing VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 10 chapter Oncology and Surgical Practice Epidemiology 273 274 Basic Principles of Cancer Epidemiology / 274 Cancer Incidence and Mortality in the United States / 274 Global Statistics on Cancer Incidence and Mortality / 275 Cancer Biology 277 Hallmarks of Cancer / 277 Cell Proliferation and Transformation / 277 Cancer Initiation / 278 Cell-Cycle Dysregulation in Cancer / 279 Oncogenes / 279 Alterations in Apoptosis in Cancer Cells / 281 Autophagy in Cancer Cells / 283 Cancer Invasion / 283 Angiogenesis / 283 Metastasis / 284 Epithelial-Mesenchymal Transition / 285 Cancer Stem Cells / 285 Cancer Etiology 285 Cancer Genomics / 285 Tumor Heterogeneity and Molecular ­Evolution / 287 Genes Associated with Hereditary Cancer Risk / 287 Oncology Funda Meric-Bernstam and Raphael E. Pollock Chemotherapy BRCA1, BRCA2, and Hereditary ­Breast-Ovarian Cancer / 291 APCGene and Familial Adenomatous ­Polyposis / 291 PTEN and Cowden Disease / 292 RET Proto-Oncogene and Multiple ­Endocrine Neoplasia Type 2 / 293 Chemical Carcinogens / 293 Physical Carcinogens / 293 Viral Carcinogens / 295 Cancer Risk Assessment Cancer Screening Cancer Diagnosis Cancer Staging Tumor Markers 296 297 299 300 301 Prognostic and Predictive Tissue Markers / 301 Serum Markers / 302 Circulating Tumor Cells / 303 Bone Marrow Micrometastases / 304 Surgical Approaches to Cancer Therapy 304 Multidisciplinary Approach to Cancer / 304 Surgical Management of Primary Tumors / 304 Surgical Management of the Regional Lymph Node Basin / 305 Surgical Management of Distant ­Metastases / 306 ONCOLOGY AND SURGICAL PRACTICE As the population ages, oncology is becoming a larger portion of surgical practice. The surgeon often is responsible for the initial diagnosis and management of solid tumors. Knowledge of cancer epidemiology, etiology, staging, and natural history is required for initial patient assessment, as well as to determination of the optimal surgical therapy. Modern cancer therapy is multidisciplinary, involving the coordinated care of patients by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radiologists, and primary care physicians. Primary (or 1 definitive) surgical therapy refers to en bloc resection of tumor with adequate margins of normal tissues and regional lymph nodes as necessary. Adjuvant therapy refers to radiation therapy and systemic therapies, including chemotherapy, 306 Clinical Use of Chemotherapy / 306 Principles of Chemotherapy / 307 Anticancer Agents / 307 Combination Chemotherapy / 307 Drug Toxicity / 308 Administration of Chemotherapy / 308 Hormonal Therapy Targeted Therapy Immunotherapy Gene Therapy Mechanisms of Intrinsic and Acquired Drug Resistance Radiation Therapy 308 309 309 312 312 313 Physical Basis of Radiation Therapy / 313 Biologic Basis of Radiation Therapy / 313 Radiation Therapy Planning / 314 Side Effects / 314 Cancer Prevention Trends in Oncology 314 316 Cancer Screening and Diagnosis / 316 Surgical Therapy / 316 Systemic Therapy / 316 i­mmunotherapy, hormonal therapy, and, increasingly, biologic therapy. The primary goal of surgical and radiation therapy is local and regional control. On the other hand, the primary goal of systemic therapy is systemic control by treatment of distant foci of subclinical disease to prevent distant recurrence. Surgeons must be familiar with adjuvant therapies to coordinate multidisciplinary care and to determine the best sequence of therapy. Recent advances in molecular biology are revolutionizing medicine. New information is being translated rapidly into clinical use, with the development of new prognostic and predictive markers and new biologic therapies. Increasingly cancer therapy is getting personalized, incorporating information about each patient’s tumor characteristics, patient’s own genome, as well as host immune responses and tumor microenvironment, into clinical decision-making. It is therefore essential that surgeons VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 Modern cancer therapy is multidisciplinary, involving coordinated care by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radiologists, and primary care physicians. Understanding cancer biology is essential to successfully implement personalized cancer therapy. understand the principles of molecular oncology to appropriately interpret these new contributions and incorporate 2 them into practice. EPIDEMIOLOGY Basic Principles of Cancer Epidemiology The term incidence refers to the number of new cases occurring. Incidence is usually expressed as the number of new cases per 100,000 persons per year. Mortality refers to the number of deaths occurring and is expressed as the number of deaths per 100,000 persons per year. Incidence and mortality data are usually available through cancer registries. Mortality data are also available as public records in many countries where deaths are registered as vital statistics, often with the cause of death. In areas where cancer registries do not exist, mortality data are used to extrapolate incidence rates. These numbers are likely to be less accurate than registry data, as the relationship between incidence and cause-specific death is likely to vary significantly among countries owing to the variation in health care delivery. The incidence of cancer varies by geography. This is due in part to genetic differences and in part to differences in environmental and dietary exposures. Epidemiologic studies that monitor trends in cancer incidence and mortality have tremendously enhanced our understanding of the etiology of cancer. Furthermore, analysis of trends in cancer incidence and mortality allows us to monitor the effects of different preventive and screening measures, as well as the evolution of therapies for specific cancers. The two types of epidemiologic studies that are conducted most often to investigate the etiology of cancer and the effect of prevention modalities are cohort studies and case-control studies. Cohort studies follow a group of people who initially do not have a disease over time and measure the rate of development of a disease. In cohort studies, a group that is exposed to a certain environmental factor or intervention usually is compared to a group that has not been exposed (e.g., smokers vs. nonsmokers). Case-control studies compare a group of patients affected with a disease to a group of individuals without the disease for a given exposure. The results are expressed in terms of an odds ratio, or relative risk. A relative risk <1 indicates a protective effect of the exposure, whereas a relative risk >1 indicates an increased risk of developing the disease with exposure. Cancer Incidence and Mortality in the United States 274 In the year 2013, it is estimated that 1.6 million new cancer cases will be diagnosed in the United States, excluding carcinoma in situ of any site except bladder, and excluding basal cell and squamous cell carcinomas of the skin.1 In addition, 3 The following alterations are critical for malignant cancer growth: self-sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, potential for limitless replication, angiogenesis, invasion and metastasis. Reprogramming of energy metabolism and evading immune destruction. 64,640 cases of carcinoma in situ of the breast, and 61,300 of melanoma in situ are expected.1 It is estimated that in 2013 estimated 580,350 people will die of cancer in the United States, corresponding to about 1600 deaths per day.1 The estimated new cancer cases and deaths by cancer type are shown in Table 10-1.1 The most common causes of cancer death in men are cancers of the lung and bronchus, prostate, and colon and rectum; in women, cancers are of the lung and bronchus, breast, and colon and rectum.1 These four cancers account for almost half (48%) of total cancer deaths among men and women. The annual age-adjusted cancer incidence rates among males and females for selected cancer types are shown in Fig. 10-1.1 Incidence rates are declining for most cancer sites, but they are increasing among both men and women for melanoma of the skin, cancers of the liver and thyroid (Fig. 10-2).1 Incidence rates are decreasing for all four major cancer sites except for breast cancer in women. Age-adjusted incidence rate of breast cancer started to decrease from 2001 to 2004.2 This decrease in breast cancer incidence has at least temporally been associated with the first report of the Women’s Health Initiative, which documented an increased risk of coronary artery disease and breast cancer with the use of hormone replacement therapy; this was followed by a drop in the use of hormone replacement therapy by postmenopausal women in the United States.2 Unfortunately after this initial drop, breast cancer incidence has remained relatively stable from 2005 to 2009. Declines in colorectal cancer incidence have been mainly attributed to increased screening that allows for removal of precancerous polyps. Prostate cancer rates rapidly increased and decreased between 1995 and 1998. These trends are thought to be attributable to increased use of prostate-specific antigen (PSA) screening.3 Although analysis now suggest prostate cancer incidence has declined steadily by 1.9% per year from 2000 to 2009, annual rates fluctuate likely reflecting variations in screening. Differences in lung cancer incidence patterns between women and men are thought to reflect historical differences in tobacco use. Differences in smoking prevalence is also thought to contribute to regional differences in lung cancer incidence. Lung cancer incidence is fourfold higher in Kentucky which has the highest smoking prevalence, compared with Utah, that has the lowest smoking prevalence (128 vs. 34 lung cancer cases per 100,000 men).1 The 5-year survival rates for selected cancers are listed in Table 10-2. From 2005 to 2009, cancer death rates decreased by 1.8% per year in males and by 1.5% per year in females.1 These declines in mortality have been consistent in the past decade, and larger than what was observed in the previous decade.3 Over the past two decades, death rates have decreased from their peak by more than 30% for colorectal cancer, female breast cancer, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 275 Table 10-1 Estimated new cancer cases and deaths, United States, 2013a ESTIMATED DEATHS ESTIMATED NEW CASES ESTIMATED DEATHS All cancers 1,660,290 580,350 Oral cavity and pharynx 41,380 7,890 Uterine cervix 339,810 58,480 12,340 4,030 Digestive system 290,200 144,570 Uterine corpus 49,560 8,190 Esophagus 17,990 Stomach 21,600 15,210 Ovary 22,240 14,030 10,990 Vulva 4,700 990 Small intestine 8,810 1,170 Vagina and other genital, female 2,890 840 Colon and rectum 142,820 Genital system 50,830 Prostate 238,590 29,720 Anus, anal canal, and anorectum 7,060 880 Testis 7,920 370 Liver and intrahepatic bile duct 30,640 21,670 Penis and other genital, male 1,570 310 Gallbladder and other biliary 10,310 3,230 140,430 29,790 Pancreas 45,220 38,460 Urinary bladder 72,570 15,210 Other digestive organs 5,750 2,130 Kidney and renal pelvis 65,150 13,680 246,210 163,890 Ureter and other urinary organs 2,710 900 Larynx 12,260 3,630 Eye and orbit 2,800 320 Lung and bronchus 228,190 159,480 Brain and other nervous system 23,130 14,080 Other respiratory organs 5,760 780 Endocrine system 62,710 2,770 Bones and joints 3,010 1,440 Thyroid 60,220 1,850 Soft tissue (including heart) 11,410 4,390 Other endocrine 2,490 920 Skin (excluding basal and squamous) 82,770 12,650 Lymphoma 79,030 20,200 Melanoma 76,690 9,480 Multiple myeloma 22,350 10,710 Other nonepithelial 6,080 3,170 Leukemia 48,610 23,720 234,580 40,030 Other and unspecified primary sitesb 31,860 45,420 Respiratory system Breast Urinary system Excludes basal and squamous cell skin cancers and in situ carcinomas except those of urinary bladder. More deaths than cases suggest lack of specificity in recording underlying causes of death on death certificate. Source: Modified with permission from John Wiley and Sons: Siegel R et al. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013;63:11. © 2013 American Cancer Society, Inc. a b male lung cancer and more than 40% for prostate cancer. The decrease in lung cancer death rates in men is thought to be due to a decrease in tobacco use, whereas the decreases in death rates from breast, colorectal cancer, and prostate cancer reflect advances in early detection and treatment. Global Statistics on Cancer Incidence and Mortality The five most common cancers for men worldwide are lung, prostate, colorectal cancer, stomach, liver, and for women are breast, colorectal, cervix, lung, and stomach.4 Notably, for several cancer types there is wide geographical variability in cancer incidence (Fig. 10-3). The mortality rates for different cancers also vary significantly among countries. This is attributable not only to variations in incidence but also to variations in survival after a cancer diagnosis. The survival rates are influenced by treatment patterns as well as by variations in cancer screening practices, which affect the stage of cancer at diagnosis. For example, the 5-year survival rate for stomach cancer is much higher in Japan, where the cancer incidence is high enough to warrant mass screening, which is presumed to lead to earlier diagnosis. In the case of prostate cancer, on the other hand, the mortality rates diverge much less than the incidence rates among countries. Survival rates for prostate cancer are much higher in North America than in developing countries.5 It is possible that the extensive screening practices in the United States allow discovery of cancers at an earlier, more curable stage; however, it is also possible that this screening leads to discovery of more latent, less biologically aggressive cancers, which may not have caused death even if they had not been identified. About one million new cases of stomach cancer were estimated to have occurred in 2008 (988,000 cases, 7.8% of the total), making it the fourth most common malignancy in the world, behind cancers of the lung, breast, and colorectal cancer. The incidence of stomach cancer varies significantly among different regions of the world. The difference in risk by country is presumed to be primarily due to differences in dietary factors. The risk is increased by high consumption of preserved salted foods such as meats and pickles, and decreased by high intake of fruits and vegetables.5 There also is some international variation VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 10 ONCOLOGY ESTIMATED NEW CASES 276 Estimated new cases* Males Females PART I BASIC CONSIDERATIONS Prostate 238,590 28% Breast 232,340 29% Lung & bronchus 118,080 14% Lung & bronchus 110,110 14% Colorectum 73,680 9% Colorectum 69,140 9% Urinary bladder 54,610 6% Uterine corpus 49,560 6% Melanoma of the skin 45,060 5% Thyroid 45,310 6% Kidney & renal pelvis 40,430 5% Non-Hodgkin lymphoma 32,140 4% Non-Hodgkin lymphoma 37,600 4% Melanoma of the skin 31,630 4% Oral cavity & pharynx 29,620 3% Kidney & renal pelvis 24,720 3% Leukemia 27,880 3% Pancreas 22,480 3% Pancreas 22,740 3% Ovary 22,240 3% All Sites 854,790 100% 805,500 100% All Sites Estimated deaths Males Females Lung & bronchus 87,260 28% Lung & bronchus 72,220 26% Prostate 29,720 10% Breast 39,620 14% Colorectum 26,300 9% Colorectum 24,530 9% Pancreas 19,480 6% Pancreas 18,980 7% Liver & intrahepatic bile duct 14,890 5% Ovary 14,030 5% Leukemia 13,660 4% Leukemia 10,060 4% Esophagus 12,220 4% Non-Hodgkin lymphoma 8,430 3% Urinary bladder 10,820 4% Uterine corpus 8,190 3% Non-Hodgkin’s lymphoma 10,590 3% Liver & intrahepatic bile duct 6,780 2% Kidney & renal pelvis 8,780 3% Brain & other nervous system 6,150 2% All Sites 306,920 100% 271,430 100% All Sites Figure 10-1. Ten leading cancer types with the estimated new cancer cases and deaths by sex in the United States, 2013. *Excludes basal and squamous cell skin cancers and in situ carcinomas except those of the urinary bladder. Estimates are rounded to the nearest 10 (Modified with permission from John Wiley and Sons: Siegel R et al. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013;63:11. © 2013 American Cancer Society, Inc.) in the incidence of infection with Helicobacter pylori, which is known to play a major role in gastric cancer development.5 Fortunately, a steady decline is being observed in the incidence and mortality rates of gastric cancer. This may be related to improvements in preservation and storage of foods as well as due to changes in the prevalence of H. pylori.5 More than 70% of cases (713,000 cases) occur in developing countries, and half the cases in the world occur in Eastern Asia (mainly in China).4 Age-standardized incidence rates are about twice as high for men as for women, ranging from 3.9 in Northern Africa to 42.4 in Eastern Asia for men, and from 2.2 in Southern Africa to 18.3 in Eastern Asia for women. Stomach cancer is the second leading cause of cancer death in both sexes worldwide. Overall, the incidence of breast cancer is rising in most countries. Incidence varies from 19.3 per 100,000 women in Eastern Africa to 89.7 per 100,000 women in Western Europe, and are high in developed regions of the world (except Japan) and low in most of the developing regions.4 Although breast cancer has been linked to cancer susceptibility genes, mutations in these genes account for only 5% to 10% of breast tumors, which suggests that the wide geographic variations in breast cancer incidence are not due to geographic variations in the prevalence of these genes. Most of the differences, therefore, are attributed to differences in reproductive factors, diet, alcohol, obesity, physical activity, and other environmental differences. Indeed, breast cancer risk increases significantly in females who have migrated from Asia to America.5 The range of breast cancer mortality rates is much less (approximately 6 to 19 per 100,000) because of the more favorable survival of breast cancer in developed regions. As a result, breast cancer ranks as the fifth cause of death from cancer overall (458,000 deaths), but it is still the most frequent cause of cancer death in women in both developing (269,000 deaths, 12.7% of total) and developed regions (estimated 189,000 deaths). 4 There is a 25-fold variation in colon cancer incidence worldwide.5 The incidence of colon and rectal cancer is higher in developed countries than in developing countries. The incidence rates are highest in North America, Australia and New Zealand, and Western Europe, and especially in Japanese men.5 In contrast, the incidence is relatively low in North Africa, South America, and eastern, Southeastern, and Western Asia. These geographic differences are thought to reflect environmental exposures and are presumed to be related mainly to dietary differences in consumption of animal fat, meat, and fiber.5 Worldwide liver cancer is the fifth most common cancer in men (523,000 cases, 7.9% of the total) and the seventh in women (226,000 cases, 6.5% of the total). Almost 85% of liver cancer cases occur in developing countries, and particularly in men.4 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Male 250 Rate per 100,000 population 225 Prostate 200 200 175 175 150 150 125 125 100 75 Lung & bronchus 25 Breast 100 75 Colorectum 50 CHAPTER 10 ONCOLOGY 225 277 Female 250 Colorectum Urinary bladder Melanoma of the skin Thyroid Lung & bronchus 50 Liver+ Uterine corpus 25 Melanoma of the skin Thyroid Liver+ 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 0 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 0 Year of diagnosis Year of diagnosis Figure 10-2. Trends in cancer incidence rates for selected cancer by sex among males and females for selected cancer types, United States, 1975 to 2009. Rates are age adjusted to the 2000 U.S. standard population. (Modified with permission from John Wiley and Sons: Siegel R et al. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013;63:11. © 2013 American Cancer Society, Inc.)1 + Liver includes intrahepatic bile duct The overall sex ratio male:female is 2:4. The regions of high incidence are Eastern and Southeastern Asia, Middle and Western Africa, as well as Melanesia and Micronesia/Polynesia (particularly in men). Low rates are estimated in developed regions, with the exception of Southern Europe. There were an estimated 694,000 deaths from liver cancer in 2008 (477,000 in men, 217,000 in women), and because of its high fatality (overall ratio of mortality to incidence of 0.93), liver cancer is the third most common cause of death from cancer worldwide. The geographical distribution of the mortality rates is similar to that observed for incidence. Worldwide, the major risk factors for liver cancer are infection with hepatitis B and C viruses and consumption of foods contaminated with aflatoxin. Hepatitis B immunization in children has recently been shown to reduce the incidence of liver cancer.5 In summary, the incidence rates of many common cancers vary widely by geography. This is due in part to genetic differences, including racial and ethnic differences. It is due also in part to differences in environmental and dietary exposures, factors that can potentially be altered. Therefore, establishment of regional and international databases is critical to improving our understanding of the etiology of cancer and will ultimately assist in the initiation of targeted strategies for global cancer prevention. Furthermore, the monitoring of cancer mortality rates and 5-year cancer-specific survival rates will identify regions where there are inequities of health care, so that access to health care can be facilitated and guidelines for treatment can be established. CANCER BIOLOGY Hallmarks of Cancer Although there are >100 types of cancer, it has been proposed that there are six essential alterations in cell physiology that dictate malignant growth: self-sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis (programmed cell death), potential for limitless replication, angiogenesis, and invasion and metastasis.6 Recently two 3 additional hallmarks have emerged—reprogramming of energy metabolism and evading immune destruction.7 These hallmarks of cancer are being pursued as targets for cancer therapy (Figure 10-4). Cell Proliferation and Transformation In normal cells, cell growth and proliferation are under strict control. In cancer cells, cells become unresponsive to normal growth controls, which leads to uncontrolled growth and proliferation. Human cells require several genetic changes for neoplastic transformation. Cell type–specific differences also exist for tumorigenic transformation. Abnormally proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly display several abnormal characteristics.8 These include loss of contact inhibition (i.e., cells continue to proliferate after a confluent monolayer is formed); an altered appearance and poor adherence to other cells or to the substratum; loss of anchorage dependence for growth; immortalization; VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 278 Table 10-2 Five-year relative survival rates adjusted to normal life expectancy by year of diagnosis, United States, 1975–2008 PART I RELATIVE 5-YEAR SURVIVAL RATES (%) BASIC CONSIDERATIONS Cancer Type 1975–1977 1987–1989 2002-2008 All cancers 49 56 68 Brain 22 29 35 Breast (female) 75 84 90 Uterine cervix 69 70 69 Colon 51 61 65 Uterine corpus 87 83 83 Esophagus 5 10 19 Hodgkin’s disease 72 79 87 Kidney 50 57 72 Larynx 66 66 63 Leukemia 34 43 58 Liver 3 5 16 Lung and bronchus 12 13 17 Melanoma of the skin 82 88 93 Multiple myeloma 25 28 43 Non-Hodgkin’s lymphoma 47 51 71 Oral cavity 53 54 65 Ovary 36 38 43 Pancreas 2 4 6 Prostate 68 83 100 Rectum 48 58 68 Stomach 15 20 28 Testis 83 95 96 Thyroid 92 95 98 Urinary bladder 73 79 80 Source: Modified with permission from John Wiley and Sons: Siegel R et al. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013;63:11. © 2013 American Cancer Society, Inc. and gain of tumorigenicity (i.e., the ability to give rise to tumors when injected into an appropriate host). Cancer Initiation Tumorigenesis is proposed to have three steps: initiation, promotion, and progression. Initiating events such as gain of function of genes known as oncogenes or loss of function of genes known as tumor-suppressor genes may lead a single cell to acquire a distinct growth advantage. Although tumors usually arise from a single cell or clone, it is thought that sometimes not a single cell but rather a large number of cells in a target organ may have undergone the initiating genetic event. Thus, many normal-appearing cells may have an increased malignant potential. This is referred to as a field effect. The initiating events are usually genetic and occur as deletions of tumor-suppressor genes or amplification or mutation of oncogenes. Subsequent events can lead to accumulations of additional deleterious mutations in the clone. Cancer is thought to be a disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior. Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers (e.g., atypical ductal hyperplasia to ductal carcinoma in situ to invasive ductal carcinoma of the breast). Fearon and Vogelstein proposed the model for colorectal tumorigenesis presented in Fig. 10-5.9 Colorectal tumors arise from the mutational activation of oncogenes coupled with mutational inactivation of tumor-suppressor genes, the latter being the predominant change.9 Mutations in at least four or five genes are required for formation of a malignant tumor, while fewer changes suffice for a benign tumor. Although genetic mutations often occur in a preferred sequence, a tumor’s biologic properties are determined by the total accumulation of its genetic changes. Gene expression is a multistep process that starts from transcription of a gene into messenger ribonucleic acid (mRNA) and then translation of this sequence into the functional protein. There are several controls at each level. In addition to alterations at the genome level (e.g., amplifications of a gene), alterations VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ All cancers 279 Breast CHAPTER 10 ONCOLOGY < 11.2 < 13.4 < 16.6 < 22.5 < 31.9 Liver cancer < 0.3 < 2.2 < 3.1 < 4.1 < 6.0 < 11.4 < 1.6 < 4.9 Stomach cancer < 0.5 < 0.7 < 1.0 < 11.2 < 0.4 < 0.7 < 1.0 Figure 10-3. Estimated cancer incidence worldwide in 2008. Age-standardized incidence rates per 100,000 for all cancers (upper left), breast cancer (upper right), liver cancer (lower left), and stomach cancer (lower right). (Modified with permission from Ferlay, IARC)4 at the transcription level (e.g., methylation of the DNA leading to transcriptional silencing) or at the level of mRNA processing, mRNA stability, mRNA translation, or protein stability, all can alter the levels of critical proteins and thus contribute to tumorigenesis. Alternatively, changes in the genomic sequence can lead to a mutated product with altered function. Cell-Cycle Dysregulation in Cancer The proliferative advantage of tumor cells is a result of their ability to bypass quiescence. Cancer cells often show alterations in signal transduction pathways that lead to proliferation in response to external signals. Mutations or alterations in the expression of cell-cycle proteins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allowing unregulated cell growth and proliferation. The cell cycle is divided into four phases (Fig. 10-6).10 During the synthetic or S phase, the cell generates a single copy of its genetic material, whereas in the mitotic or M phase, the cellular components are partitioned between two daughter cells. The G1 and G2 phases represent gap phases during which the cells prepare themselves for completion of the S and M phases, respectively. When cells cease proliferation, they exit the cell cycle and enter the quiescent state referred to as G0. In human tumor cell-cycle regulators like INK4A, INK4B, and KIP1 are frequently mutated or altered in expression. These alterations underscore the importance of cell-cycle regulation in the prevention of human cancers. Oncogenes Normal cellular genes that contribute to cancer when abnormal are called oncogenes. The normal counterpart of such a gene is referred to as a proto-oncogene. Oncogenes are usually designated by three-letter abbreviations, such as myc or ras. Oncogenes are further designated by the prefix “v-” for virus or “c-” for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased protein levels) by translocation (e.g., abl), promoter insertion (e.g., c-myc), mutation (e.g., ras), or amplification (e.g., HER2/neu). More than 100 oncogenes have been identified. Oncogenes may be growth factors (e.g., platelet-derived growth factor), growth factor receptors (e.g., HER2), intracellular signal transduction molecules (e.g., ras), nuclear transcription factors (e.g., c-myc), or other molecules involved in the regulation of cell growth and proliferation. Growth factors are ubiquitous proteins that are produced and secreted by cells locally and that stimulate cell proliferation by binding specific cell-surface receptors on the same cells (autocrine stimulation) or on neighboring cells (paracrine stimulation). Persistent overexpression VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 280 EGFR inhibitors Cyclin-dependent kinase inhibitors PART I Sustaining proliferative signaling Aerobic glycolysis inhibitors Evading growth suppressors Immune activating anti-CTLA4 mAb BASIC CONSIDERATIONS Avoiding immune destruction Deregulating cellular energetics Proapoptotic BH3 mimetics Resisting cell death Enabling replicative immortality Tumorpromoting inflammation Genome instability & mutation PARP inhibitors Telomerase Inhibitors Inducing angiogenesis Inhibitors of VEGF signaling Selective antiinflammatory drugs Activating invasion & metastasis Inhibitors of HGF/c-Met Figure 10-4. Hallmarks of cancer and their therapeutic implications. Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression are in clinical trials and in some cases approved for clinical use in treating forms of human cancer. The drugs listed are illustrative examples.(Modified with permission from ­Hanahan et al. Copyright Elsevier.)7 of growth factors can lead to uncontrolled autostimulation and neoplastic transformation. Alternatively, growth factor receptors can be aberrantly activated (turned on) through mutations or overexpressed (continually presenting cells with growthstimulatory signals, even in the absence of growth factors), which leads cells to respond as if growth factor levels are altered. The growth-stimulating effect of growth factors and other mitogens is mediated through postreceptor signal transduction molecules. Chromosome 5q alteration Mutation or loss gene: FAP These molecules mediate the passage of growth signals from the outside to the inside of the cell and then to the cell nucleus, initiating the cell cycle and DNA transcription. Aberrant activation or expression of cell-signaling molecules, cell-cycle molecules, or transcription factors may play an important role in neoplastic transformation. Protein tyrosine kinases account for a large portion of known oncogenes. One of the best-studied oncogenes, HER2 is discussed as an example later. 12p Mutation K-ras 17p Loss p53 18q Loss DCC? Other alterations DNA hypomethylation Normal epithelium Hyperprolif epithelium Early adenoma Intermediate adenoma Late adenoma Carcinoma Metastasis Figure 10-5. A genetic model for colorectal tumorigenesis. Tumorigenesis proceeds through a series of genetic alterations involving oncogenes and tumor-suppressor genes. In general, the three stages of adenomas represent tumors of increasing size, dysplasia, and villous content. Individuals with familial adenomatous polyposis (FAP) inherit a mutation on chromosome arm 5q. In tumors arising in individuals without polyposis, the same region may be lost or mutated at a relatively early stage of tumorigenesis. A ras gene mutation (usually K-ras) occurs in one cell of a pre-existing small adenoma which, through clonal expansion, produces a larger and more dysplastic tumor. The chromosome arms most frequently deleted include 5q, 17p, and 18q. Allelic deletions of chromosome arms 17p and 18q usually occur at a later stage of tumorigenesis than do deletions of chromosome arm 5q or ras gene mutations. The order of these changes varies, however, and accumulation of these changes, rather than their order of appearance, seems most important. Tumors continue to progress once carcinomas have formed, and the accumulated chromosomal alterations correlate with the ability of the carcinomas to metastasize and cause death. DCC = deleted in colorectal cancer gene. (Modified with permission from Fearon et al. Copyright Elsevier.)9 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Cell with chromosomes in the nucleus G1 DNA synthesis Mitosis M CDK Cyclin S Chromosome duplication Chromosome separation G2 Cell with duplicated chromosomes Figure 10-6. Schematic representation of the phases of the cell cycle. Mitogenic growth factors can drive a quiescent cell from G0 into the cell cycle. Once the cell cycle passes beyond the restriction point, mitogens are no longer required for progression into and through S phase. The DNA is replicated in S phase, and the chromosomes are condensed and segregated in mitosis. In early G1 phase, certain signals can drive a cell to exit the cell cycle and enter a quiescent phase. Cell-cycle checkpoints have been identified in G1, S, G2, and M phases. CDK = cyclin-dependent kinase. (Adapted from Kastan et al )10 HER2, also known as neu or c-erbB-2, is a member of the epidermal growth factor receptor (EGFR) family and is one of the best-characterized tyrosine kinases. Unlike other receptor tyrosine kinases, HER2/neu does not have a direct soluble ligand. It plays a key role in signaling, however, because it is the preferred partner in heterodimer formation with all the other EGFR family members (EGFR/c-erbB-1, HER2/c-erbB-3, and HER3/c-erbB-4), which bind at least 30 ligands, including epidermal growth factor (EGF), transforming growth factor α (TGFα), heparin-binding EGF-like growth factor, amphiregulin, and heregulin.11 Heterodimerization with HER2 potentiates recycling of receptors rather than degradation, enhances signal potency and duration, increases affinity for ligands, and increases catalytic activity.11 HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways (Fig. 10-7). The specificity and potency of the intracellular signals are affected by the identity of the ligand, the composition of the receptors, and the phosphotyrosine-binding proteins associated with the erbB molecules. The Ras- and Shc-activated mitogen-activated protein kinase (MAPK) pathway is a target of all erbB ligands, which increase the transcriptional activity of early response genes such as c-myc, c-fos, and c-jun.12 MAPK-independent pathways such as the phosphoinositide-3 kinase (PI3K) pathway also are activated by most erbB dimers, although the potency and kinetics of activation may differ. Stimulation of the PI3K pathway through HER2 signaling also can lead to activation of survival molecule Akt, which suppresses apoptosis through multiple mechanisms. The critical role of HER2 in cancer biology has been leveraged for therapeutics, leading to several HER2- targeted drugs with different mechanism of action Alterations in Apoptosis in Cancer Cells Apoptosis is a genetically regulated program to dispose of cells. Cancer cells must avoid apoptosis if tumors are to arise. The growth of a tumor mass is dependent not only on an increase in proliferation of tumor cells but also on a decrease in their apoptotic rate. Apoptosis is distinguished from necrosis because it leads to several characteristic changes. In early apoptosis, the changes in membrane composition lead to extracellular exposure of phosphatidylserine residues, which avidly bind annexin, a characteristic that is used to discriminate apoptotic cells in laboratory studies. Late in apoptosis there are characteristic changes in nuclear morphology, such as chromatin condensation, nuclear fragmentation, and DNA laddering, as well as membrane blebbing. Apoptotic cells are then engulfed and degraded by phagocytic cells. The effectors of apoptosis are a family of proteases called caspases (cysteine-dependent and aspartate-directed proteases). The initiator caspases (e.g., 8, 9, and 10), which are upstream, cleave the downstream executioner caspases (e.g., 3, 6, and 7) that carry out the destructive functions of apoptosis. Two principal molecular pathways signal apoptosis by cleaving the initiator caspases with the potential for crosstalk: the mitochondrial pathway and the death receptor pathway. In the mitochondrial (or intrinsic) pathway, death results from the release of cytochrome c from the mitochondria. Cytochrome c, procaspase 9, and apoptotic protease activating factor 1 (Apaf-1) form an enzyme complex, referred to as the apoptosome, that activates the effector caspases. In addition to these proteins, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 281 CHAPTER 10 ONCOLOGY Cell division approved by the Food and Drug Administration (FDA): monoclonal antibodies trastuzumab and pertuzumab, small molecule inhibitor lapatinib, and antibody-drug conjugate ado-trastuzumab emtansine. The mutant rat neu gene was first recognized as an oncogene in neuroblastomas from carcinogen-treated rats.13 The HER2 gene is frequently amplified and the protein overexpressed in many cancers, including breast, ovarian, lung, gastric, and oral cancers. Overexpression of HER2 results in ligand-independent activation of HER2 kinase, which leads to mitogenic signaling. HER2 overexpression is associated with increased cell proliferation and anchorage-independent growth as well as resistance to proapoptotic stimuli. Further, overexpression of HER2 increases cell migration and upregulates the activities of matrix metalloproteinases (MMPs) and in vitro invasiveness. In animal models, HER2 increases tumorigenicity, angiogenesis, and metastasis. These results all suggest that HER2 plays a key role in cancer biology. More recently HER2 mutations have also been reported in human cancer. HER2 mutations have been detected in 2% to 4% of nonsmall cell lung cancer.14-17 In frame insertions within exon 20 has been the most commonly reported mutation. HER2 mutations are more common in nonsmokers and are nonoverlapping with other oncogenic mutations in lung cancer (e.g., EGFR and Ras). Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification.18 Seven of 13 mutations were functionally characterized and found to be activating mutations. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. A prospective, multi-institutional clinical trial has been launched to screen patients with stage IV breast cancer for HER2 somatic mutations and determine the clinical outcome of treating them with HER2-targeted therapy. 282 Ligands PART I HER 1/3/4 HER2 BASIC CONSIDERATIONS PI3K PLC-γ IP3 Ca++ mobilization Shc src Ras 1,2 diacylglycerol Protein kinase C Akt TSC1/2 MEK MAPK MYC ILK CREB mTOR JUN IKK p21 p27 SEK SAPK Adhesion Growth GSK3 MDM2 MEKK S6K S6 IκB Bad Caspase-9 Forkhead NF-κB Bcl-xL Caspases Fas-L 4E-BP1 elF4E Alterations in gene expression Migration EZH2 sos FAK Raf-1 ELK Grb2 Survival Proliferation Angiogenesis Figure 10-7. The HER2 signaling pathway. HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways. 4E-BP1= eIF4E binding protein 1; CREB = cyclic adenosine monophosphate element binding; eIF4E = eukaryotic initiation factor 4E; EZH = enhancer of zeste homolog; FAK = focal adhesion kinase; Fas-L = Fas ligand; GSK3 = glycogen synthase kinase-3; HER = human epidermal growth receptor; IKK = IκB kinase; ILK= integrin-linked kinase; IP3 = inositol triphosphate; IκB = inhibitor of NF-κB; MAPK = mitogen-activated protein kinase; MDM2 = mouse double minute 2 homologue; MEK = mitogen-activated protein/extracellular signal regulated kinase kinase; MEKK = MEK kinase; mTOR = mammalian target of rapamycin; NF-κB = nuclear factor κB; PI3K = phosphoinositide-3 kinase; PLC-γ = phospholipase Cγ; SAPK = stress-activated protein kinase; SEK = SAPK/extracellular signal regulated kinase kinase; TSC = tuberous sclerosis complex. (Modified with permission from Meric-Bernstam et al.)171 the mitochondria contain other proapoptotic proteins such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO. The mitochondrial pathway can be stimulated by many factors, including DNA damage, reactive oxygen species, or the withdrawal of survival factors. The permeability of the mitochondrial membrane determines whether the apoptotic pathway will proceed. The Bcl-2 family of regulatory proteins includes both proapoptotic proteins (e.g., Bax, BAD, and Bak) and antiapoptotic proteins (e.g., Bcl-2 and Bcl-xL). The activity of the Bcl-2 proteins is centered on the mitochondria, where they regulate membrane permeability. Growth factors promote survival signaling through the PI3K/Akt pathway, which phosphorylates and inactivates proapoptotic BAD. In contrast, growth factor withdrawal may promote apoptosis through signaling by unphosphorylated BAD. The heat shock proteins, including Hsp70 and Hsp27, are also involved in inhibition of downstream apoptotic pathways by blocking formation of the apoptosome complex and inhibiting release of cytochrome c from the mitochondria.19 The second principal apoptotic pathway is the death receptor pathway, sometimes referred to as the extrinsic pathway. Cell-surface death receptors include Fas/APO1/CD95, tumor necrosis factor receptor 1, and KILL-ER/DR5, which bind their ligands Fas-L, tumor necrosis factor (TNF), and TNFrelated apoptosis-inducing ligand (TRAIL), respectively. When the receptors are bound by their ligands, they form a deathinducing signaling complex (DISC). At the DISC, procaspase 8 and procaspase 10 are cleaved, yielding active initiator caspases.20 The death receptor pathway may be regulated at the cell surface by the expression of “decoy” receptors for Fas (DcR3) and TRAIL (TRID and TRUNDD). The decoy receptors are closely related to the death receptors but lack a functional death domain; therefore, they bind death ligands but do not transmit a death signal. Another regulatory group is the FADD-like interleukin-1 protease-inhibitory proteins (FLIPs). FLIPs have homology to caspase 8; they bind to the DISC and inhibit the activation of caspase 8. Finally, inhibitors of apoptosis proteins (IAPs) block caspase 3 activation and have the ability to regulate both the death receptor and the mitochondrial pathway. In human cancers, aberrations in the apoptotic program include increased expression of Fas and TRAIL decoy receptors; increased expression of antiapoptotic Bcl-2; increased expression VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Autophagy in Cancer Cells Autophagy (self-eating) is a major cellular pathway for protein and organelle turnover. This process helps maintain a balance between anabolism and catabolism for normal cell growth and development. Inability to activate autophagy in response to nutrient deprivation, or constitutive activation of autophagy in response to stress, can lead to cell death; thus autophagy is sometimes referred to as a second form of programmed cell death. Autophagy plays an essential role during starvation, cellular differentiation, cell death, and aging. Autophagy is also involved in the elimination of cancer cells by triggering a nonapoptotic cell death program, which suggests a negative role in tumor development. Mouse models that are heterozygotes for the beclin 1 gene, an important gene for autophagy, have altered autophagic response and show a high incidence of spontaneous tumors, which establishes a role for autophagy in tumor suppression.21 This also suggests that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy. However, autophagy also acts as a stress response mechanism to protect cancer cells from low nutrient supply or therapeutic insults. Studies on the molecular determinants of autophagy are ongoing to determine whether autophagy can be modulated for therapeutic purposes. Cancer Invasion A feature of malignant cells is their ability to invade the surrounding normal tissue. Tumors in which the malignant cells appear to lie exclusively above the basement membrane are referred to as in situ cancer, whereas tumors in which the malignant cells are demonstrated to breach the basement membrane, penetrating into surrounding stroma, are termed invasive cancer. The ability to invade involves changes in adhesion, initiation of motility, and proteolysis of the extracellular matrix (ECM). Cell-to-cell adhesion in normal cells involves interactions between cell-surface proteins. Calcium adhesion molecules of the cadherin family (E-cadherin, P-cadherin, and N-cadherin) are thought to enhance the cells’ ability to bind to one another and suppress invasion. Migration occurs when cancer cells penetrate and attach to the basal matrix of the tissue being invaded; this allows the cancer cell to pull itself forward within the tissue. Attachment to glycoproteins of the ECM such as fibronectin, laminin, and collagen is mediated by tumor cell integrin receptors. Integrins are a family of glycoproteins that form heterodimeric receptors for ECM molecules. The integrins can form at least 25 distinct pairings of their α and β subunits, and each pairing is specific for a unique set of ligands. In addition to regulating cell adhesion to the ECM, integrins relay molecular signals regarding the cellular environment that influence shape, survival, proliferation, gene transcription, and migration. Factors that are thought to play a role in cancer cell motility include autocrine motility factor, autotaxin, scatter factor (also known as hepatocyte growth factor), TGFα, EGF, and insulin-like growth factors. Serine, cysteine, and aspartic proteinases and MMPs have all been implicated in cancer invasion. Urokinase and ­tissue plasminogen activators (uPA and tPA) are serine proteases that convert plasminogen into plasmin. Plasmin, in return, can degrade several ECM components. Plasmin also may activate MMPs. uPA has been more closely correlated with tissue invasion and metastasis than tPA. Plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2) are produced in tissues and counteract the activity of plasminogen activators. MMPs comprise a family of metal-dependent endopeptidases. Upon activation, MMPs degrade a variety of ECM components. Although MMPs often are referred to by their common names, which reflect the ECM component for which they have specificity, a sequential numbering system has been adopted for standardization. For example, collagenase-1 is now referred to as MMP-1. The MMPs are further classified as secreted and membrane-type MMPs. Most of the MMPs are synthesized as inactive zymogens (pro-MMP) and are activated by proteolytic removal of the propeptide domain outside the cell by other active MMPs or serine proteinases. MMPs are upregulated in almost every type of cancer. Some of the MMPs are expressed by cancer cells, whereas others are expressed by the tumor stromal cells. Experimental models have demonstrated that MMPs promote cancer progression by increasing cancer cell growth, migration, invasion, angiogenesis, and metastasis. MMPs exert these effects by cleaving not only structural components of the ECM but also growth factor– binding proteins, growth factor precursors, cell adhesion molecules, and other proteinases. The activity of MMPs is regulated by their endogenous inhibitors and tissue inhibitors of MMPs (TIMP-1, TIMP-2, TIMP-3, and TIMP-4). Angiogenesis Angiogenesis is the establishment of new blood vessels from a pre-existing vascular bed. This neovascularization is essential for tumor growth and metastasis. Tumors develop an angiogenic phenotype as a result of accumulated genetic alterations and in response to local selection pressures such as hypoxia. Many of the common oncogenes and tumor-suppressor genes have been shown to play a role in inducing angiogenesis. In response to the angiogenic switch, pericytes retract and the endothelium secretes several growth factors such as basic fibroblast growth factor, platelet-derived growth factor (PDGF), and insulin-like growth factor. The basement membrane and stroma around the capillary are proteolytically degraded, a process that is mediated in most part by uPA. The endothelium then migrates through the degraded matrix, initially as a solid cord and later forming lumina. Finally, sprouting tips anastomose to form a vascular network surrounded by a basement membrane. Angiogenesis is mediated by factors produced by various cells, including tumor cells, endothelial cells, stromal cells, and inflammatory cells. The first proangiogenic factor was identified by Folkman and colleagues in 1971.22 Since then, several other factors have been shown to be proangiogenic or antiangiogenic. Of the angiogenic stimulators, the best studied are the vascular endothelial growth factors (VEGFs). The VEGF family consists of six growth factors (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor) and three receptors (VEGFR1 or Flt-1, VEGFR2 or KDR/FLK-1, and VEGFR3 or Flt-4).23 Neuropilin 1 and 2 also may act as receptors for VEGF.24 VEGF is induced by hypoxia and by different growth factors and cytokines, including EGF, PDGF, TNF-α, TGFβ, and interleukin-1β. VEGF has various functions, including increasing vascular permeability, inducing endothelial cell VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 283 CHAPTER 10 ONCOLOGY of the IAP-related protein survivin; increased expression of c-FLIP; mutations or downregulation of proapoptotic Bax, caspase 8, APAF1, XAF1, and death receptors CD95, TRAIL-R1, and TRAIL-R2; alterations of the p53 pathway; overexpression of growth factors and growth factor receptors; and activation of the PI3K/Akt survival pathway.20 284 PART I BASIC CONSIDERATIONS proliferation and tube formation, and inducing endothelial cell synthesis of proteolytic enzymes such as uPA, PAI-1, urokinase plasminogen activator receptor, and MMP-1. Furthermore, VEGF may mediate blood flow by its effects on the vasodilator nitric oxide and act as an endothelial survival factor, thus protecting the integrity of the vasculature. The proliferation of new lymphatic vessels, lymphangiogenesis, is also thought to be controlled by the VEGF family. Signaling in lymphatic cells is thought to be modulated by VEGFR3.25 Experimental studies with VEGF-C and VEGF-D have shown that they can induce tumor lymphangiogenesis and direct metastasis via the lymphatic vessels and lymph nodes.25, 26 PDGFs A, B, C, and D also play important roles in angiogenesis. PDGFs cannot only enhance endothelial cell proliferation directly but also upregulate VEGF expression in vascular smooth muscle cells, promoting endothelial cell survival via a paracrine effect.23 The angiopoietins angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), in return, are thought to regulate blood vessel maturation. Ang-1 and Ang-2 both bind angiopoietin-1 receptor (also known as tyrosine-protein kinase receptor TIE-2), but only the binding of Ang-1 activates signal transduction; thus Ang-2 is an Ang-1 antagonist. Ang-1, via the Tie-2 receptor, induces remodeling and stabilization of blood vessels. Upregulation of Ang-2 by hypoxic induction of VEGF inhibits Ang-1–induced Tie-2 signaling, which results in destabilization of vessels and makes endothelial cells responsive to angiogenic signals, thus promoting angiogenesis in the presence of VEGF. Therefore the balance between these factors determines the angiogenetic capacity of a tumor. Tumor angiogenesis is regulated by several factors in a coordinated fashion. In addition to upregulation of proangiogenic molecules, angiogenesis also can be encouraged by suppression of naturally occurring inhibitors. Such inhibitors of angiogenesis include thrombospondin 1 and angiostatin. Angiogenesis is a prerequisite not only for primary tumor growth but also for metastasis. Angiogenesis in the primary tumor, as determined by microvessel density, has been demonstrated to be an independent predictor of distant metastatic disease and survival in several cancers. Expression of angiogenic factors such as VEGFs has had prognostic value in many studies. These findings further emphasize the importance of angiogenesis in cancer biology. Metastasis Metastases arise from the spread of cancer cells from the primary site and the formation of new tumors in distant sites. The metastatic process consists of a series of steps that need to be completed successfully (Fig. 10-8).27 First, the primary cancer must develop access to the circulation through either the blood circulatory system or the lymphatic system. After the cancer cells are shed into the circulation, they must survive. Next, the circulating cells lodge in a new organ and extravasate into the Figure 10-8. A schematic representation of the metastatic process. A. The metastatic process begins with an in situ cancer surrounded by an intact basement membrane. B. Invasion requires reversible changes in cell-cell and cell–extracellular matrix adherence, destruction of proteins in the matrix and stroma, and motility. C. Metastasizing cells can enter the circulation via the lymphatics. D. They can also directly enter the circulation. E. Intravascular survival of the tumor cells and extravasation of the circulatory system follow. F. Metastatic single cells can colonize sites and remain dormant for years as occult micrometastases. G. Subsequent progression and neovascularization leads to clinically detectable metastases and progressively growing, angiogenic metastases. (Adapted by permission from Macmillan Publishers Ltd. Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 2003;3:55. Copyright © 2003.)27 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ patient will remain free of distant metastasis.31 This suggests that the metastatic potential of a tumor is already predetermined by the genetic alterations that the cancer cells acquire early in tumorigenesis. Notably, this hypothesis differs from the multistep tumorigenesis theory in that the ability to metastasize is considered an inherent quality of the tumor from the beginning. It is assumed that metastasis develops not from a few rare cells in the primary tumor that acquire the ability to metastasize but that all cells in tumors with such molecular signatures develop the ability to metastasize. The reality probably lies in between since some early genetic changes detectable in the entire tumor can give tumors an advantage in the metastatic process, whereas additional genetic changes can give a clone of cells additional advantages, thus allowing them to succeed in metastasis. Epithelial-Mesenchymal Transition A regulatory program referred to as epithelial-mesenchymal transition (EMT) is a fundamental event in morphogenesis. During EMT epithelial cells are converted to migratory and invasive cells.32 EMT, has also been implicated as the mechanism through which epithelial cells acquire the ability to migrate, invade, resist apoptosis and metastasize. EMT is a developmental process, and a set of pleiotropically acting transcriptional factors, including Snail, Twist, Slug, and Zeb1/2orchestrateEMT. Several of these transcription factors can directly repress E-cadherin gene expression, depriving ­cancer cells of this key suppressor of motility and invasiveness. It has been proposed that the process of invasion and metastases requires significant plasticity, suggesting that EMT is required for invasion, intravasation and extravasation, and suppression of EMT regulators (and consequently EMT reversion, or MET) is required for metastatic outgrowth.33-35 Cancer Stem Cells Stem cells are cells that have the ability to perpetuate themselves through self-renewal and to generate mature cells of a particular tissue through differentiation.36 It has recently been proposed that stem cells themselves may be the target of transformation. It was first documented for leukemia and multiple myeloma that only a small subset of cancer cells is capable of extensive proliferation. It has subsequently also been shown for many solid cancers that only a small proportion of cells is clonogenic in culture and in vivo. In leukemia and multiple myeloma only a small subset of cancer cells is capable of extensive proliferation. Similarly, in many solid tumor types only a small proportion of cells is clonogenic in culture and in vivo. If indeed tumor growth and metastasis are driven by a small population of cancer stem cells, this may alter our current approaches to cancer therapy. Currently available drugs can shrink metastatic tumors but often cannot eradicate them. The failure of these treatments usually is attributed to the acquisition of drug resistance by the cancer cells; however, the cancer stem cell hypothesis raises the possibility that existing therapies may simply fail to kill cancer stem cells effectively. Therapeutic approaches targeting stem cells specifically are under study. CANCER ETIOLOGY Cancer Genomics One widely held opinion is that cancer is a genetic disease that arises from an accumulation of genomic alterations that leads to the selection of cells with increasingly aggressive behavior. These alterations may lead either to a gain of function by oncogenes VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 285 CHAPTER 10 ONCOLOGY new tissue. Next, the cells need to initiate growth in the new tissue and eventually establish vascularization to sustain the new tumor. Overall, metastasis is an inefficient process, although the initial steps of hematogenous metastasis (the arrest of tumor cells in the organ and extravasation) are believed to be performed efficiently. Only a small subset of cancer cells is then able to initiate micrometastases, and an even smaller portion goes on to grow into macrometastases. Metastases can sometimes arise several years after the treatment of primary tumors. For example, although most breast cancer recurrences occur within the first 10 years after the initial treatment and recurrences are rare after 20 years, breast cancer recurrences have been reported decades after the original tumor. This phenomenon is referred to as dormancy, and it remains one of the biggest challenges in cancer biology. Persistence of solitary cancer cells in a secondary site such as the liver or bone marrow is one possible contributor to dormancy.28 Another explanation of dormancy is that cells remain viable in a quiescent state and then become reactivated by a physiologically perturbing event. Interestingly, primary tumor removal has been proposed to be a potentially perturbing factor.29 An alternate explanation is that cells establish preangiogenic metastases in which they continue to proliferate but that the proliferative rate is balanced by the apoptotic rate. Therefore, when these small metastases acquire the ability to become vascularized, substantial tumor growth can be achieved at the metastatic site, leading to clinical detection. Several types of tumors metastasize in an organ-specific pattern. One explanation for this is mechanical and is based on the different circulatory drainage patterns of the tumors. When different tumor types and their preferred metastasis sites were compared, 66% of organ-specific metastases were explained on the basis of blood flow alone. The other explanation for preferential metastasis is what is referred to as the “seed and soil” theory, the dependence of the seed (the cancer cell) on the soil (the secondary organ). According to this theory, once cells have reached a secondary organ, their growth efficiency in that organ is based on the compatibility of the cancer cell’s biology with its new microenvironment. For example, breast cancer cells may grow more efficiently in bone than in some other organs because of favorable molecular interactions that occur in the bone microenvironment. The ability of cancer cells to grow in a specific site likely depends on features inherent to the cancer cell, features inherent to the organ, and the interplay between the cancer cell and its microenvironment.30 Many of the oncogenes discovered to date, such as HER2 and ras, are thought to potentiate not only malignant transformation but also one or more of the steps required in the metastatic process. Experimental models have suggested a role for several molecules, including RhoC, osteopontin and interleukin-11, and Twist, in tumor metastasis. Metastasis also may involve the loss of metastasis-suppressor genes. Laboratory work involving cancer cell lines that have been selected to have a higher metastatic potential have led to the realization that these more highly metastatic cells have a different gene expression profile than their less metastatic parental counterparts. This in turn has led to the currently held belief that the ability of a primary tumor to metastasize may be predictable by analysis of its gene expression profile. Indeed, several studies have recently focused on identifying a gene expression profile or a molecular signature that is associated with metastasis. It has been shown that such a gene expression profile can be used to predict the probability that the 286 Fertilized egg Gestation PART I Intrinsic mutation processes Infancy Childhood Adulthood BASIC CONSIDERATIONS Environmental and lifestyle exposures Early clonal expansion Benign tumour Early invasive Late invasive Chemotherapyresistant cancer cancer recurrence Mutator phenotype Passenger mutation Driver mutation Chemotherapy resistance mutation Chemotherapy 1–10 or more driver mutations 10s–1,000s of mitoses depending on the organ 10s–100s of mitoses depending on the cancer 10s–100,000 of more passenger mutations Figure 10-9. Accumulation of somatic mutations acquired by the cancer cell. Mutations may be acquired while the cell lineage is phenotypically normal, reflecting intrinsic mutations acquired during normal cell division as well as the effects of exogenous mutagens. Other processes such as example DNA repair defects may contribute to the mutational burden. Passenger mutations do not have any effect on the cancer cell, but driver mutations cause clonal expansion. Relapse after chemotherapy can be associated with resistance mutations that may predate the initiation of treatment.(Adapted by permission from Macmillan Publishers Ltd. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719. Copyright © 2009.)37 or to a loss of function by tumor-suppressor genes. These acquired gene alterations are termed somatic mutations to distinguish them from germline mutations that are inherited from parents and transmitted to offspring. Somatic mutations in a cancer genome may consist of several classes of DNA sequence changes. These include substitutions of one base by another; insertions or deletions of small or large segments of DNA; rearrangements, in which the DNA sequence has been broken and then rejoined to another DNA segment; copy number losses that may result in complete absence of a DNA sequence and copy number gains from the two copies present in the normal diploid genome. Somatic mutations in a cancer cell genome have accumulated over the lifetime of the patient (Fig. 10-9).37 DNA in normal cells is continuously damaged by internal and external mutagens. Most of this damage is repaired; however, a small fraction may remain as fixed mutations. Mutation rates increase in the presence of substantial exogenous mutagenic exposures, such as tobacco carcinogens or various forms of radiation, including ultraviolet light. These exposures are associated with increased rates of lung and skin cancer, respectively, and somatic mutations within such cancers often exhibit the distinctive mutational signatures known to be associated with the mutagen.38 The rates of somatic mutations are also increased in several rare inherited diseases, such as Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum, which are associated with increased risks of cancer.39, 40 The rest of the somatic mutations in a cancer cell have been acquired after the cancer cell already shows phenotypic evidence of neoplastic change. Whether the somatic mutation rate is always higher during this part of the lineage is controversial. This is clearly the case for some cancers. For instance, colorectal and endometrial cancers with defective DNA mismatch repair due to abnormalities in genes such as MLH1 and MSH2, exhibit increased rates of single nucleotide changes and small insertions/deletions atpolynucleotide tract.41 These tumor types are often referred to as “mutator phenotypes.” To date about 300 genes that have been reported to be mutated and causally implicated in cancer development.42 Ninety percent of cancer genes show somatic mutations in cancer, 20% show germline mutations, and 10% show both. The most common class of genomic alterations among the known cancer genes is a chromosomaltranslocation that creates a chimeric gene. Many more cancer genes have been found in leukemias, lymphomas, and sarcomas than in other types of cancer; and these genes are usually altered by chromosomal translocation. The most common cancer genes are protein kinases. Several domains that are involved in DNA binding and transcriptional regulation are also common in proteins encoded by cancer genes. Somatic mutations in a cancer genome may be classified according to its consequences for cancer development. “Driver” mutations confer a growth advantage to the cells carrying them and have been positively selected during the evolution of the cancer. The remainder of mutations are “bystanders” or “passengers” that do not confer growth advantage. It is likely that most somatic mutations are passenger mutations. Each tumor may have dozens to hundreds of genomic alterations, making it critical to determine which alterations are indeed drivers, and potentially better therapeutic targets. There are several ongoing large scale studies to characterize and catalogue genomic alterations in different cancer types, including the Cancer Genome Project at the Sanger Institute, United Kingdom, and The Cancer Genome Atlas project (TCGA). There are also increasing number of publically accessible resources, including COSMIC (http:// www.sanger.ac.uk/cosmic), which curates comprehensive information on somatic mutations in human cancer.43 These resources are being utilized to determine the most common genomic alterations in common tumor types. This information is being integrated into clinical practice in many tumor types, such as lung cancer, where molecular drivers are being chosen taking into consideration in systemic therapy selection (Fig. 10-10). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Genes Associated with Hereditary Cancer Risk Unknown EGFR KRAS Figure 10-10. Molecular subsets of lung adenocarcinoma. Pie chart shows the percentage of tumors with each potentially actionable alteration.(Adapted by permission from Macmillan Publishers Ltd. Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med. 2012;18:349. Copyright © 2012.)172 Tumor Heterogeneity and Molecular Evolution There is increasing recognition that tumors are heterogeneous; this represents an important challenge to utilizing genomic alterations to personalize cancer therapy (Fig. 10-11).44 First, there is significant intertumoral heterogeneity, such that patients with tumors that seem similar histologically, may differ in genomic alterations and in malignant potential.45-47 Second, during cancer progression, subclones frequently arise, resulting in differences in the proportion and pattern of genomic alterations between the primary tumor and the metastases or local-regional recurrences.44 Third, there may also be significant intratumoral heterogeneity, with spatially separated heterogeneous somatic mutations and chromosomal imbalances.48 Such spatial heterogeneity of subclones within the primary tumor or metastases provides an additional challenge, as it has been proposed that Hereditary: Nonhereditary: Tumor Tumor Figure 10-11. “Two-hit” tumor formation in both hereditary and nonhereditary cancers. A “one-hit” clone is a precursor to the tumor in nonhereditary cancer, whereas all cells are one-hit clones in hereditary cancer. (Adapted by permission from Macmillan Publishers Ltd. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer. 2001;1:157. Copyright © 2001.)51 Most of our information on human cancer genes has been gained from hereditary cancers. In the case of hereditary cancers, the individual carries a particular germline mutation in every cell. To date, over 70 genes have been associated with hereditary cancers (Table 10-3).42 A few of these hereditary cancer genes are oncogenes, but most are tumor-suppressor genes. Although hereditary cancer syndromes are rare, somatic mutations that occur in sporadic cancer have been found to disrupt the cellular pathways altered in hereditary cancer syndromes, which suggests that these pathways are critical to normal cell growth, cell cycle, and proliferation. The following factors may suggest the presence of a hereditary cancer49: 1. Tumor development at a much younger age than usual 2. Presence of bilateral disease 3. Presence of multiple primary malignancies 4.  Presentation of a cancer in the less affected sex (e.g., male breast cancer) 5. Clustering of the same cancer type in relatives 6.  Occurrence of cancer in association with other conditions such as mental retardation or pathognomonic skin lesions It is crucial that all surgeons caring for cancer patients be aware of hereditary cancer syndromes, because a patient’s genetic background has significant implications for patient counseling, planning of surgical therapy, and cancer screening and prevention. Some of the more commonly encountered hereditary cancer syndromes are discussed here. rb1Gene. The retinoblastoma gene rb1 was the first tumor suppressor to be cloned. The rb1 gene product, the Rb protein, is a regulator of transcription that controls the cell cycle, differentiation, and apoptosis in normal development. 50 ­Retinoblastoma has long been known to occur in hereditary and nonhereditary forms. Interestingly, although most children with an affected parent develop bilateral retinoblastoma, some develop unilateral retinoblastoma. Furthermore, some children with an affected parent are not affected themselves but then have an affected child, which indicates that they are rb1 mutation carriers. These findings led to the theory that a single mutation is not sufficient for tumorigenesis. Alfred Knudson hypothesized that hereditary retinoblastoma involves two mutations, of which one is germline and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutations (Fig. 10-12).51 Thus, both hereditary and nonhereditary forms of retinoblastoma involve the same number of mutations, a hypothesis known as Knudson’s “two-hit” hypothesis. A “hit” may be a point mutation, a chromosomal deletion referred to as allelic loss, or a loss of heterozygosity, or silencing of an existing gene. p53 and Li-Fraumeni Syndrome. Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including early-onset breast cancer, soft tissue sarcomas, brain tumors, adrenocortical tumors, and leukemia.52 Criteria for classic LFS in an individual (the proband) include: VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 287 CHAPTER 10 ONCOLOGY sequencing of a biopsy specimen or only a portion of the tumor could miss therapeutically relevant genomic alterations. The genomic alterations found in a tumor can also change under the selective pressure of a targeted therapy, adding to the challenge of implementing genomically-informed personalized therapy. MAP2K1 NRAS AKT1 ROS1 fusions PIK3CA KIF5B-RET BRAF HER2 ALK fusions 288 Table 10-3 Selected genes associated with hereditary cancer PART I BASIC CONSIDERATIONS SYMBOL NAME TUMOR TYPES (GERMLINE MUTATIONS) CANCER SYNDROME ALK anaplastic lymphoma kinase (Ki-1) Neuroblastoma Familial neuroblastoma APC adenomatous polyposis of the colon gene Colorectal, pancreatic, Adenomatous polyposis coli; Turcot desmoid, hepatoblastoma, syndrome glioma, other CNS ATM ataxia telangiectasia mutated Leukemia, lymphoma, medulloblastoma, glioma Ataxia-telangiectasia BLM Bloom Syndrome Leukemia, lymphoma, skin squamous cell, other cancers Bloom Syndrome BMPR1A bone morphogenetic protein receptor, type IA Gastrointestinal polyps Juvenile polyposis BRCA1 familial breast/ovarian cancer gene 1 Breast, ovarian Hereditary breast/ovarian cancer BRCA2 familial breast/ovarian cancer gene 2 Breast, ovarian, pancreatic Hereditary breast/ovarian cancer BRIP1 BRCA1 interacting protein C-terminal helicase 1 AML, leukemia, breast BUB1B BUB1 budding uninhibited by benzimidazoles Rhabdomyosarcoma 1 homolog beta (yeast) Mosaic variegated aneuploidy CDH1 cadherin 1, type 1, E-cadherin (epithelial) (ECAD) Gastric, lobular cancer Familial gastric carcinoma CDK4 cyclin-dependent kinase 4 Melanoma Familial malignant melanoma CDKN2A cyclin-dependent kinase inhibitor 2A (p16(INK4a)) gene Melanoma, pancreatic Familial malignant melanoma CDKN2a(p14) cyclin-dependent kinase inhibitor 2A– p14ARF protein Melanoma, pancreatic Familial malignant melanoma CHEK2 CHK2 checkpoint homolog (S. pombe) Breast Familial breast cancer CYLD familial cylindromatosis gene Cylindroma Familial cylindromatosis DDB2 damage-specific DNA binding protein 2 Skin basal cell, skin Xeroderma pigmentosum (E) squamous cell, melanoma DICER1 dicer 1, ribonuclease type III Pleuropulmonary blastoma Familial Pleuropulmonary Blastoma EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) NSCLC ERCC2, 3, 4, 5 excision repair cross-complementing rodent repair deficiency, complementation group Skin basal cell, skin Xeroderma pigmentosum squamous cell, melanoma (D, B, F, G)) EXT1 multiple exostoses type 1 gene exostoses, osteosarcoma exostoses, osteosarcoma FANCA, C, D2, Fanconi anemia, complementation group E, F, G AML, leukemia Fanconi anaemia A, C, D2, E, F, G FH fumarate hydratase leiomyomatosis, renal Hereditary leiomyomatosis and renal cell cancer GPC3 glypican 3 Wilms’ tumor Simpson-Golabi-Behmel syndrome HRAS v-Ha-ras Harvey rat sarcoma viral oncogene homolog v-Ha-ras Harvey rat sarcoma viral oncogene homolog Costello syndrome HRPT2 Hyperparathyroidism 2 (parafibromin) parathyroid adenoma, mulitiple ossifying jaw fibroma Hyperparathyroidism-jaw tumor syndrome KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral GIST, epithelioma oncogene homolog VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Fanconi anaemia J, breast cancer susceptiblity Familial lung cancer Familial gastrointestinal stromal tumor 289 Table 10-3 Selected genes associated with hereditary cancer (continued) CANCER SYNDROME Homolog of Drosophila Mothers Against Decapentaplegic 4 gene Gastrointestinal polyps Juvenile polyposis MEN1 multiple endocrine neoplasia type 1 gene Parathyroid adenoma, pituitary adenoma, pancreatic islet cell, carcinoid Parathyroid adenoma, pituitary adenoma, pancreatic islet cell, carcinoid MLH1 E. coli MutL homolog gene Colorectal, endometrial, ovarian, CNS Hereditary nonpolyposis colorectal cancer, Turcot syndrome MPL myeloproliferative leukemia virus oncogene, thrombopoietin receptor MPD Familial essential thrombocythemia MSH2 mutS homolog 2 (E. coli) colorectal, endometrial, ovarian Hereditary non-polyposis colorectal cancer MSH6 mutS homolog 6 (E. coli) colorectal, endometrial, ovarian Hereditary non-polyposis colorectal cancer MUTYH mutY homolog (E. coli) Colorectal Adenomatous polyposis coli NBS1 Nijmegen breakage syndrome 1 (nibrin) NHL, glioma, medulloblastoma, rhabdomyosarcoma Nijmegen breakage syndrome NF1 neurofibromatosis type 1 gene Neurofibroma, glioma Neurofibromatosis type 1 NF2 neurofibromatosis type 2 gene Meningioma, acoustic neuroma Neurofibromatosis type 2 PALB2 partner and localizer of BRCA2 Wilms tumor, medulloblastoma, AML, breast Fanconi anaemia N, breast cancer susceptibility PHOX2B paired-like homeobox 2b Neuroblastoma Familial neuroblastoma PMS1 PMS1 postmeiotic segregation increased 1 (S. cerevisiae) Colorectal, endometrial, ovarian Hereditary non-polyposis colorectal cancer PMS2 PMS2 postmeiotic segregation increased 2 (S. cerevisiae) Colorectal, endometrial, Hereditary nonpolyposis colorectal ovarian, medulloblastoma, cancer, Turcot syndrome glioma PRKAR1A protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1) Myxoma, endocrine, papillary thyroid Carney complex PTCH Homolog of Drosophila Patched gene Skin basal cell, medulloblastoma Nevoid Basal Cell Carcinoma Syndrome PTEN phosphatase and tensin homolog gene Hamartoma, glioma, prostate, endometrial Cowden Syndrome, BannayanRiley-Ruvalcaba syndrome RB1 retinoblastoma gene Retinoblastoma, sarcoma, Familial retinoblastoma breast, small cell lung RECQL4 RecQ protein-like 4 Osteosarcoma, skin basal and squamous cell Rothmund-Thompson Syndrome RET ret proto-oncogene Medullary thyroid, papillary thyroid, pheochromocytoma Multiple endocrine neoplasia 2A/2B SBDS Shwachman-Bodian-Diamond syndrome protein AML, MDS Schwachman-Diamond syndrome SDH5 chromosome 11 open reading frame 79 Paraganglioma Familial paraganglioma SHD, B, D succinate dehydrogenase complex Paraganglioma, pheochromocytoma Familial paraganglioma NAME MADH4 (Continued ) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 10 ONCOLOGY TUMOR TYPES (GERMLINE MUTATIONS) SYMBOL 290 Table 10-3 Selected genes associated with hereditary cancer (continued) PART I SYMBOL TUMOR TYPES (GERMLINE MUTATIONS) CANCER SYNDROME SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 Malignant rhabdoid Rhabdoid predisposition syndrome BASIC CONSIDERATIONS STK11 serine/threonine kinase 11 gene (LKB1) Jejunal hamartoma, ovarian, Peutz-Jeghers syndrome testicular, pancreatic SUFU suppressor of fused homolog (Drosophila) Medulloblastoma Medulloblastoma predisposition TCF1 transcription factor 1, hepatic (HNF1) Hepatic adenoma, hepatocellular carcinoma Familial Hepatic Adenoma TP53 tumor protein p53 Breast, sarcoma, Li-Fraumeni syndrome adrenocortical carcinoma, glioma, multiple other tumor types TSC1 tuberous sclerosis 1 gene Hamartoma, renal cell Tuberous sclerosis 1 TSC2 tuberous sclerosis 2 gene Hamartoma, renal cell Tuberous sclerosis 2 TSHR thyroid stimulating hormone receptor Thyroid adenoma VHL von Hippel-Lindau syndrome gene Renal, hemangioma, pheochromocytoma von Hippel-Lindau syndrome WRN Werner syndrome (RECQL2) Osteosarcoma, meningioma, others Werner Syndrome WT1 Wilms’ tumor 1 gene Wilms’ Denys-Drash syndrome, Frasier syndrome, Familial Wilms tumor XPA, C xeroderma pigmentosum, complementation group Skin basal cell, skin Xeroderma pigmentosum (A C) squamous cell, melanoma NAME SMARCB1 A, amplification; AEL, acute eosinophilic leukemia; AL, acute leukemia; ALCL, anaplastic large-cell lymphoma; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; AML*, acute myelogenous leukemia (primarily treatment associated); APL, acute promyelocytic leukemia; B-ALL, B-cell acute lymphocytic leukaemia; B-CLL, B-cell Lymphocytic leukemia; B-NHL, B-cell Non-Hodgkin Lymphoma; CLL, chronic lymphatic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; CNS, central nervous system; D, large deletion; DFSP, dermatofibrosarcoma protuberans; DLBL, diffuse large B-cell lymphoma; DLCL, diffuse large-cell lymphoma; Dom, dominant; E, epithelial; F, frameshift; GIST, gastrointestinal stromal tumour; JMML, juvenile myelomonocytic leukemia; L, leukaemia/lymphoma; M, mesenchymal; MALT, mucosa-associated lymphoid tissue lymphoma; MDS, myelodysplastic syndrome; Mis, Missense; MLCLS, mediastinal large cell lymphoma with sclerosis; MM, multiple myeloma; MPD, Myeloproliferative disorder; N, nonsense; NHL, non-Hodgkin lymphoma; NK/T, natural killer T cell; NSCLC, non small cell lung cancer; O, other; PMBL, primary mediastinal B-cell lymphoma; pre-B All, pre-B-cell acute lymphoblastic leukaemia; Rec, recessive; S, splice site; T, translocation; T-ALL, T-cell acute lymphoblastic leukemia; T-CLL, T-cell chronic lymphocytic leukaemia; TGCT, testicular germ cell tumour; T-PLL, T cell prolymphocytic leukemia Source: Adapted by permission from Macmillan Publishers Ltd. Futreal PA et al. A census of human cancer genes. Nat Rev Cancer. 2004;4:177. Copyright © 2004. A Intratumoural heterogeneity between patients B Intratumoural heterogeneity between primary and metastatic sites C Intratumoural spatial heterogeneity Figure 10-12. Tumor heterogeneity. A. Patients with tumors with similar histologies may differ in genetic mutation status and other molecular features B. Cells within the primary tumor can acquire or lose genomic alterations in metastatic sites. C. Intratumoral spatial heterogeneity: common initiating genomic events usually exist in all tumor cells but additional spatially separated heterogeneous somatic mutations or copy number changes may accumulate. (Adapted with permission from Meric-Bernstam and Mills)44 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ BRCA1, BRCA2, and Hereditary Breast-Ovarian Cancer Syndrome. It is estimated that 5% to 10% of breast cancers are hereditary. Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline mutation in one of the breast cancer genes BRCA1 or BRCA2.57 Mutation carriers are more prevalent among women who have a first- or seconddegree relative with premenopausal breast cancer or ovarian cancer at any age. The likelihood of a BRCA mutation is higher in patients who belong to a population in which founder mutations may be prevalent, such as in the Ashkenazi Jewish population. For a female BRCA1 mutation carrier, the cumulative risks of developing breast cancer and ovarian cancer by age 70 have been estimated to be 87% and 44%, respectively.58 The cumulative risks of breast cancer and ovarian cancer by age 70 in families with BRCA2 mutation have been estimated to be 84% and 27%, respectively.59 Although male breast cancer can occur with either BRCA1 or BRCA2 mutation, the majority of families (76%) with both male and female breast cancer have mutations in BRCA2.59 Besides breast and ovarian cancer, BRCA1 and BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfold increased risk for colon cancer and threefold increased risk for prostate cancer.58 BRCA2 mutations confer a fivefold increased risk for prostate cancer, sevenfold in men younger than 65 years.60 Furthermore, BRCA2 mutations confer a fivefold increased risk for gallbladder and bile duct cancers, fourfold increased risk for pancreatic cancer, and threefold increased risk for gastric cancer and malignant melanoma.60 BRCA1 was the first breast cancer susceptibility gene identified and has been mapped to 17q21. BRCA2, mapped to 13q12.3, was reported shortly afterward. BRCA1 and BRCA2 encode large nuclear proteins, 208 kDa and 384 kDa, respectively, that have been implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of the cell cycle, and transcription.61 Although early studies suggested that the two proteins function together as a complex, subsequent data demonstrated that they have distinct functions.62, 63 In fact, breast cancers arising from BRCA1 or BRCA2 mutations are different at the molecular level and have been found to have distinct gene expression profiles.64 BRCA1associated tumors are more likely to be estrogen receptor negative, whereas BRCA2-associated tumors are more likely to be estrogen receptor positive. Currently, studies are ongoing to determine whether BRCA1 and BRCA2 status can be used to guide systemic therapy choices for breast cancer. APC Gene and Familial Adenomatous Polyposis Patients affected with familial adenomatous polyposis (FAP) characteristically develop hundreds to thousands of polyps in the colon and rectum. The polyps usually appear in adolescence and, if left untreated, progress to colorectal cancer. FAP is associated with benign extracolonic manifestations that may be useful in identifying new cases, including congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and osteomas. In addition to colorectal cancer, patients with FAP are at risk for upper intestinal neoplasms (gastric and duodenal polyps, duodenal and periampullary cancer), hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), thyroid carcinomas, desmoid tumors, and medulloblastomas. The product of the adenomatous polyposis coli tumorsuppressor gene (APC) plays an important role in cell-cell interactions, cell adhesion, regulation of β-catenin, and maintenance of cytoskeletal microtubules. Alterations in APC lead to dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, including cell-cycle progression, migration, differentiation, and apoptosis. Mutations in the APC have been identified in FAP and in 80% of sporadic colorectal cancers.65 Furthermore, APC mutations are the earliest known genetic alterations in colorectal cancer progression, which emphasizes its importance in cancer initiation. The germline mutations in APC may arise from point mutations, insertions, or deletions that lead to a premature stop codon and a truncated, functionally inactive protein. The risk of developing specific manifestations of FAP is correlated with the position of the FAP mutations, a phenomenon referred to as genotype-phenotype correlation. For example, desmoids usually are associated with mutations between codons 1403 and 1578.66, 67 Mutations in the extreme 5’ or 3’ ends of APC, or in the alternatively spliced region of exon 9, are associated with an attenuated version of FAP. Better understanding of the genotype-phenotype correlations may assist in patient counseling and therapeutic planning. Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer. Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome 1, which entails hereditary predisposition for colorectal cancer with early age of onset (approximately age 44 years) and an excess of synchronous and metachronous colonic cancers; and Lynch syndrome 2, featuring a similar colonic phenotype accompanied by a high risk VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 291 CHAPTER 10 ONCOLOGY (a) a bone or soft tissue sarcoma when younger than 45 years, (b) a first-degree relative with cancer before age 45 years, and (c) another first- or second-degree relative with either a sarcoma diagnosed at any age or any cancer diagnosed before age 45 years.53 Approximately 70% of LFS families have been shown to have germline mutations in the tumor-suppressor gene p53.54 Breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms’ tumor, and phyllodes tumor of the breast are strongly associated; pancreatic cancer is moderately associated; and leukemia and neuroblastoma are weakly associated with germline p53 mutations.55 Mutations of p53 have not been detected in approximately 30% of LFS families, and it is hypothesized that genetic alterations in other proteins interacting with p53 function may play a role in these families. Of the known genes in human cancer, p53 is the most commonly mutated. The p53 protein regulates cell-cycle progression as well as apoptotic cell death as part of stress response pathways after exposure to ionizing or ultraviolet (UV) irradiation, chemotherapy, acidosis, growth factor deprivation, or hypoxia. When cells are exposed to stressors, p53 acts as a transcription factor for genes that induce cell-cycle arrest or apoptosis. A majority of p53 mutations are found within a central DNA recognition motif and disrupt DNA binding by p53. Families with germline missense mutations in the DNA-binding domain show a more highly penetrant phenotype than families with other p53 mutations.56 Furthermore, proband cancers are linked with significantly younger age at diagnosis in patients with missense mutations in the DNA-binding domain.56 292 Table 10-4 Revised criteria for hereditary nonpolyposis colon ­cancer (HNPCC) (Amsterdam criteria II) PART I BASIC CONSIDERATIONS Three or more relatives with an HNPCC-associated cancer (colorectal cancer, endometrial cancer, cancer of the small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two At least two successive generations affected At least one case diagnosed before age 50 y Familial adenomatous polyposis excluded Tumors verified by pathologic examination Source: Modified with permission from Vasen et al. Copyright ­Elsevier.69 for carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas.68 The diagnostic criteria for HNPCC are referred to as the Amsterdam criteria, or the 3-2-1-0 rule. The classic Amsterdam criteria were revised to include other HNPCC-related cancers (Table 10-4). 69 These criteria are met when three or more family members have histologically verified, HNPCC-associated cancers (one of whom is a first-degree relative of the other two), two or more generations are involved, at least one individual was diagnosed before age 50 years, and no individuals have FAP.69 During DNA replication, DNA polymerases may introduce single nucleotide mismatches or small insertion or deletion loops. These errors are corrected through a process referred to as mismatch repair. When mismatch repair genes are inactivated, DNA mutations in other genes that are critical to cell growth and proliferation accumulate rapidly. In HNPCC, germline mutations have been identified in several genes that play a key role in DNA nucleotide mismatch repair: hMLH1 (human mutL homologue 1), hMSH2 (human mutS homologue 2), hMSH6, and hPMS1 and hPMS2 (human postmeiotic segregation 1 and 2), of which hMLH1 and hMSH2 are the most common.70-75 The hallmark of HNPCC is microsatellite instability, which occurs on the basis of unrepaired mismatches and small insertion or deletion loops. Microsatellite instability can be tested by comparing the DNA of a patient’s tumor with DNA from adjacent normal epithelium, amplifying the DNA with polymerase chain reaction (PCR) using a standard set of markers, comparing the amplified genomic DNA sequences, and classifying the degree of microsatellite instability as high, low, or stable. Such microsatellite instability testing may help select patients who are more likely to have germline mutations. PTEN and Cowden Disease Somatic deletions or mutations in the tumor-suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) have been observed in a number of glioma breast, prostate, and renal carcinoma cell lines and several primary tumor specimens.76 PTEN encodes a 403-amino-acid protein, tyrosine phosphatase. PTEN negatively controls the PI3K signaling pathway for the regulation of cell growth and survival by dephosphorylating phosphoinositol 3,4,5-triphosphate; thus mutation of PTEN leads to constitutive activation of the PI3K/Akt signaling pathway. The “hot spot” for PTEN mutations has been identified in exon 5. Forty-three percent of CD mutations have been identified in this exon, which contains the tyrosine phosphatase core domain. This suggests that the PTEN catalytic activity is vital for its biologic function. PTEN was identified as the susceptibility gene for the autosomal dominant syndrome Cowden disease (CD) or multiple hamartoma syndrome.77 Trichilemmomas, benign tumors of the hair follicle infundibulum, and mucocutaneous papillomatosis are pathognomonic of CD. Other common features include thyroid adenomas and multinodular goiters, breast fibroadenomas, and hamartomatous GI polyps. The diagnosis of CD is made when an individual or family has a combination of pathognomonic major and/or minor criteria proposed by the International Cowden Consortium.78 CD is associated with an increased risk of breast and thyroid cancers. Breast cancer develops in 25% to 50% of affected women.78 p16 and Hereditary Malignant Melanoma. The gene p16, also known as INK4A, CDKN1, CDKN2A, and MTS1, is a tumor suppressor that acts by binding CDK4 and CDK6 and inhibiting the catalytic activity of the CDK4-CDK6/cyclin D complex that is required for phosphorylation of Rb and subsequent cell-cycle progression. Studies suggest that germline mutations in p16 can be found in 20% of melanoma-prone families.79 Mutations in p16 that alter its ability to inhibit the catalytic activity of the CDK4-CDK6/cyclin D complex not only increase the risk of melanoma by 75-fold but also increase the risk of pancreatic cancer by 22-fold.80 Interestingly, p16 mutations that do not appear to alter its function increase the risk of melanoma by 38-fold and do not increase the risk of pancreatic cancer.80 Genomic characterization of primary tumors has revealed that p16 is inactivated through point mutation, promoter methylation, or deletion in a significant portion of sporadic tumors, including cancers of the pancreas, esophagus, head and neck, stomach, breast, and colon, as well as melanomas. E-cadherin and Hereditary Diffuse Gastric Cancer. E-cadherin is a cell adhesion molecule that plays an important role in normal architecture and function of epithelial cells. The adhesive function of E-cadherin is dependent on interaction of its cytoplasmic domain with β- and γ-catenins and may be regulated by phosphorylation of β-catenin. Hereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome that results from germline mutations in the E-cadherin gene, CDH1. Carriers of CDH1 mutations have a 70% to 80% chance of developing gastric cancer.81 Furthermore, mutations of CDH1 have been described in sporadic cancers of the ovary, endometrium, breast, and thyroid. However, frequent mutations have been identified in only two particular tumors: diffuse gastric carcinomas and lobular breast carcinomas. Invasive lobular breast carcinomas often show inactivating mutations in combination with a loss of heterozygosity of the wild-type CDH1 allele.82 Interestingly, in gastric carcinomas the predominant mutations are exon skipping causing in-frame deletions, whereas most mutations identified in lobular breast cancers are premature stop codons; this suggests a genotypephenotype correlation. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2 Genetic Modifiers of Risk. Individuals carrying identical germline mutations vary in regard to cancer penetrance (whether cancer will develop or not) and cancer phenotype (the tissues involved). It is thought that this variability may be due to environmental influences or, if genetic, to genetic modifiers of risk. Similarly, genetic modifiers of risk also can play a role in determining whether an individual will develop cancer after exposure to carcinogens. Chemical Carcinogens The first report indicating that cancer could be caused by environmental factors was by John Hill, who in 1761 noted the association between nasal cancer and excessive use of tobacco snuff.84 Currently, approximately 60% to 90% of cancers are thought to be due to environmental factors. Any agent that can contribute to tumor formation is referred to as a carcinogen and can be a chemical, physical, or viral agent. Chemicals are classified into three groups based on how they contribute to tumor formation. The first group of chemical agents, the genotoxins, can initiate carcinogenesis by causing a mutation. The second group, the cocarcinogens, by themselves cannot cause cancer but potentiate carcinogenesis by enhancing the potency of genotoxins. The third group, tumor promoters, enhances tumor formation when given after exposure to genotoxins. The International Agency for Research on Cancer (IARC) maintains a registry of human carcinogens that is available through the World Wide Web (http://www.iarc.fr). The compounds are categorized into five groups based on an analysis of epidemiologic studies, animal models, and short-term mutagenesis tests. Group 1 contains what are considered to be proven human carcinogens, based on formal epidemiologic studies among workers who were exposed for long periods (several years) to the chemicals.85 Group 2A contains what are considered to be probable human carcinogens. Suggestive epidemiologic evidence exists for compounds in this group, but the data are insufficient to establish causality. There is evidence of carcinogenicity, however, from animal studies carried out under conditions relevant to human exposure. Group 2B contains what are considered to be possible carcinogens, because these substances are associated with a clear statistically and biologically significant increase in the incidence of malignant tumors in more than one animal species or strain. Group 3 agents are not classifiable, and Group 4 agents are probably not carcinogenic to humans. Physical Carcinogens Physical carcinogenesis can occur through induction of inflammation and cell proliferation over a period of time or through exposure to physical agents that induce DNA damage. Foreign bodies can cause chronic irritation that can expose cells to carcinogenesis due to other environmental agents. In animal models, for example, subcutaneous implantation of a foreign body can lead to the development of tumors that have been attributed to chronic irritation from the foreign objects. In humans, clinical scenarios associated with chronic irritation and inflammation such as chronic nonhealing wounds, burns, and inflammatory bowel syndrome have all been associated with an increased risk of cancer. H. pylori infection is associated with gastritis and gastric cancer, and thus, its carcinogenicity may be considered physical carcinogenesis. Infection with the liver fluke Opisthorchis viverrini similarly leads to local inflammation and ­cholangiocarcinoma. The induction of lung and mesothelial cancers by asbestos fibers and nonfibrous particles such as silica are other examples of foreign body-induced physical carcinogenesis.87 Animal experiments have demonstrated that the dimensions and durability of the asbestos and other fibrous minerals are the key determinants of their carcinogenicity.88 Short fibers can be inactivated by phagocytosis, whereas long fibers (>10 μm) are cleared less effectively and are encompassed by proliferating epithelial cells. The long fibers support cell proliferation and have been shown to preferentially induce tumors. Asbestosassociated biologic effects also may be mediated through reactive oxygen and nitrogen species. Furthermore, an interaction occurs between asbestos and silica and components of cigarette smoke. Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are metabolized by epithelial cells and form DNA adducts. If PAH is coated on asbestos, PAH uptake is increased.87 Both PAH and asbestos impair lung clearance, potentially increasing uptake further. Therefore, physical carcinogens may be synergistic with chemical carcinogens. Radiation is the best-known agent of physical carcinogens and is classified as ionizing radiation (X-rays, gamma rays, and alpha and beta particles) or nonionizing radiation (UV). The carcinogenic potential of ionizing radiation was recognized soon after Wilhelm Conrad Roentgen’s discovery of X-rays in 1895. Within the next 20 years, a large number of radiation-related skin cancers were reported. Long-term follow-up of survivors of the atomic bombing of Hiroshima and Nagasaki revealed that virtually all tissues exposed to radiation are at risk for cancer. Radiation can induce a spectrum of DNA lesions that includes damage to the nucleotide bases and cross-linking, and DNA single- and double-strand breaks (DSBs). Misrepaired DSBs are the principal lesions of importance in the induction of chromosomal abnormalities and gene mutations. DSBs in irradiated cells are repaired primarily by a nonhomologous endjoining process, which is error prone; thus, DSBs facilitate the production of chromosomal rearrangements and other largescale changes such as chromosomal deletions. It is thought that radiation may initiate cancer by inactivating tumor-suppressor genes. Activation of oncogenes appears to play a lesser role in radiation carcinogenesis. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 293 CHAPTER 10 ONCOLOGY The RET (rearranged during transfection) gene encodes for a transmembrane receptor tyrosine kinase that plays a role in proliferation, migration, and differentiation of cells derived from the neural crest. Gain-of-function mutations in the RET gene are associated with medullary thyroid carcinoma in isolation or multiple endocrine neoplasia type 2 (MEN2) syndromes. MEN2A is associated with medullary thyroid carcinoma and pheochromocytoma (in 50%) or parathyroid adenoma (in 20%), whereas MEN2B is associated with medullary thyroid carcinoma, marfanoid habitus, mucosal neuromas, and ganglioneuromatosis.83RET mutations lead to uncontrolled growth of the thyroid C cells, and in familial medullary cancer, C-cell hyperplasia progresses to bilateral, multicentric medullary thyroid cancer. Mutations in the RET gene have also been identified in half of sporadic medullary thyroid cancers. Selected substances that have been classified as proven carcinogens (group 1) by the IARC in an expert panel review in 2009 are listed in Table 10-5.86 294 Table 10-5 Group 1 chemical carcinogens and evidence for carcinogenicity in humans and for genotoxicity as the main mechanism PART I BASIC CONSIDERATIONS TUMOR SITES OR TYPES WITH SUFFICIENT EVIDENCE IN HUMANS EVIDENCE OF GENOTOXICITY AS THE MAIN MECHANISM 4-Aminobiphenyl Urinary bladder Strong Benzidine Urinary bladder Strong Dyes metabolized to benzidine .. Strong* 4,4’-Methylenebis(2-chloroaniline) .. Strong* 2-Napthylamine Urinary bladder Strong Ortho-toluidine Urinary bladder Moderate Auramine production Urinary bladder Weak/lack of data† Magenta production Urinary bladder Weak/lack of data† Benzo[α]pyrene .. Strong* Soot (chimney sweeping) Skin, lung Moderate Coal gasification Lung Strong Coal-tar distillation Skin Strong Coke production Lung Strong Coal-tar pitches (paving, roofing) Lung Strong Aluminum production Lung, urinary bladder Weak/moderate†‡ Aflatoxins Hepatocellular carcinoma Strong Benzene ANLL Strong Bis(chloromethyl)ether/ chloromethyl methylether Lung Moderate/strong 1,3-Butadiene Haematolymphatic organs Strong Dioxin (2,3,7,8-TCDD) All cancers combined** See text§ 2,3,4,7,8-Pentachlorodibenzofuran .. See text*§ 3,3’,4,4’,5-Pentachlorobiphenyl (PCB-126) .. See text*§ Ethylene oxide .. Strong* Formaldehyde Nasopharynx Leukemia** Strong Moderate Sulfur mustard Lung Strong Vinyl chloride Hepatic angiosarcoma, hepatocellular carcinoma Strong Iron and steel founding Lung Weak/moderate Isopropyl alcohol manufacture using strong acids Nasal cavity Weak/lack of data Mineral oils Skin Weak/lack of data Occupational exposure as a painter Lung, urinary bladder, pleural mesothelioma Strong‡ Rubber-manufacturing industry Leukaemia, lymphoma**, urinary bladder, lung**, stomach** Strong‡ Shale oils Skin Weak/lack of data Strong inorganic acid mists Larynx Weak/lack of data ANLL, acute non-lymphocytic leukaemia; ALL, acute lymphocytic leukaemia; CLL, chronic lymphocytic leukaemia; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; STS, soft-tissue sarcoma. *Agents classified in Group 1 on the basis of mechanistic information. †Weak evidence in workers, but strong evidence for some chemicals in this industry. ‡Due to the diversity and complexity of these exposures, other mechanisms may also be relevant. §Strong evidence for an aryl hydrocarbon receptor (AhR)-mediated mechanism. ¶Particularly myeloid leukemia. ||After maternal exposure (before or ­during pregnancy, or both). **New epidemiological findings. Source: Adapted from Baan et al 2009. Copyright Elsevier.86 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Viral Carcinogens One of the first observations that cancer may be caused by transmissible agents was by Peyton Rous in 1910 when he demonstrated that cell-free extracts from sarcomas in chickens could transmit sarcomas to other animals injected with these extracts.89 This was subsequently discovered to represent viral transmission of cancer by the Rous sarcoma virus. At present, several human viruses are known to have oncogenic properties, and several have been causally linked to human cancers (Table 10-6).85 It is estimated that 15% of all human tumors worldwide are caused by viruses.90 Table 10-6 Selected viral carcinogensa VIRUS PREDOMINANT TUMOR TYPEb Epstein-Barr virus Burkitt’s lymphoma Hodgkin’s disease Immunosuppression-related lymphoma Sinonasal angiocentric T-cell lymphoma Nasopharyngeal carcinoma Hepatitis B virus Hepatocellular carcinoma Hepatitis C virus Hepatocellular carcinoma HIV type 1 Kaposi’s sarcoma Non-Hodgkin’s lymphoma Human papillomavirus 16 and 18 Cervical cancer Anal cancer Human T-cell lymphotropic viruses Adult T-cell leukemia/lymphoma Data based on information in the International Agency for Research on Cancer monographs.85 b Only tumor types for which causal relationships are established are listed. Other cancer types may be linked to the agents with a lower ­frequency or with insufficient data to prove causality. a Viruses may cause or increase the risk of malignancy through several mechanisms, including direct transformation, expression of oncogenes that interfere with cell-cycle checkpoints or DNA repair, expression of cytokines or other growth factors, and alteration of the immune system. Oncogenic viruses may be RNA or DNA viruses. Oncogenic RNA viruses are retroviruses and contain a reverse transcriptase. After the viral infection, the single-stranded RNA viral genome is transcribed into a double-stranded DNA copy, which is then integrated into the chromosomal DNA of the cell. Retroviral infection of the cell is permanent; thus, integrated DNA sequences remain in the host chromosome. Oncogenic transforming retroviruses carry oncogenes derived from cellular genes. These cellular genes, referred to as proto-oncogenes, usually are involved in mitogenic signaling and growth control, and include protein kinases, G proteins, growth factors, and transcription factors (Table 10-7).90 Integration of the provirus upstream of a proto-oncogene may produce chimeric virus-cell transcripts and recombination during the next round of replication that could lead to incorporation of the cellular gene into the viral genome.90 Then again, many retroviruses do not possess oncogenes but can cause tumors in animals regardless. This occurs by integration of the provirus near a normal cellular proto-oncogene and activation of the expression of these genes by the strong promoter and enhancer sequences in the integrated viral sequence. Unlike the oncogenes of the RNA viruses, those of the DNA tumor viruses are viral, not cellular, in origin. These genes are required for viral replication using the host cell machinery. In permissive hosts, infection with an oncogenic DNA virus may result in a productive lytic infection, which leads to cell death and the release of newly formed viruses. In nonpermissive cells, the viral DNA can be integrated into the cellular chromosomal DNA, and some of the early viral genes can be synthesized persistently, which leads to transformation of cells to a neoplastic state. The binding of viral oncoproteins to cellular tumor-suppressor proteins p53 and Rb is fundamental to the carcinogenesis induced by most DNA viruses, although some target different cellular proteins. Like other types of carcinogenesis, viral carcinogenesis is a multistep process. Some retroviruses contain two cellular oncogenes, rather than one, in their genome and are more rapidly tumorigenic than single-gene transforming retroviruses, which emphasizes the cooperation between transforming genes. Furthermore, some viruses encode genes that suppress or delay apoptosis. Although immunocompromised individuals are at elevated risk, most patients infected with oncogenic viruses do not develop cancer. When cancer does develop, it usually occurs several years after the viral infection. It is estimated, for example, that the risk of hepatocellular carcinoma (HCC) among individuals infected with hepatitis C virus is 1% to 3% after 30 years.91 There may be synergy between various environmental factors and viruses in carcinogenesis. Recognition of a viral origin for some tumors has led to the pursuit of vaccination as a preventive strategy. The use of childhood hepatitis B vaccination has already translated into a decrease in liver cancer incidence in the Far East.5 Similarly, it is recognized that cervical cancer and its obligate precursors, cervical intraepithelial neoplasia grades 2 and 3, and adenocarcinoma in situ, are caused by oncogenic human papillomavirus (HPV); administration of HPV vaccine to HPV-naive women, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 295 CHAPTER 10 ONCOLOGY Although it has been assumed that the initial genetic events induced by radiation constitute direct mutagenesis from radiation, other indirect effects may contribute to carcinogenesis. For example, radiation induces genomic instability in cells that persists for at least 30 generations after irradiation. Therefore, even if cells do not acquire mutations at initial irradiation, they remain at risk for developing new mutations for several generations. Moreover, even cells that have not been directly irradiated appear to be at risk, a phenomenon referred to as the bystander effect. Nonionizing UV radiation is a potent DNA-damaging agent and is known to induce skin cancer in experimental animals. Most nonmelanoma human skin cancers are thought to be induced by repeated exposure to sunlight, which leads to a series of mutations that allow the cells to escape normal growth control. Patients with inherited xeroderma pigmentosum lack one or more DNA repair pathways, which confers susceptibility to UV-induced cancers, especially on sun-exposed body parts. Patients with ataxia telangiectasia mutated syndrome also have a radiation-sensitive phenotype. 296 Table 10-7 Selected cellular oncogenes in retroviruses PART I BASIC CONSIDERATIONS ONCOGENE VIRUS NAME ORIGIN PROTEIN PRODUCT abl Abelson murine leukemia virus Mouse Tyrosine kinase fes ST feline sarcoma virus Cat Tyrosine kinase fps Fujinami sarcoma virus Chicken Tyrosine kinase src Rous sarcoma virus Chicken Tyrosine kinase erbB Avian erythroblastosis virus Chicken Epidermal growth factor receptor fms McDonough feline sarcoma virus Cat Colony-stimulating factor receptor kit Hardy-Zuckerman 4 feline sarcoma virus Cat Stem cell factor receptor mil Avian myelocytoma virus Chicken Serine/threonine kinase mos Moloney murine sarcoma virus Mouse Serine/threonine kinase raf Murine sarcoma virus 3611 Mouse Serine/threonine kinase sis Simian sarcoma virus Monkey Platelet-derived growth factor H-ras Harvey murine sarcoma virus Rat GDP/GTP binding K-ras Kirsten murine sarcoma virus Rat GDP/GTP binding erbA Avian erythroblastosis virus Chicken Transcription factor (thyroid hormone receptor) ets Avian myeloblastosis virus E26 Chicken Transcription factor fos FBJ osteosarcoma virus Mouse Transcription factor (AP1 component) jun Avian sarcoma virus 17 Chicken Transcription factor (AP1 component) myb Avian myeloblastosis virus Chicken Transcription factor myc MC29 myelocytoma virus Chicken Transcription factor (NF-κB family) AP1, activator protein 1; FBJ, Finkel-Biskis-Jinkins; GDP, guanosine diphosphate; GTP, guanosine triphosphate; NF-κB, nuclear factor κB. Source: Modified from Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis. 2000;21:405. By permission of Oxford University Press. substantially reduces the incidence of HPV16/18-related cervical precancers and cervical cancer.92 The American Cancer Society now recommends routine HPV vaccination principally for females aged 11 to 12 years, but also for females aged 13 to 18 years to ‘’catch up’’ those who missed the opportunity to be vaccinated or who need to complete the vaccination series.93 CANCER RISK ASSESSMENT Cancer risk assessment is an important part of the initial evaluation of any patient. A patient’s cancer risk not only is an important determinant of cancer screening recommendations but also may alter how aggressively an indeterminant finding will be pursued for diagnosis. A “probably benign” mammographic lesion, for example, defined as one with <2% probability of malignancy (American College of Radiology category III) is usually managed with a 6-month follow-up mammogram in a patient at baseline cancer risk, but obtaining a tissue diagnosis may be preferable in a patient at high risk for breast cancer.94 Cancer risk assessment starts with taking a complete history that includes history of environmental exposures to potential carcinogens and a detailed family history. Risk assessment for breast cancer, for example, includes obtaining a family history to determine whether another member of the family is known to carry a breast cancer susceptibility gene; whether there is familial clustering of breast cancer, ovarian cancer, thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, brain tumors, dermatologic manifestations, leukemia, or lymphoma; and whether the patient is from a population at increased risk, such as individuals of Ashkenazi Jewish descent. Patients who have a family history suggestive of a cancer susceptibility syndrome such as hereditary breast-ovarian syndrome, LFS, or CD would benefit from genetic counseling and possibly genetic testing. There are several models that can estimate risk based on complex family histories and assist clinicians in estimating breast cancer risk or the likelihood that a BRCA mutation is present, including the Claus model, Tyrer-Cuzick model BRCAPRO model, and the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model.95-98 Patients who do have a strong hereditary component of risk can be evaluated on the basis of their age, race, personal history, and exposures. One of the most commonly used models for risk assessment in breast cancer is the Gail model.99 Gail and colleagues analyzed the data from 2852 breast cancer cases and 3146 controls from the Breast Cancer Detection and Demonstration Project, a mammography screening project conducted in the 1970s, and developed a model for projecting breast cancer incidence. The model uses risk factors such as an individual’s age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, number of previous breast biopsy specimens, and whether the biopsy specimen results revealed atypical ductal hyperplasia (Table 10-8).99 This model has led to the development of a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 10-8 Assessment of risk for invasive breast cancer RELATIVE RISK (%) Age at menarche (years) >14 1.00 12–13 1.10 <12 1.21 Age at first live birth (years) Patients with no first-degree relatives with cancer <20 1.00 20–24 1.24 25–29 or nulliparous 1.55 ≥30 1.93 Patients with one first degree-relative with cancer <20 1.00 20–24 2.64 25–29 or nulliparous 2.76 ≥30 2.83 CANCER SCREENING Patients with ≥2 first-degree relatives with cancer <20 6.80 20–24 5.78 25–29 or nulliparous 4.91 ≥30 4.17 Breast biopsies (number) Patients aged <50 y at counseling 0 1.00 1 1.70 ≥2 2.88 Patients aged ≥50 y at counseling 0 1.00 1 1.27 ≥2 1.62 Atypical hyperplasia No biopsies 1.00 At least 1 biopsy, no atypical   hyperplasia 0.93 No atypical hyperplasia, hyperplasia    status unknown for at least 1 biopsy 1.00 Atypical hyperplasia in at least 1 biopsy 1.82 Source: Modified from Gail MH et al.99 breast cancer risk assessment tool, which is available on the World Wide Web.100 This tool incorporates the risk factors used in the Gail model, as well as race and ethnicity, and allows a health professional to ­project a woman’s individualized ­estimated risk for invasive breast cancer over a 5-year period Early detection is the key to success in cancer therapy. Screening for common cancers using relatively noninvasive tests is expected to lead to early diagnosis, allow more conservative surgical therapies with decreased morbidity, and potentially improve surgical cure rates and overall survival rates. Key factors that influence screening guidelines are how prevalent the cancer is in the population, what risk is associated with the screening measure, and whether early diagnosis actually affects outcome. The value of a widespread screening measure is likely to go up with the prevalence of the cancer in a population, which often determines the age cutoffs for screening and explains why screening is done only for common cancers. The risks associated with the screening measure are a significant consideration, especially with more invasive screening measures such as colonoscopy. The consequences of a false-positive screening test result also need to be considered. For example, when 1000 screening mammograms are taken, only 2 to 4 new cases of cancer will be identified; this number is slightly higher (6 to 10 prevalent cancers per 1000 mammograms) for initial screening mammograms.102 However, as many as 10% of screening mammograms may be potentially suggestive of an abnormality, which requires further imaging (i.e., a 10% recall rate). Of those women with abnormal mammogram findings, only 5% to 10% will be determined to have a breast cancer. Among women for whom biopsy specimen is recommended, 25% to 40% will have a breast cancer. A false-positive screening result is likely to induce significant emotional distress in patients, leads to unnecessary biopsy specimens, and has cost implications for the health care system. The 2013 American Cancer Society guidelines for the early detection of cancer are listed in Table 10-9.93 These guidelines are updated periodically to incorporate emerging technologies and new data on the efficacy of screening measures. Besides the American Cancer Society, several other professional bodies make recommendations for screening. Although the screening guidelines differ somewhat, most organizations do not emphasize one screening strategy as superior to another, but all emphasize the importance of age-appropriate screening. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 297 CHAPTER 10 ONCOLOGY RISK FACTOR and over her l­ifetime (to age 90 years). Notably, these risk projections assume that the woman is undergoing regular clinical breast examinations and screening mammograms. Also of note is that this ­program ­underestimates the risk for women who have already had a diagnosis of invasive or noninvasive breast cancer and does not take into account specific genetic predispositions such as mutations in BRCA1 or BRCA2. However, risk assessment tools such as this have been validated and are now in widespread clinical use. Similar models are in development or are being validated for other cancers. For example, a lung cancer risk prediction model, which includes age, sex, asbestos exposure history, and smoking history, has been found to predict risk of lung cancer.101 There is now growing interest in using each individuals genotype, such as presence or absence of single nucleotide polymorphisms which each may confer low or intermediate cancer risk. Risk models that include biological as well as environmental factors may accurately predict cancer risk, providing better guidance as to which patients should undergo more intensive screening (e.g., screening with magnetic resonance imaging of the breast, computerized tomography screening of the lung), and should be considered for preventive strategies. 298 Table 10-9 American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individuals PART I POPULATION TEST OR PROCEDURE FREQUENCY Breast Women, aged ≥20y BSE It is acceptable for women to choose not to do BSE or to do BSE regularly (monthly) or irregularly. Beginning in their early 20s, women should be told about the benefits and limitations of BSE. Whether a woman ever performs BSE, the importance of prompt reporting of any new breast symptoms to a health professional should be emphasized. Women who choose to do BSE should receive instruction and have their technique reviewed on the occasion of a periodic health examination. CBE For women in their 20s and 30s, it is recommended that CBE be part of a periodic health examination, preferably at least every 3 y. Asymptomatic women aged ≥40 y should continue to receive a CBE as part of a periodic health examination, preferably annually. Mammography Begin annual mammography at age 40 y.a BASIC CONSIDERATIONS CANCER SITE Cervix Woman, aged 21–65 y Pap test and HPV DNA test Cervical cancer screening should begin at age 21 y. For women aged 21–29 y, screening should be done every 3 y with conventional or liquid-based Pap tests. For women aged 30–65 y, screening should be done every 5 y with both the HPV test and the Pap test (preferred), or every 3 y with the Pap test alone (acceptable). Women aged >65 y who have had ≥3 consecutive negative Pap tests or ≥2 consecutive negative HPV and Pap tests within the last 10 y, with the most recent test occurring within the last 5 y, and women who have had a total hysterectomy should stop cervical cancer screening. Women at any age should not be screened annually by any screening method. Colorectal Men and women aged ≥50 y FOBT with at least 50% test sensitivity for cancer, or FIT with at least 50% test sensitivity for cancer, or Annual, starting at age 50 y. Testing at home with adherence to manufacturer’s recommendation for collection techniques and number of samples is recommended. FOBT with the single stool sample collected on the clinician’s fingertip during a DRE in the healthcare setting is not recommended. Guaiac-based toilet bowl FOBT tests also are not recommended. In comparison with guaiac-based tests for the detection of occult blood, immunochemical tests are more patient-friendly, and are likely to be equal or better insensitivity and specificity. There is no justification for repeating FOBT in response to an initial positive finding. Stool DNA testb, or Interval uncertain, starting at age 50 y. FSIG, or Every 5 y, starting at age 50 y. FSIG can be performed alone, or consideration can be given to combining FSIG performed every 5 y with a highly sensitive guaiac-based FOBT or FIT performed annually. DCBE, or Every 5 y, starting at age 50 y. Colonoscopy Every 10 y, starting at age 50 y. CT colonography Every 5 yr, starting at age 50 y. Endometrial Women, at menopause At the time of menopause, women at average risk should be informed about the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 299 Table 10-9 CANCER SITE POPULATION TEST OR PROCEDURE Lung Current or former LDCT smokers aged 50–74 in good health with at least a 30 pack-year history Clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about lung cancer screening with apparently healthy patients aged 55–74 y who have at least a 30 pack-y smoking history, and who currently smoke or have quit within the past 15 y. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with LDCT should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation. Prostate Men, aged ≥50 y Men who have at least a 10-y life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened for prostate cancer, after receiving information about the potential benefits, risks, and uncertainties associated with prostate cancer screening. Prostate cancer screening should not occur without an informed decision-making process. Cancer-related checkup Men and women aged ≥20 y DRE and PSA FREQUENCY On the occasion of a periodic health examination, the cancerrelated checkup should include examination for cancers of the thyroid, testicles, ovaries, lymph nodes, oral cavity, and skin, as well as health counseling about tobacco, sun exposure, diet and nutrition, risk factors, sexual practices, and environmental and occupational exposures. ACS, American Cancer Society; BSE, breast self-examination; CBE, clinical breast examination; Pap, Papanicolaou; HPV, human papillomavirus; FOBT, fecal occult blood test; FIT, fecal immunochemical test; DRE, digital rectal examination; FSIG, flexible sigmoidoscopy; DCBE, double-contrast barium enema; CT, computed tomography; LDCT, low-dose helical CT; PSA, prostate-specific antigen. a Beginning at age 40 y, annual CBE should ideally be performed prior to mammography. b The stool DNA test approved for colorectal cancer screening in 2008 is no longer commercially available. New stool DNA tests are presently undergoing evaluation and may become available at some future time. Source: Modified with permission from John Wiley and Sons: Smith RA et al. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA: a cancer journal for clinicians. 2013;63:87. © 2013 American Cancer Society, Inc. Screening guidelines are developed for the general baselinerisk population. These guidelines need to be modified for patients who are at high risk. For example, more intensive colorectal cancer screening is recommended for individuals at increased risk because of a history of adenomatous polyps, a personal history of colorectal cancer, a family history of either colorectal cancer or colorectal adenomas diagnosed in a first-degree relative before age 60 years, a personal history of inflammatory bowel disease of significant duration, or a family history or genetic test result indicating FAP or HNPCC. For some diseases, in higher risk populations, both the screening modality and the screening intensity may be altered. For example, breast magnetic resonance imaging is recommended as an adjunct to mammography for breast cancer screening in BRCA mutation carriers, firstdegree relatives of carriers, and women with a lifetime breast cancer risk of 20% to 25% or higher.103 More recently, the National Lung Screening Trial demonstrated a 20% reduction in lung cancer deaths in adults aged 55 to 74 years who were at high risk of lung cancer and randomized to low-dose helical computed tomography (LDCT) screening compared with screening with annual CXR.104 In 2013, the American Cancer Society updated their lung cancer screening recommendations to emphasize that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should ascertain the smoking history of their patients 55 to 74 years of age, and should discuss lung cancer screening with those who have at least a 30 pack-year smoking history, currently smoke, or have quit within the past 15 years, and who are in relatively good health.105 It is recommended that this discussion include the benefits, uncertainties, and harms associated with screening for lung cancer with LDCT. CANCER DIAGNOSIS The definitive diagnosis of solid tumors is obtained by performing a biopsy specimen of the lesion. Biopsy findings determine the tumor histology and grade and thus, assist in definitive therapeutic planning. Biopsy specimens of mucosal lesions usually are VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 10 ONCOLOGY American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individuals (continued) 300 PART I BASIC CONSIDERATIONS obtained endoscopically (e.g., via colonoscope, bronchoscope, or cystoscope). Lesions that are easily palpable, such as those of the skin, can either be excised or sampled by punch biopsy ­specimen. Deep-seated lesions can be localized with computed tomographic (CT) scan or ultrasound guidance for biopsy specimen. A sample of a lesion can be obtained with a needle or with an open incisional or excisional biopsy specimen. Fine-needle aspiration is easy and relatively safe, but has the disadvantage of not giving information on tissue architecture. For example, fine-needle aspiration biopsy specimen of a breast mass can make the diagnosis of malignancy but cannot differentiate between an invasive and noninvasive tumor. Therefore coreneedle biopsy specimen is more advantageous when the histologic findings will affect the recommended therapy. Core biopsy specimen, like fine-needle aspiration, is relatively safe and can be performed either by direct palpation (e.g., a breast mass or a soft tissue mass) or can be guided by an imaging study (e.g., stereotactic core biopsy specimen of the breast). Core biopsy specimens, like fine-needle aspirations, have the disadvantage of introducing sampling error. For example, 19% to 44% of patients with a diagnosis of atypical ductal hyperplasia based on core biopsy specimen findings of a mammographic abnormality are found to have carcinoma upon excision of the lesion.106 It is crucial to ensure that the histologic findings are consistent with the clinical scenario and to know the appropriate interpretation of each histologic finding. A needle biopsy specimen for which the report is inconsistent with the clinical scenario should be either repeated or followed by an open biopsy specimen. Open biopsy specimens have the advantage of providing more tissue for histologic evaluation and the disadvantage of being an operative procedure. Incisional biopsy specimens are reserved for very large lesions in which a definitive diagnosis cannot be made by needle biopsy specimen. Excisional biopsy specimens are performed for lesions for which either core biopsy specimen is not possible or the results are nondiagnostic. Excisional biopsy specimens should be performed with curative intent, that is, by obtaining adequate tissue around the lesion to ensure negative surgical margins. Marking of the orientation of the margins by sutures or clips by the surgeon and inking of the specimen margins by the pathologist will allow for determination of the surgical margins and will guide surgical re-excision if one or more of the margins are positive for microscopic tumor or are close. The biopsy specimen incision should be oriented to allow for excision of the biopsy specimen scar if repeat operation is necessary. Furthermore, the biopsy specimen incision should directly overlie the area to be removed rather than tunneling from another site, which runs the risk of contaminating a larger field. Finally, meticulous hemostasis during a biopsy specimen is essential, because a hematoma can lead to contamination of the tissue planes and can make subsequent follow-up with physical examinations much more challenging. CANCER STAGING Cancer staging is a system used to describe the anatomic extent of a malignant process in an individual patient. Staging systems may incorporate relevant clinical prognostic factors such as tumor size, location, extent, grade, and dissemination to regional lymph nodes or distant sites. Accurate staging is essential in designing an appropriate treatment regimen for an individual patient. Staging of the lymph node basin is considered a standard part of primary surgical therapy for most surgical procedures and is discussed later in this chapter. Cancer patients who are considered to be at high risk for distant metastasis ­usually undergo a preoperative staging work-up. This involves a set of imaging studies of sites of preferential metastasis for a given cancer type. For a patient with breast cancer, for example, a staging work-up would include a chest radiograph, bone scan, and liver ultrasound, or CT scan of the abdomen to evaluate for lung, bone, and liver metastases, respectively. A distant staging work-up usually is performed only for patients likely to have metastasis based on the characteristics of the primary tumor; for example, a staging work-up for a patient with ductal carcinoma in situ of the breast or a small invasive breast tumor is likely to be low yield and not cost effective. Recently there also is interest in using molecular imaging with positron emission tomography (PET) scanning, or PET/ CT, for cancer staging. Most commonly PET scanning is performed with fluorine 18 incorporated into fluorodeoxyglucose (FDG). FDG PET assesses the rate of glycolysis. FDG uptake is increased in most malignant tissues but also in benign pathologic conditions such as inflammatory disorders, trauma, infection, and granulomatous disease. It may be especially useful in the staging and management of lymphoma, lung cancer, and colorectal cancer. The role of PET in evaluating many other cancers is evolving, and additional molecular tracers, such as 3′-deoxy-3′-18 F-fluorothymidine, used to assess proliferation, are being actively pursued. Standardization of staging systems is essential to allow comparison of results from different studies from different institutions and worldwide. The staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (International Union Against Cancer, or UICC) are among the most widely accepted staging systems. Both the AJCC and the UICC have adopted a shared tumor, node, and metastasis (TNM) staging system that defines the cancer in terms of the anatomic extent of disease and is based on assessment of three components: the size of the primary tumor (T), the presence (or absence) and extent of nodal metastases (N), and the presence (or absence) and extent of distant metastases (M). The TNM staging applies only to tumors that have been microscopically confirmed to be malignant. Standard TNM staging (clinical and pathologic) is completed at initial diagnosis. Clinical staging (cTNM or TNM) is based on information gained up until the initial definitive treatment. Pathologic staging (pTNM) includes clinical information and information obtained from pathologic examination of the resected primary tumor and regional lymph nodes. Other classifications, such as retreatment staging (rTNM) or autopsy staging (aTNM), should be clearly identified as such. The clinical measurement of tumor size (T) is the one judged to be the most accurate for each individual case based on physical examination and imaging studies. For example, in breast cancer the size of the tumor could be obtained from a physical examination, mammogram, or ultrasound, and the tumor size is based only on the invasive component. If even one lymph node is involved by tumor, the N component is at least N1. For many solid tumor types, simply the absence or presence of lymph node involvement is recorded, and the tumor is categorized either as N0 or N1. For other tumor types, the number of lymph nodes involved, the size of the lymph nodes or the lymph node metastasis, or the regional lymph node basin involved also has been shown to have prognostic value. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Prognostic and Predictive Tissue Markers Tumor markers are substances that can be detected in higher than normal amounts in the serum, urine, or tissues of patients with certain types of cancer. Tumor markers are produced either by the cancer cells themselves or by the body in a response to the cancer. Over the past decade, there has been an especially high interest in identifying tissue tumor markers that can be used as prognostic or predictive markers. Although the terms prognostic marker and predictive marker are sometimes used interchangeably, the term prognostic marker generally is used to describe molecular markers that predict disease-free survival, disease-specific survival, and overall survival, whereas the term predictive marker often is used in the context of predicting response to certain therapies. The goal is to identify prognostic markers that can give information on prognosis independent of other clinical characteristics and therefore can provide information to supplement the projections based on clinical presentation. This would allow practitioners to further classify patients as being at higher or lower risk within clinical subgroups and to identify patients who may benefit most from adjuvant therapy. For example, ideal prognostic tumor markers would be able to help determine which patients with node-negative breast cancer are at higher risk of relapse so that adjuvant systemic therapy could be given only to that group. However, although a large number of studies have identified potential novel prognostic markers, most have not been tested with enough vigor to be shown to be of clinical utility. In the 2007 American Society of Clinical Oncology (ASCO) guidelines, it was decided that level of uPA/ PAI-1 measured by enzyme-linked immunosorbent assay could be used to determine prognosis in cases of newly diagnosed ­node-negative breast cancer.107 In contrast, the data for many other markers, including DNA content, proportion of tumor cells in S phase, Ki-67, cyclin E, p27, p21, thymidine kinase, topoisomerase II, HER2, p53, and cathepsin D, were felt to be insufficient to support their use in the management of breast cancer patients.107 Similarly, in the 2006 ASCO GI tumor guidelines, 40 Rate of distant recurrence at 10 y (% of patients) TUMOR MARKERS the data were felt to be insufficient to recommend the routine use of p53, ras, thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, microsatellite instability, 18q loss of heterozygosity, or deleted-in-colon-cancer protein in the management of patients with colorectal cancer.108 Predictive markers are markers that can prospectively identify patients who will benefit from a certain therapy. For example in breast cancer, estrogen receptor (ER) and HER2 assessment can identify patients who can benefit from antiestrogen therapies (e.g., tamoxifen) and anti-HER2 targeted therapies (e.g., trastuzumab), respectively, and the 2007 ASCO guidelines recommend that these markers be routinely assessed.107 High-throughput techniques such as transcriptional profiling allow for assessment of the relative mRNA levels of thousands of genes simultaneously in a given tumor using microarray technology. With the advent of such molecular profiling technologies, researchers have focused on identifying expression profiles that are prognostic for different cancer types. For breast cancer, although many such multiparameter tests are under development, few have reached the large-scale validation stage.109 In 2007, ASCO guidelines suggested that one of these, the Oncotype DX assay, can be used to predict recurrence in women with node-negative, ER-positive breast cancer who are treated with tamoxifen.107 Oncotype DX is a quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) test that used paraffinfixed tissue. A 21-gene recurrence score (RS) is generated based on the expression of 16 cancer genes and 5 reference genes. The levels of expression are used to derive an RS that ranges from 0 to 100, using a prospectively defined mathematical algorithm. This novel quantitative approach to the evaluation of the best-known molecular pathways in breast cancer has produced impressive results. Use of this multigene assay to predict recurrence was validated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial, in which ER-positive, node-negative patients had received tamoxifen.110 By multivariate Cox proportional analysis, RS was found to be independently associated with recurrence risk, with a hazard ratio of 3.21 (95% confidence interval of 2.23 to 4.65, P<.001). The RS was indeed able to stratify patients by freedom from distant recurrence (Fig. 10-13).110 The Trial Assessing Individualized Low-risk group 35 Intermediaterisk group High-risk group 30 25 20 15 10 5 0 0 5 10 15 20 25 30 35 40 45 50 Recurrence score Figure 10-13. Distant recurrence as a continuous function of the recurrence score derived from tumor levels of expression of 21 genes. (From Paik S, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:281. Copyright © 2004 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)110 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 301 CHAPTER 10 ONCOLOGY In these cancers, the designations N1, N2, and N3 suggest an increasing abnormality of lymph nodes based on size, characteristics, and location. NX indicates that the lymph nodes cannot be fully assessed. Cases in which there is no distant metastasis are designated M0, cases in which one or more distant metastases are detected are designated M1, and cases in which the presence of distant metastasis cannot be assessed are designated MX. In clinical practice, negative findings on clinical history and examination are sufficient to designate a case as M0. However, in clinical trials, routine follow-up often are performed to standardize the detection of distant metastases. The practice of dividing cancer cases into groups according to stage is based on the observation that the survival rates are higher for localized (lower-stage) tumors than for tumors that have extended beyond the organ of origin. Therefore, staging assists in selection of therapy, estimation of prognosis, evaluation of treatments, and exchange of information among treatment centers. Notably, the AJCC regularly updates its staging system to incorporate advances in prognostic technology to improve the predictive accuracy of the TNM system. Therefore it is important to know which revision of a staging system is being used when evaluating studies. 302 PART I BASIC CONSIDERATIONS Options for Treatment for breast cancer (TAILORx) is evaluating the utility of Oncotype DX for predicting prognosis in patients with ER-positive, node-negative tumors and will focus on women with intermediate RS scores in whom the role of chemotherapy is unclear. Several other multigene predictors for breast cancer are available including MammaPrint, a gene expression profiling platform assessing a 70-gene transcriptional signature.111 This assay was approved by the Food and Drug Administration (FDA) in February 2007. The usefulness of this assay in making therapy-related decisions is being tested prospectively in a large-scale study, the Microarray in NodeNegative Disease May Avoid Chemotherapy (MINDACT) trial. Multigene profiles to predict prognosis are in development or in validation phases for many other solid tumor types, including lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, and melanoma. Gene signatures and genomic alterations also are being studied for their ability to predict response to specific chemotherapy regimens or targeted therapies. Many of these multigene marker sets will likely be incorporated into clinical practice in the years to come. Serum Markers Serum markers are under active investigation because they may allow early diagnosis of a new cancer or may be used to follow cancer response to therapy or monitor for recurrence. Unfortunately, identification of serum markers of clinical value has been challenging. Many of the tumor markers proposed so far have had low sensitivities and specificities.109 Tumor marker levels may not be elevated in all patients with cancer, especially in the early stages, when a serum marker would be most useful for diagnosis. Therefore when a tumor marker is used to monitor recurrence, it is important to be certain that the level of the tumor marker was elevated before primary therapy. Moreover, tumor marker levels can be elevated in benign conditions. Many tumor markers are not specific for a certain type of cancer and can be elevated with more than one type of tumor. Since there may be significant laboratory variability, it is important to obtain serial results from the same laboratory. In spite of these many clinical limitations, several serum markers are in clinical use. A few of the commonly measured serum tumor markers are discussed in the following sections. Prostate-Specific Antigen. Prostate-specific antigen (PSA) is an androgen-regulated serine protease produced by the prostate epithelium. PSA is normally present in low concentrations in the blood of all adult males. PSA levels may be elevated in the blood of men with benign prostate conditions such as prostatitis and benign prostatic hyperplasia, as well as in men with prostate cancer. PSA levels have been shown to be useful in evaluating the effectiveness of prostate cancer treatment and monitoring for recurrence after therapy. In monitoring for recurrence, a trend of increasing levels is considered more significant than a single absolute elevated value. Although PSA has been widely used for prostate cancer screening, the utility of PSA screening remains controversial. There is concern that the number of men who avoid dying from prostate cancer due to screening is small, while the harms relatedto the treatment of screen-detected cancers, including incontinence and erectile dysfunction are at least moderate. In 2012, the US Preventive Services Task Force concluded with moderate certainty that the harms of PSA testing outweigh the benefits and on that basis recommended against PSA-based screening for all men.112 In 2010, the American Cancer Society updated its guidelines for the early detection of prostate cancer to state that men who have at least a 10-year life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened for prostate cancer with digital rectal exam and serum PSA, after receiving information about the benefits, risks, and uncertainties associated with prostate cancer screening;113 this recommendation was reinforced in their 2013 guidelines.93 Carcinoembryonic Antigen. Carcinoembryonic antigen (CEA) is a glycoprotein found in the embryonic endodermal epithelium. Elevated CEA levels have been detected in patients with primary colorectal cancer as well as in patients with breast, lung, ovarian, prostate, liver, and pancreatic cancer. Levels of CEA also may be elevated in benign conditions, including diverticulitis, peptic ulcer disease, bronchitis, liver abscess, and alcoholic cirrhosis, especially in smokers and in elderly persons. CEA measurement is most commonly used in the management of colorectal cancer. However, the appropriate use of CEA testing in patients with colorectal cancer has been debated. Use of CEA level as a screening test for colorectal cancer is not recommended. CEA levels may be useful if obtained preoperatively and postoperatively in patients with a diagnosis of colorectal cancer. Preoperative elevation of CEA level is an indicator of poor prognosis. However, the 2007 ASCO clinical practice guidelines state that the data are insufficient to support the use of CEA to determine whether to give a patient adjuvant therapy; the data are stronger for the use of CEA for monitoring for postoperative recurrence.107 CEA measurement is the most cost-effective approach for detecting metastasis, with 64% of recurrences being detected first by an elevation in CEA level. Therefore, in cases in which the patient would be a candidate for resection of recurrent colorectal cancer or systemic therapy, the 2006 ASCO guidelines recommend that postoperative CEA testing be performed every 3 months in patients with stage II or III disease for at least 3 years.108 CEA is the marker of choice for monitoring metastatic colorectal cancer during systemic therapy.108 There is also interest in using CEA levels for monitoring patients with breast cancer. However, the 2007 ASCO guidelines state that the routine use of CEA for screening, diagnosis, staging, or surveillance of breast cancer is not recommended because available data are insufficient.107 For monitoring patients during active therapy, CEA can be used in conjunction with diagnostic imaging and history and physical examination.107 In the absence of measurable disease, an increase in CEA level may be taken to indicate treatment failure. However, caution is advised when interpreting rising levels in the first 4 to 6 weeks of therapy.107 Alpha-Fetoprotein. Alpha-fetoprotein (AFP) is a glycoprotein normally produced by a developing fetus. AFP levels decrease soon after birth in healthy adults. An elevated level of AFP suggests the presence of either primary liver cancer or a germ cell tumor of the ovary or testicle. Rarely, other types of cancer such as gastric are associated with an elevated AFP level. Benign conditions that can cause elevations of AFP include cirrhosis, hepatic necrosis, acute hepatitis, chronic active hepatitis, ataxiatelangiectasia, Wiskott-Aldrich syndrome, and pregnancy.114 The sensitivity of an elevated AFP level for detecting HCC is approximately 60%. AFP is considered to be sensitive VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ as in cancers of the colon, stomach, kidney, lung, ovary, pancreas, uterus, and liver. First-trimester pregnancy, endometriosis, benign breast disease, kidney disease, and liver disease also may be associated with elevated CA 27-29 levels. CA 27-29 has been reported to have a sensitivity of 57%, a specificity of 98%, a positive predictive value of 83%, and a negative predictive value of 93% in detecting breast cancer recurrences.116 Although CA 27-29 has been found to predict recurrence an average of 5.3 months before other symptoms or tests, testing of CA 27-29 levels has not been demonstrated to affect disease-free and overall survival rates.116, 117 Therefore, the 2007 ASCO guidelines state that, as with CA 15-3, the routine use of CA 27-29 for screening, diagnosis, staging, or surveillance of breast cancer is not recommended because available data are insufficient.107 CA 27-29 levels can be used together with diagnostic imaging and history and physical examination to monitor patients during active therapy.107 When no measurable disease is present, an increase in level may be considered to indicate treatment failure. However, rising levels in the first 4 to 6 weeks of therapy should be interpreted with caution.107 Circulating Tumor Cells Circulating tumor cells (CTCs) are cells present in the blood that possess antigenic or genetic characteristics of a specific tumor type.107 One CTC detection methodology is capture and quantitation of CTCs with immunomagnetic beads coated with antibody specific for cell-surface, epithelial, or cancer antigens. Another methodology used to detect cancer cells in the peripheral blood is RT-PCR. It has been suggested that measurement of CTCs can be an effective tool for selecting patients who have a high risk of relapse and for monitoring efficacy of cancer ­therapy. CTCs have probably been most extensively studied in breast cancer.107 The most promising data come from the use of CTC measures in metastatic breast cancer. In a prospective multicenter trial, the number of CTCs (≥5 CTCs vs. <5 CTCs per 7.5 mL of whole blood) before treatment of metastatic breast cancer was an independent predictor of progression-free and overall survival rates.118 The presence of >5 CTCs after the first course of therapy predicted lack of response to treatment. This technology, known as CellSearch, has been approved by the FDA for clinical use. Further, in a recent single institutional study, detection of one or more CTCs in Stage I-III breast cancer patients was associated with both decreased progression-free survival and overall survival.119 However, there is limited data to prove that the use of CTC testing leads to improved survival or improved quality of life; thus the ASCO 2007 guidelines update did not recommend the use of CTC measurement in any clinical setting.107 The clinical utility of measuring CTC response to initial therapy is now being tested prospectively in a multicenter clinical trial. The use of CTC levels as a tool in treating many other types of tumor is also under active investigation. The prognostic implications of detection of CTCs by RT-PCR have been intensively studied for melanoma. In the recent multicenter Sunbelt Melanoma Trial, serial RT-PCR was performed on peripheral blood samples using four markers— tyrosinase, melanoma antigen reacting to T cell (MART-1), melanoma antigen 3 (MAGE3), and gp 100—to detect occult melanoma cells in the bloodstream.120 Although there were no differences in survival between patients in whom at least one marker was detected and those in whom no markers were VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 303 CHAPTER 10 ONCOLOGY and specific enough to be used for screening for HCC in highrisk populations. Current consensus recommendations are to screen healthy hepatitis B virus carriers with annual or semiannual measurement of AFP level and to screen carriers with cirrhosis or chronic hepatitis and patients with cirrhosis of any etiology with twice-yearly measurement of AFP level and liver ultrasonography.115 Although AFP testing has been used widely for a long time, its efficacy in early diagnosis of HCC is limited. With improvements in imaging technology, a larger proportion of patients diagnosed with HCC are now AFP seronegative. Cancer Antigen 19-9. Cancer antigen 19-9 (CA 19-9) is a tumor-related antigen that was originally defined by a monoclonal antibody produced by a hybridoma prepared from murine spleen cells immunized with a human colorectal cancer cell line.108 The data are insufficient to recommend use of CA 19-9 for screening, diagnosis, surveillance, or monitoring of therapy for colon cancer.108 Based on the 2006 ASCO guidelines, there are also insufficient data to recommend use of CA 19-9 for screening, diagnosis, or determination of the operability of pancreatic cancer.108 However, for patients with locally advanced or metastatic cancer receiving active therapy, CA 19-9 can be measured at the start of therapy and every 1 to 3 months while therapy is given; elevations in serial CA 19-9 levels may indicate progressive disease and should be confirmed by additional studies.108 Cancer Antigen 15-3. Cancer antigen 15-3 (CA 15-3) is an epitope of a large membrane glycoprotein encoded by the MUC1 gene that tumor cells shed into the bloodstream. The CA 15-3 epitope is recognized by two monoclonal antibodies in a sandwich radioimmunoassay. CA 15-3 levels are most useful in following the course of treatment in women diagnosed with advanced breast cancer. CA 15-3 levels are infrequently elevated in early-stage breast cancer. CA 15-3 levels can be increased in benign conditions such as chronic hepatitis, tuberculosis, sarcoidosis, pelvic inflammatory disease, endometriosis, systemic lupus erythematosus, pregnancy, and lactation, and in other types of cancer such as lung, ovarian, endometrial, and GI cancers. The sensitivity of CA 15-3 is higher for metastatic disease, and in these cases studies have shown sensitivity to be between 54% and 87%, with specificity as high as 96%. This has led to interest in using CA 15-3 for monitoring patients with advanced breast cancer for recurrence. Elevated CA 15-3 levels have been reported before relapse in 54% of patients, with a lead time of 4.2 months. Therefore, detection of elevated CA 15-3 levels during follow-up should prompt evaluation for recurrent disease. However, 6% to 8% of patients without recurrence will have elevated CA 15-3 levels that require evaluation. Furthermore, monitoring with the use of CA 15-3 levels has shown no demonstrated impact on survival. Therefore, the 2007 ASCO guidelines state that the routine use of CA 15-3 for screening, diagnosis, staging, or surveillance of breast cancer is not recommended because available data are insufficient.107 For monitoring patients during active therapy, CA 15-3 can be used in conjunction with diagnostic imaging and history and physical examination.107 In the absence of measurable disease, an increase may be interpreted to indicate treatment failure. However, caution is advised when interpreting rising levels in the first 4 to 6 weeks of therapy.107 Cancer Antigen 27-29. The MUC-1 gene product in the serum may be quantitated by using radioimmunoassay with a monoclonal antibody against the cancer antigen 27-29 (CA 27-29). CA 27-29 levels can be elevated in breast cancer as well 304 PART I detected, the disease-free survival and distant disease-free survival were worse for patients in whom more than one marker was detected at any time during follow-up.120 The detection of occult cancer cells with RT-PCR remains investigational, however, and is not used to direct therapy for melanoma and other cancer types at this time. Bone Marrow Micrometastases BASIC CONSIDERATIONS Micrometastatic disease in the bone marrow, also referred to as minimal residual disease, also is being investigated as a potential prognostic marker. Bone marrow micrometastatic disease usually is detected by staining bone marrow aspirates with monoclonal antibodies to cytokeratin, but other methodologies such as flow cytometry and RT-PCR are being explored. Breast cancer patients with bone marrow micrometastasis have larger tumors, tumors with a higher histologic grade, more lymph node metastases, and more hormone receptor-negative tumors than patients without bone marrow micrometastasis. In 4700 patients with stage I, II, or III breast cancer, micrometastasis was a significant prognostic factor associated with poor overall survival, breast cancer-specific survival, disease-free survival, and distant disease-free survival during a 10-year observation period.121 Recently, in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study to determine to determine the association between survival and metastases detected by immunochemical staining of bone marrow specimens from patients with early-stage breast cancer.122 Of 3413 bone marrow specimens examined by immunocytochemistry, only 104 (3.0%) were positive for tumor. Bone marrow involvement was associated with a decreased overall survival but this association was not significant on multivariable analysis. The prognostic implication of bone marrow involvement is also being studied by the National Surgical Adjuvant Breast and Bowel Project Protocol BP-59. At this time the routine use of bone marrow testing is not recommended.107 Ongoing clinical trials are evaluating the role of routine assessment of bone marrow status in the care of patients with early and advanced breast cancer. The utility of assessment of bone marrow micrometastasis is also being evaluated in other tumor types, including gastric, esophageal, colorectal, lung, cervical, and ovarian cancer.123 SURGICAL APPROACHES TO CANCER THERAPY Multidisciplinary Approach to Cancer Although surgery is an effective therapy for most solid tumors, patients who die from cancer usually die of metastatic disease. Therefore, to improve patient survival rates, a multimodality approach, including systemic therapy and radiation therapy is key for most tumors. It is important that surgeons involved in cancer care not only know the techniques for performing a cancer operation but also know the alternatives to surgery and be well versed in reconstructive options. It is also crucial that the surgeon be familiar with the indications for and complications of preoperative and postoperative chemotherapy and radiation therapy. Although the surgeon may not be delivering these other therapies, as the first physician to see a patient with a cancer diagnosis, he or she is ultimately responsible for initiating the appropriate consultations. For this reason, the surgeon often is responsible for determining the most appropriate adjuvant t­herapy for a given patient as well as the best sequence for therapy. In most instances, a multidisciplinary approach beginning at the patient’s initial presentation is likely to yield the best result. Surgical Management of Primary Tumors The goal of surgical therapy for cancer is to achieve oncologic cure. A curative operation presupposes that the tumor is confined to the organ of origin or to the organ and the regional lymph node basin. Patients in whom the primary tumor is not resectable with negative surgical margins are considered to have inoperable disease. The operability of primary tumors is best determined before surgery with appropriate imaging studies that can define the extent of local-regional disease. For example, a preoperative thin-section CT scan is obtained to determine resectability of pancreatic cancer, which is based on the absence of extrapancreatic disease, the absence of tumor extension to the superior mesenteric artery and celiac axis, and a patent superior mesenteric vein-portal vein confluence.124 Disease involving multiple distant metastases is deemed inoperable because it is usually not curable with surgery of the primary tumor. Therefore patients who are at high risk of having distant metastasis should undergo a staging work-up before surgery for the primary tumor. On occasion, primary tumors are resected in these patients for palliative reasons, such as improving the quality of life by alleviating pain, infection, or bleeding. An example of this is toilet mastectomies for large ulcerated breast tumors. Patients with limited metastases from a primary tumor on occasion are considered surgical candidates if the natural history of isolated distant metastases for that cancer type is favorable or the potential complications associated with leaving the primary tumor intact are significant. In the past it was presumed that the more radical the surgery, the better the oncologic outcome would be. Over the past three decades, this has been recognized as not necessarily being true, which has led to more conservative operations, with wide local excisions replacing compartmental resections of sarcomas, and partial mastectomies, skin-sparing mastectomies, and breast-conserving therapies replacing radical mastectomies for breast cancer. The uniform goal for all successful oncologic operations seems to be achieving widely negative margins with no evidence of macroscopic or microscopic tumor at the surgical margins. The importance of negative surgical margins for local tumor control and/or survival has been documented for many tumor types, including sarcoma, breast cancer, pancreatic cancer, and rectal cancer. Thus it is clear that every effort should be made to achieve microscopically negative surgical margins. Inking of the margins, orientation of the specimen by the surgeon, and immediate gross evaluation of the margins by a pathologist using frozen-section analysis when necessary may assist in achieving negative margins at the first operation. In the end, although radiation therapy and systemic therapy can assist in decreasing local recurrence rates in the setting of positive margins, adjuvant therapy cannot substitute for adequate surgery. Although it is clear that the surgical gold standard is negative surgical margins, the appropriate surgical margins for optimal local control are controversial for many cancer types. In contrast, in melanoma the optimal margin width for any tumor depth has been better defined, owing to the systematic study of this question in randomized clinical trials.125, 126 Although such randomized studies may not be possible for all tumor types, it VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Management of the Regional Lymph Node Basin Most neoplasms have the ability to metastasize via the lymphatics. Therefore, most oncologic operations have been designed to remove the primary tumor and draining lymphatics en bloc. This type of operative approach usually is undertaken when the lymph nodes draining the primary tumor site lie adjacent to the tumor bed, as is the case for colorectal cancers and gastric cancers. For tumors in which the regional lymph node basin is not immediately adjacent to the tumor (e.g., melanomas), lymph node surgery can be performed through a separate incision. Unlike most carcinomas, soft tissue sarcomas rarely metastasize to the lymph nodes (<5%); therefore lymph node surgery usually is not necessary. It is generally accepted that a formal lymphadenectomy is likely to minimize the risk of regional recurrence of most cancers. For example, the introduction of total mesorectal excision of rectal cancer has been associated with a large decline in localregional recurrence, and this procedure has become the new standard of operative management.127 On the other hand, there have been two opposing views regarding the role of lymphadenectomy in survival of cancer patients. The traditional Halsted view states that lymphadenectomy is important for staging and survival. The opposing view counters that cancer is systemic at inception and that lymphadenectomy, although useful for staging, does not affect survival. For most cancers, involvement of the lymph nodes is one of the most significant prognostic factors. Interestingly, in some studies removal of a larger number of lymph nodes has been found to be associated with an improved overall survival rate for many tumors, including breast cancer, colon cancer, and lung cancer. Although this seems to support the Halsted theory that more extensive lymphadenectomy yielding of nodes reduces the risk of regional recurrence, there may be alternative explanations for the same finding. For example, the surgeon who performs a more extensive lymphadenectomy may obtain wider margins around the tumor or even provide better overall care, such as ensuring that patients receive the appropriate adjuvant therapy or undergo a more thorough staging work-up. Alternatively, the pathologist may perform a more thorough examination, identifying more nodes and more accurately staging the nodes. The effect of appropriate staging on survival is twofold. Patients with nodal metastases may be offered adjuvant therapy, which improves their survival chances. Further, the improved staging can improve perceived survival rates through a “Will Rogers effect”; that is, identification of metastases that had formerly been silent and unidentified leads to stage migration and thus to a perceived improvement in chances of survival. Clearly the impact of lymphadenectomy on survival will not be easily resolved. Surgical management of the clinically negative regional lymph node basin has evolved with the introduction of lymphatic mapping technology (Fig. 10-14).128 Lymphatic mapping and sentinel lymph node biopsy specimen were first reported in 1977 by Cabanas for penile cancer.129 Now, sentinel node biopsy specimen is the standard of care for the management of melanoma and breast cancer. Moreover, the utility of sentinel node biopsy specimen in other cancer types is being explored. The first node to receive drainage from the tumor site is termed the sentinel node. This node is the node most likely to contain metastases, if metastases to that regional lymph node basin are present. The goal of lymphatic mapping and sentinel lymph node biopsy specimen is to identify and remove the lymph node most likely to contain metastases in the least invasive fashion. The practice of sentinel lymph node biopsy specimen followed by regional lymph node dissection for selected patients with a positive sentinel lymph node avoids the morbidity of lymph node dissections in patients with negative nodes. An additional advantage of the sentinel lymph node technique is that it directs attention to a single node, which allows more careful analysis of the lymph node most likely to have a positive yield and increases the accuracy of nodal staging. Two criteria are used to assess the efficacy of a sentinel lymph node biopsy specimen: the sentinel lymph node identification rate and the false-negative rate. The sentinel lymph node identification rate is the proportion of patients in whom a sentinel lymph node was identified and removed among all patients undergoing an attempted sentinel lymph node biopsy specimen. The falsenegative rate is the proportion of patients with regional lymph node metastases in whom the sentinel lymph node was found Figure 10-14. Lymphatic mapping and sentinel lymph node biopsy specimen for breast cancer. A. Peritumoral injection of blue dye. B. Blue dye draining into the sentinel lymph node. (Modified with permission from Meric F, Hunt KK. With kind permission from Springer Science and Business Media.)128 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 305 CHAPTER 10 ONCOLOGY is important to determine optimum surgical margins for each cancer type so that adjuvant radiation and systemic therapy can be offered to patients deemed to be at increased risk for local treatment failure. There are also ongoing studies on approaches to assess margins intraoperatively, to allow immediate intraoperative reexcisions as needed, and maximizing local control. 306 PART I BASIC CONSIDERATIONS to be negative. False-negative biopsy specimen results may be due to identifying the wrong node or to missing the sentinel node (i.e., surgical error) or they may be due to the cancer cells’ establishing metastases not in the first node encountered but in a second-echelon node (i.e., biologic variation). Alternatively, false-negative biopsy specimen results may be due to inadequate histologic evaluation of the lymph node. The false-negative rates for sentinel lymph node biopsy specimen in study series range between 0% and 11%. Both increases in the identification rate and decreases in the false-negative rate have been observed as surgeons gain experience with the technique. Lymphatic mapping is performed by using isosulfan blue dye, technetium-labeled sulfur colloid or albumin, or a combination of both techniques to detect sentinel nodes. The combination of blue dye and technetium has been reported to improve the capability of detecting sentinel lymph nodes. The nodal drainage pattern usually is determined with a preoperative lymphoscintigram, and the “hot” and/or blue nodes are identified with the assistance of a gamma probe and careful nodal basin exploration. Careful manual palpation is a crucial part of the procedure to minimize the false-negative rate. The nodes are evaluated with serial sectioning, hematoxylin and eosin staining, and immunohistochemical analysis with S-100 protein and homatropine methylbromide staining for melanoma and cytokeratin staining for breast cancer. The utility of molecular techniques such as RT-PCR to assess the sentinel nodes is still being explored. Another area of active investigation is the prognostic value of minimal nodal involvement. For example, in breast cancer, nodes with isolated tumor cell deposits of <0.2 mm (also called nanometastasis) are considered to be N0 by the sixth edition of the AJCC staging manual. However, some retrospective studies have suggested that even this amount of nodal disease burden has negative prognostic implications.130 Molecular ultrastaging with RT-PCR for patients with node-negative disease was assessed in a prospective multicenter trial and was found not to be prognostic in malignant melanoma.120 However, a recent meta-analysis of 22 studies enrolling 4019 patients found that PCR positivity was associated with worse overall and disease-free survival.131 Further study of the utility of ultrastaging of nodes in breast cancer, melanoma, and several other tumor types is ongoing. Until recently, in breast cancer management, when sentinel node mapping revealed a positive sentinel node, this was followed by a completion axillary lymph node dissection. Recently results of the American College of Surgeons Oncology Group Z0011 trial, challenged this practice. ACOSOG Z11 was a phase 3 multicenter noninferiority trial conducted to determine the effects of complete axillary lymph node dissectionon survival of patients with sentinel lymph node metastasis of breast cancer.122 Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. All patients underwent breast-conserving surgery and tangential whole-breast irradiation. Those with sentinel node metastases identified by sentinel node biopsy specimen were randomized to undergo axillary lymph node dissection or no further axillary treatment. At a median follow-up of 6.3 years, 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with axillary lymph node dissection and 92.5% (95% CI, 90.0%–95.1%) with sentinel node alone. The 5-year disease-free survival was 82.2% (95% CI, 78.3%–86.3%) with axillary lymph node d­ issection, and 83.9% (95% CI, 80.2%– 87.9%) with sentinel node alone. Thus ACOSOGZ11 demonstrated that among breast cancer patients with limited sentinel node metastasis treated with breast conservation and systemic therapy, the use of sentinel node alone compared with axillary lymph node dissection did not result in inferior survival. This study challenges the traditional surgical dictum of regional management, and has led to a selective utilization of completion axillary lymph node dissection in breast cancer patients undergoing breast conservation. The role of completion lymph node dissections in melanoma is under investigation. Surgical Management of Distant Metastases The treatment of a patient with distant metastases depends on the number and sites of metastases, the cancer type, the rate of tumor growth, the previous treatments delivered and the responses to these treatments, and the patient’s age, physical condition, and desires. Although once a tumor has metastasized it usually is not curable with surgical therapy, such therapy has resulted in cure in selected cases with isolated metastases to the liver, lung, or brain. Patient selection is the key to the success of surgical therapy for distant metastases. The cancer type is a major determinant in surgical decision making. A liver metastasis from a colon cancer is more likely to be an isolated and thus resectable lesion than a liver metastasis from a pancreatic carcinoma. The growth rate of the tumor also plays an important role and can be determined in part by the disease-free interval and the time between treatment of the primary tumor and detection of the distant recurrence. Patients with longer disease-free intervals have a higher survival rate after surgical metastasectomy than those with a short disease-free interval. Similarly, patients who have synchronous metastases (metastases diagnosed at the initial cancer diagnosis) do worse after metastasectomy than patients who develop metachronous metastases (metastasis diagnosed after a disease-free interval). The natural history of metastatic disease is so poor for some tumors (e.g., pancreatic cancer) that there is no role at this time for surgical metastasectomy. In cancers with a more favorable outlook, observation for several weeks or months, potentially with initial treatment with systemic therapy, can allow the surgeon to monitor for metastases at other sites. In curative surgery for distant metastases, as with surgery for primary tumors, the goal is to resect the metastases with negative margins. In patients with hepatic metastases that are unresectable because their location near intrahepatic blood vessels precludes a margin-negative resection, or because they are multifocal or hepatic function is inadequate, tumor ablation with cryotherapy or radiofrequency ablation is an alternative.132, 133 Curative resections or ablative procedures should be attempted only if the lesions are accessible and the procedure can be ­performed safely. CHEMOTHERAPY Clinical Use of Chemotherapy In patients with documented distant metastatic disease, chemotherapy is usually the primary modality of therapy. The goal of therapy in this setting is to decrease the tumor burden, thus prolonging survival. It is rare to achieve cure with chemotherapy for metastatic disease for most solid tumors. Chemotherapy administered to a patient who is at high risk for distant recurrence but has no evidence of distant disease is referred to as VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ ­ ell-cycle phase-nonspecific agents (e.g., alkylating agents) C have a linear dose-response curve, such that the fraction of cells killed increases with the dose of the drug.137 In contrast, the cell-cycle phase-specific drugs have a plateau with respect to cell killing ability, and cell kill will not increase with further increases in drug dose. Principles of Chemotherapy Combination chemotherapy may provide greater efficacy than single-agent therapy by three mechanisms: (a) it provides maximum cell kill within the range of toxicity for each drug that can be tolerated by the host, (b) it offers a broader range of coverage of resistant cell lines in a heterogeneous population, and (c) it prevents or delays the emergence of drug-resistant cell lines.137 When combination regimens are devised, drugs known to be active as single agents usually are selected. Drugs with different mechanisms of action are combined to allow for additive or synergistic effects. Combining cell-cycle–specific and cell-cycle– nonspecific agents may be especially advantageous. Drugs with differing dose-limiting toxic effects are combined to allow for Chemotherapy destroys cells by first-order kinetics, which means that with the administration of a drug a constant percentage of cells is killed, not a constant number of cells. If a patient with 1012 tumor cells is treated with a dose that results in 99.9% cell kill (3-log cell kill), the tumor burden will be reduced from 1012 to 109 cells (or 1 kg to 1 g). If the patient is re-treated with the same drug, which theoretically could result in another 3-log cell kill, the cells would decrease in number from 109 to 106 (1 g to 1 mg) rather than being eliminated totally. Chemotherapeutic agents can be classified according to the phase of the cell cycle during which they are effective. Anticancer Agents Alkylating Agents. Alkylating agents are cell-cycle–nonspecific agents, that is, they are able to kill cells in any phase of the cell cycle. They act by cross-linking the two strands of the DNA helix or by causing other direct damage to the DNA. The damage to the DNA prevents cell division and, if severe enough, leads to apoptosis. The alkylating agents are composed of three main subgroups: classic alkylators, nitrosoureas, and miscellaneous DNA-binding agents (Table 10-10). Antitumor Antibiotics. Antitumor antibiotics are the products of fermentation of microbial organisms. Like the alkylating agents, these agents are cell-cycle nonspecific. Antitumor antibiotics damage the cell by interfering with DNA or RNA synthesis, although the exact mechanism of action may differ by agent. Antimetabolites. Antimetabolites are generally cell-cycle– specific agents that have their major activity during the S phase of the cell cycle and have little effect on cells in G0. These drugs are most effective, therefore, in tumors that have a high growth fraction. Antimetabolites are structural analogues of naturally occurring metabolites involved in DNA and RNA synthesis. Therefore, they interfere with normal synthesis of nucleic acids by substituting for purines or pyrimidines in the metabolic pathway to inhibit critical enzymes in nucleic acid synthesis. The antimetabolites include folate antagonists, purine antagonists, and pyrimidine antagonists. Plant Alkaloids. Plant alkaloids are derived from plants such as the periwinkle plant, Vinca rosea (e.g., vincristine, a vinca alkaloid), or the root of American mandrake, Podophyllum peltatum (e.g., etoposide, a podophyllotoxin).137 Vinca alkaloids affect the cell by binding to tubulin in the S phase. This blocks microtubule polymerization, which results in impaired mitotic spindle formation in the M phase. Taxanes such as paclitaxel, on the other hand, cause excess polymerization and stability of microtubules, which blocks the cell cycle in mitosis. The epipodophyllotoxins act to inhibit a DNA enzyme called topoisomerase II by stabilizing the DNA-topoisomerase II complex. This results in an inability to synthesize DNA, and thus the cell cycle is stopped in the G1 phase.137 Combination Chemotherapy VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 307 CHAPTER 10 ONCOLOGY adjuvant chemotherapy. The goal of adjuvant chemotherapy is eradication of micrometastatic disease, with the intent of decreasing relapse rates and improving survival rates. Adjuvant therapy can be administered after surgery (postoperative chemotherapy) or before surgery (preoperative chemotherapy, neoadjuvant chemotherapy, or induction therapy). A portion or all of the planned adjuvant chemotherapy can be administered before the surgical removal of the primary tumor. Preoperative chemotherapy has three potential advantages. The first is that preoperative regression of tumor can facilitate resection of tumors that were initially inoperable or allow more conservative surgery for patients whose cancer was operable to begin with. In the NSABP B-18 project, for example, women were randomly assigned to receive adjuvant doxorubicin and cyclophosphamide preoperatively or postoperatively. More patients treated before surgery than after surgery underwent breast-conserving surgery (68% vs. 60%).134 The second advantage of preoperative chemotherapy is the treatment of micrometastases without the delay of postoperative recovery. The third advantage is the ability to assess a cancer’s response to treatment clinically, after a number of courses of chemotherapy, and pathologically, after surgical resection. This is especially important if alternative treatment regimens are available to be offered to patients whose disease responded inadequately. Molecular characterization of the residual disease may also give insight into mechanisms of chemoresistance and possible therapeutic targets. There are some potential disadvantages to preoperative chemotherapy, however. Although disease progression while the patient is receiving preoperative chemotherapy is rare in chemotherapy-sensitive tumors such as breast cancer, it is more frequent in relatively chemotherapy-resistant tumors such as sarcomas.135 Thus, patient selection is critical to ensure that the opportunity to treat disease surgically is not lost by giving preoperative chemotherapy. Often, rates of postoperative wound infection, flap necrosis, and delays in postoperative adjuvant therapy do not differ between patients who are treated with preoperative chemotherapy and patients who are treated with surgery first. However, preoperative chemotherapy can introduce special challenges to tumor localization, margin analysis, lymphatic mapping, and pathologic staging. Response to chemotherapy is monitored clinically with imaging studies as well as physical examinations. Response usually is defined as complete response, partial response, stable disease, or progression. Response generally is assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.136 Objective tumor response assessment is critical, because tumor response is used as a prospective endpoint in clinical trials and tumor response is a guide to clinicians regarding continuation of current therapy. 308 Table 10-10 Classification of chemotherapeutic agents PART I BASIC CONSIDERATIONS Alkylating agents Classic alkylating agents Busulfan Chlorambucil Cyclophosphamide Ifosfamide Mechlorethamine (nitrogen mustard) Melphalan Mitomycin C Triethylene thiophosphoramide (thiotepa) Nitrosoureas Carmustine (BCNU) Lomustine (CCNU) Semustine (MeCCNU) Streptozocin Miscellaneous DNA-binding agents Carboplatin Cisplatin Dacarbazine (DTIC) Hexamethylmelamine Procarbazine Antitumor antibiotics Bleomycin Dactinomycin (actinomycin D) Daunorubicin Doxorubicin Idarubicin Plicamycin (mithramycin) Antimetabolites Folate analogues Methotrexate Purine analogues Azathioprine Mercaptopurine Thioguanine Cladribine (2-chlorodeoxyadenosine) Fludarabine Pentostatin Pyrimidine analogues Capecitabine Cytarabine Floxuridine Gemcitabine Ribonucleotide reductase inhibitors Hydroxyurea Plant alkaloids Vinca alkaloids Vinblastine Vincristine Vindesine Vinorelbine Epipodophyllotoxins Etoposide Teniposide Taxanes Paclitaxel Docetaxel Miscellaneous agents Asparaginase Estramustine Mitotane each drug to be given at therapeutic doses. Drugs with different patterns of resistance are combined whenever possible to minimize cross-resistance. The treatment-free interval between cycles is kept to the shortest possible time that will allow for recovery of the most sensitive normal tissue. Drug Toxicity Tumors are more susceptible than normal tissue to chemotherapeutic agents, in part because they have a higher proportion of dividing cells. Normal tissues with a high growth fraction, such as the bone marrow, oral and intestinal mucosa, and hair follicles, are also sensitive to chemotherapeutic effects. Therefore, treatment with chemotherapeutic agents can produce toxic effects such as bone marrow suppression, stomatitis, ulceration of the GI tract, and alopecia. Toxic effects usually are graded from 0 to 4 on the basis of World Health Organization standard criteria.138 Significant drug toxicity may necessitate a dosage reduction. A toxic effect requiring a dose modification or change in dose intensity is referred to as a dose-limiting toxic effect. Because maintaining dose intensity is important to preserve as high a tumor cell kill as possible, several supportive strategies have been developed, such as administration of colony-stimulating factors and erythropoietin to treat poor bone marrow reserve and administration of cytoprotectants such as mesna and amifostine to prevent renal dysfunction. Administration of Chemotherapy Chemotherapy usually is administered systemically (IV, IM, SC, or PO). Systemic administration treats micrometastases at widespread sites and prevents systemic recurrence. However, it increases the drug’s toxicity to a wide range of organs throughout the body. One method to minimize systemic toxicity while enhancing target organ delivery of chemotherapy is regional administration of chemotherapy. Many of these approaches require surgical access, such as intrahepatic delivery of chemotherapy for hepatic carcinomas or metastatic colorectal cancer using a hepatic artery infusion pump, limb perfusion for extremity melanoma and sarcoma, and intraperitoneal hyperthermic perfusion for pseudomyxoma peritonei. Alternately, percutaneous access may be utilized, such as limb infusion with percutaneously placed catheters. HORMONAL THERAPY Some tumors, most notably breast and prostate cancers, originate from tissues whose growth is under hormonal control. The first attempts at hormonal therapy were through surgical ablation of the organ producing the hormones involved, such as oophorectomy for breast cancer. Currently, hormonal anticancer agents include androgens, antiandrogens, antiestrogens, estrogens, glucocorticoids, gonadotropin inhibitors, progestins, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ TARGETED THERAPY Over the past decade, increased understanding of cancer biology has fostered the emerging field of molecular therapeutics. The basic principle of molecular therapeutics is to exploit the molecular differences between normal cells and cancer cells to develop targeted therapies. Thus targeted therapies usually are directed at the processes involved in tumor growth rather than directly targeting the tumor cells. The ideal molecular target would be exclusively expressed in the cancer cells, be the driving force of the proliferation of the cancer cells, and be critical to their survival. A large number of molecular targets are currently being explored, both preclinically and in clinical trials. The major groups of targeted therapy agents are inhibitors of growth factor receptors, inhibitors of intracellular signal transduction, cell-cycle inhibitors, apoptosis-based therapies, and antiangiogenic compounds. Protein kinases have come to the forefront as attractive therapeutic targets with the success of imatinib mesylate (Gleevec) in treating chronic myelogenous leukemia and GI stromal tumors, and trastuzumab (Herceptin) in treating breast cancer, and vemurafanib in treating melanoma. These drugs work by targeting bcr-abland c-kit (imatinib) and HER2 and Braf, respectively. For example, recently a phase III randomized trial demonstrated that, compared with dacarbazine, standard of care chemotherapy option for patients with metastatic melanoma with a V600E BRAF mutation, the BRAF inhibitor vemurafenib led to significantly higher response rates (48% vs. 5%).139 At 6 months, overall survival was 84% (95% CI, 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. The hazard ratio for tumor progression in the vemurafenib group was 0.26 (95% CI, 0.20 to 0.33; P<0.001). The estimated median progression-free survival was 5.3 months in the vemurafenib group and 1.6 months in the dacarbazine group. This trial highlights the fact that in at least some tumor types targeted therapies that inhibit a genomic alteration that is a driver is likely to be more effective than an unselected therapeutic option. Sequencing of the human genome has revealed approximately 500 protein kinases. Several tyrosine kinases have been shown to have oncogenic properties and many other protein kinases have been shown to be aberrantly activated in cancer cells.90 Therefore, protein kinases involved in these aberrantly activated pathways are being aggressively pursued in molecular therapeutics. Potential targets like HER2 can be targeted via different strategies, such as transcriptional downregulation, targeting of mRNA, RNA inhibition, antisense strategies, direct inhibition of protein activity, and induction of immunity against the protein. Most of the compounds in development are monoclonal antibodies like trastuzumab or small-molecule kinase inhibitors like imatinib or vemurafanib. Some other agents, such as sunitinib, are multi-targeted kinase inhibitors. Selected FDA-approved targeted therapies are listed in Table 10-11. Many of the promising pathways, such as the PI3K/Akt/mTOR pathway are being pursued as therapeutic targets with several drugs in development, targeting different aspects of the pathway (Fig. 10-15).140 Development of molecularly targeted agents for clinical use presents several unique challenges. Once an appropriate compound is identified and confirmed to have activity in preclinical testing, predictive markers for activity in the preclinical setting must be defined. Expression of a target may not be sufficient to predict response, because the pathway of interest may not be activated or critical to the cancer’s survival. Although in traditional phase I trials the goal is to identify the maximum tolerated dosage, the maximum dosage of biologic agents may not be necessary to achieve the desired biologic effect. Thus assays to verify modulation of the target need to be developed to determine at what dosage the desired effect is achieved. When phase II and III clinical trials are initiated, biomarker modulation studies should be integrated into the trial to determine whether clinical response correlates with target modulation and thus to identify additional parameters that impact response. Rational dose selection and limitation of study populations to patients most likely to respond to the molecular therapy as determined by predictive markers are most likely to lead to successful clinical translation of a product. Finally, most biologic agents are cytostatic, not cytotoxic. Thus rational combination therapy mixing new biologic agents with either established chemotherapeutic agents that have synergy or with other biologic agents is more likely to lead to cancer cures. IMMUNOTHERAPY The aim of immunotherapy is to induce or potentiate inherent antitumor immunity that can destroy cancer cells. Central to the process of antitumor immunity is the ability of the immune system to recognize tumor-associated antigens present on human cancers and to direct cytotoxic responses through humoral or T-cell–mediated immunity. Overall, T-cell–mediated immunity appears to have the greater potential of the two for eradicating tumor cells. T cells recognize antigens on the surfaces of target cells as small peptides presented by class I and class II MHC molecules. Several antitumor strategies are under investigation. One approach to antitumor immunity is nonspecific immunotherapy, which stimulates the immune system as a whole through administration of bacterial agents or their products, such as bacille Calmette-Guérin. This approach is thought to activate the effectors of antitumor response such as natural killer cells and macrophages, as well as polyclonal lymphocytes.141 Another approach to nonspecific immunotherapy is systemic administration of cytokines such as interleukin-2, interferon-α, and interferon-γ. Interleukin-2 stimulates proliferation of cytotoxic T lymphocytes and maturation of effectors such as natural killer cells into lymphokine-activated killer cells. Interferons, on the other hand, exert antitumor effects directly by inhibiting tumor cell proliferation and indirectly by activating host immune cells, including macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression on tumor cells.141 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 309 CHAPTER 10 ONCOLOGY aromatase inhibitors, and somatostatin analogues. Hormones or hormone-like agents can be administered to inhibit tumor growth by blocking or antagonizing the naturally occurring substance, such as with the estrogen antagonist tamoxifen. Other substances that block the synthesis of the natural hormone can be administered as alternatives. Aromatase inhibitors, for example, block the peripheral conversion of endogenous androgens to estrogens in postmenopausal women. Hormonal therapy provides a highly tumor-specific form of therapy in sensitive tissues. In breast cancer, estrogen and progesterone receptor status is used to predict the success of hormonal therapy. Androgen receptor is also being pursued as a therapeutic target for breast cancer treatment. 310 Table 10-11 Selected FDA-approved targeted therapies PART I BASIC CONSIDERATIONS GENERIC NAME TRADE NAME TARGET FDA-APPROVED INDICATIONS Ado-trastuzumab emtansine Kadcyla HER2 Breast cancer Axitinib Inlyta KIT, FDGFRβ, VEGFR1/2/3 RCC Bevacizumab Avastin VEGF Colorectal cancer, lung cancer, glioblastoma, NSCLC RCC Bosutinib Bosulif ABL CML(Philadelphia chromosome+) Cabozantinib Cometriq FLT3, KIT, MET, RET, VEGR2 Medullary thyroid cancer Cetuximab Erbitux EGFR Colorectal cancer (KRAS wild-type) Squamous cell cancer of the head and neck Dasatinib Sprycel ABL, src family, KIT, EPHA2, PDGFR-β CML Erlotinib Tarceva EGFR NSCLC, Pancreatic cancer Everolimus Afinitor mTOR PNET, RCC, Breast cancer. Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosis Gefitinib Iressa EGFR NSCLC with known/previous benefit from gefitinib (limited approval) Imatinib Gleevec KIT, ABL, PDGFR CML, GIST (KIT+), Dermatofibrosarcoma protuberans Lapatinib Tykerb EGFR and HER2 Breast cancer (HER2+) Nilotinib Tasigna ABL CML (Philadelphia chromosome+) Panitumumab Vectibix EGFR Colorectal cancer (KRAS wild type) Pazopanib Votrient VEGFR, PDGFR, KIT RCC Pertuzumab Perjeta HER2 Breast cancer (HER+) Ponatinib Iclusig ABL, FGFR1-3, FLT3, VEGFR2 CML, ALL (Philadelphia chromosome+) Regorafenib Stivarga KIT, PDGFRβ, RAF, RET, VEGFR1/2/3 Colorectal cancer, GIST Sorafenib Nexavar VEGFR, PDGFR, KIT, RAF HCC RCC Sunitinib Sutent VEGFR PDGFR KIT, Flt-3, RET GIST, RCC, PNET Temsirolimus Torisel mTOR RCC Trastuzumab Herceptin HER2 Breast cancer (HER2+) Gastric cancer (HER2+) Vandetanib Caprelsa EGFR, RET, VEGFR2 Medullary thyroid cancer Vemurafenib Zelboraf BRAF Melanoma (BRAF V600E mutant) CML, chronic myelogenous leukemia; EGFR, epidermal growth factor receptor; EPHA2, ephrin A2; FDA, Food and Drug Administration; Flt-3, fmsrelated tyrosine kinase 3; GIST, GI stromal tumor; HCC, Hepatocellular cancer, HER2, human epidermal growth factor receptor 2; mTOR, mammalian target of rapamycin; NSCLC, non-small cell lung cancer, PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PNET, Pancreatic neuroendocrine tumor, RCC, renal cell carcinoma; RET, rearranged during transfection; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 311 Amino Acids Glucose P P PDK1 AMPK Activators PI3K PI3K Inhibitors PIP2 ATP PIP3 MAP4K3 AMPK PTEN Akt Inhibitors Rapalogs Akt FKBP12 GSK3 mTORC2 Proctor RICTOR mTOR FOXO TSC2 TSC1 mTORC1 BAD PRAS40 ASK1 mLST8 SIN1 Rheb Rheb GDP GTP mTOR eIF4B Dual Pl3K/mTOR Kinase Inhibitors mTOR Kinase Inhibitors S6K RAPTOR mLST8 4EBP1 S6 eEF3K PDCD4 eIF4E Figure 10-15. Targeting PI3K/Akt/mTOR signaling. This central pathway is altered in many tumor types and is being pursued as a therapeutic target through development of numerous pathway inhibitors targeting PI3K, Akt, mTOR, dual inhibitors as well as several upstream and downstream regulators. (Modified with permission from McAuiliffe et al. Copyright Elsevier.)140 Antigen-specific immunotherapy can be active, as is achieved through antitumor vaccines, or passive. In passive immunotherapy, antibodies to specific tumor-associated antigens can be produced by hybridoma technique and then administered to patients whose cancers express these antigens, inducing antibody-dependent cellular cytotoxicity. The early attempts at vaccination against cancers used allogeneic cultured cancer cells, including irradiated cells, cell lysates, and shed antigens isolated from tissue culture supernatants. An alternate strategy is the use of autologous tumor vaccines. These have the potential advantage of being more likely to contain antigens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for preparation, which restricts eligibility of patients for this modality. Strategies to enhance immunogenicity of tumor cells include the introduction of genes encoding cytokines or chemokines, and fusion of the tumor cells to allogeneic MHC class II-bearing cells.142 Alternatively, heat shock proteins derived from a patient’s tumor can be used, because heat shock protein peptide complexes are readily taken up by dendritic cells for presentation to T cells.142 Identification of tumor antigens has made it possible to perform antigen-specific vaccination. For example in the case of melanoma, several antigens have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.143 Antigens tested usually are o­ verexpressed or mutated in cancer cells. Tissue specificity and immunogenicity are important determinants in choosing an appropriate target. Vaccines directed at defined tumor antigens aim to combine selected tumor antigens and appropriate routes for delivering these antigens to the immune system to optimize antitumor immunity.144 Several different vaccination approaches are under study, including tumor cell-based vaccines, peptidebased vaccines, recombinant virus-based vaccines, DNA-based vaccines, and dendritic cell vaccines. In adoptive transfer, antigen-specific effector cells (i.e., cytotoxic T lymphocytes) or antigen-nonspecific effector cells (i.e., natural killer cells) can be transferred to a patient. These effector cells can be obtained from the tumor (tumor-infiltrating lymphocytes) or the peripheral blood. Clinical experience in patients with metastatic disease has shown objective tumor responses to a variety of immunotherapeutic modalities. It is thought, however, that the immune system is overwhelmed with the tumor burden in this setting, and thus adjuvant therapy may be preferable, with immunotherapy reserved for decreasing tumor recurrences. Trials to date suggest that immunotherapy is a potentially useful approach in the adjuvant setting. How to best select patients for this approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types. Tolerance to self-antigens expressed in tumors is a limitation in generating antitumor responses.145 Recently, several VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 10 ONCOLOGY IRS1 312 PART I BASIC CONSIDERATIONS pathways that modulate tolerance and approaches to manipulating these pathways have been identified: pathways that activate professional antigen-presenting cells such as Toll-like receptors, growth factors, and the CD40 pathway; cytokines to enhance immunoactivation; and pathways that inhibit T-cell inhibitory signals or Tregs.145 A new strategy being actively explored involves the use of cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 exists on the surfaces of T cells and has a homeostatic immunosuppressive function, downregulating the response of T cells to stimuli.146 In a recent phase 3 study, ipilimumab—which blocks CTLA-4, was administered with or without glycoprotein 100 (gp100) peptide vaccine and was compared with gp100 alone in HLA-A*0201-positive patients with previously treated metastatic melanoma. The median overall survival was significantly longer for patients receiving ipilimumab with or without gp100, compared with patients who receiving gp100.147 In another Phase III trial, ipilimumab in combination with dacarbazine, compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma.148 Anti-CTLA-4 antibodies are under study for use in melanoma as well as several other cancer types as single agents, in combination with targeted therapies, interleukin-2, chemotherapy, or peptide vaccines.146 Programmed death ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that is thought to play an important role in suppressing the immune system. PD-L1 binds to its receptor, PD-1, which is found on activated T cells, B cells, and myeloid cells. The PD1/PDL1 pathway is increasingly recognized as a key contributor to tumor-mediated immune suppression. Thus both anti-PD1 and anti-PD-L1 strategies are actively being pursued for cancer therapy. GENE THERAPY Gene therapy is being pursued as a possible approach to modifying the genetic program of cancer cells as well as treating metabolic diseases. The field of cancer gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.149 Indeed, in preclinical models, approaches such as replacement of tumor-suppressor genes leads to growth arrest or apoptosis. However, the translation of these findings into clinically useful tools presents special challenges. One of the main difficulties in getting gene therapy technology from the laboratory to the clinic is the lack of a perfect delivery system. An ideal vector would be administered through a noninvasive route and would transduce all of the cancer cells and none of the normal cells. Furthermore, the ideal vector would have a high degree of activity, that is, it would produce an adequate amount of the desired gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer requires either that the therapeutic gene be delivered to all of the cancer cells or that a therapeutic effect be achieved on nontransfected cells as well as transfected cells through a bystander effect. But then, treatment of a metabolic disease requires prolonged gene expression, whereas transient expression may be sufficient for cancer therapy. Several vector systems are under study for gene therapy; however, none is considered ideal. One of the promising approaches to increase the number of tumor cells transduced is the use of a replication-competent virus like a parvovirus, human reovirus, or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes exploits tumor-specific expression elements, such as the MUC-1, PSA, CEA, or VEGF promoters, that can be used to achieve tissue-specific or tumor-specific expression of the desired gene. Because the goal in cancer therapy is to eradicate systemic disease, optimization of delivery systems is the key to success for gene therapy strategies. Gene therapy is likely to be most successful when combined with standard therapies, but it will provide the advantage of customization of therapy based on the molecular status of an individual’s tumor. MECHANISMS OF INTRINSIC AND ACQUIRED DRUG RESISTANCE Several tumor factors influence tumor cell kill. Tumors are heterogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell clones. This has been used as an argument for giving chemotherapy as soon as possible in treatment to reduce the likelihood that resistant clones will emerge. Tumor size is another important variable. Large tumor, may have greater heterogeneity, although heterogeneity may also differ based on biological subtype. Moreover, according to the gompertzian model, cancer cells initially grow rapidly (exponential growth phase), then the growth slows down owing to hypoxia and decreased nutrient supply. Because of the larger proportion of cells dividing, smaller tumors may be more chemosensitive. Multiple mechanisms of systemic therapy resistance have been identified (Table 10-12).150 Cells may exhibit reduced sensitivity to drugs by virtue of their cell-cycle distribution. For example, cells in the G0 phase are resistant to drugs active in the S phase. This phenomenon of “kinetic resistance” usually is temporary, and if the drug level can be maintained, all cells will eventually pass through the vulnerable phase of the cell cycle.137 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insufficient drug concentration. This may occur when tumor cells are located in sites where effective drug concentrations are difficult to achieve (such as the central nervous system) or can be due to enhanced metabolism of the drug after its administration, decreased conversion of the drug to its active form, or decrease in the intracellular drug level caused by increased removal of the drug from the cell associated with enhanced expression of P-glycoprotein, the protein product of multidrug resistance gene 1. Other mechanisms of resistance include decreased affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is improper dosing. A dose reduction of 20% because of drug toxicity can lead to a decline in the cure rate by as much as 50%.137 Furthermore, a twofold increase in dose can be associated with a tenfold (1 log) increase in tumor cell kill. Cancer cells demonstrate adaptive responses to targeted therapy, like activating alternate pathways of survival; thus these alterations may blunt therapeutic efficacy. Cancer cells also acquire resistance upon prolonged treatment with targeted therapy through a variety of mechanisms. One mechanism is through the loss of the target. For example, this was observed in a study of patients with HER2-positive breast cancer patients VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 10-12 General mechanisms of drug resistance Source: Modified with permission from Morrow et al.150 who were treated with neoadjuvant trastuzumab-based chemotherapy.151 Post-neoadjuvant treatment, a third of the samples from patients who did not have a complete pathologic response displayed loss of the HER2 amplification that had been present in their pretreatment-biopsy specimens151. Another means by which cancers develop resistance is the acquisition of additional genomic aberrations. In lung cancer, a second mutation in EGFR (T790M) and MET amplification have been described as two main mechanisms of drug resistance to EGFR inhibitors erlotinib and gefinitib.152-154 Other mechanisms like novel genetic changes, including HER2 and EGFR amplification, PIK3CA mutations, and markers of epithelial-to-mesenchymal transition have also been reported in EGFR inhibitor resistant lung.155, 156 Analysis of metastases from patients with colorectal cancer who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% of the cases.157 These studies emphasize the utility of repeat tumor biopsy specimens at the time of relapse or progression to identify mechanisms of resistance and best combinatorial therapies. RADIATION THERAPY Physical Basis of Radiation Therapy Ionizing radiation is energy strong enough to remove an orbital electron from an atom. This radiation can be electromagnetic, like a high-energy photon, or particulate, such as an electron, proton, neutron, or alpha particle. Radiation therapy is delivered primarily as Biologic Basis of Radiation Therapy Radiation deposition results in DNA damage manifested by single- and double-strand breaks in the sugar phosphate backbone of the DNA molecule.158 Cross-linking between the DNA strands and chromosomal proteins also occurs. The mechanism of DNA damage differs by the type of radiation delivered. Electromagnetic radiation is indirectly ionizing through short-lived hydroxyl radicals produced primarily by the ionization of cellular hydrogen peroxide (H2O2).158 Protons and other heavy particles are directly ionizing and directly damage DNA. Radiation damage is manifested primarily by the loss of cellular reproductive integrity. Most cell types do not show signs of radiation damage until they attempt to divide, so slowly proliferating tumors may persist for months and appear viable. Some cell types, however, undergo apoptosis. The extent of DNA damage after radiation exposure is dependent on several factors. The most important of these is cellular oxygen. Hypoxic cells are significantly less radiosensitive than aerated cells. Because the presence of oxygen is thought to prolong the half-life of free radicals produced by the interaction of X-rays and cellular H2O2, indirectly ionizing radiation is less efficacious in tumors with areas of hypoxia.158 In contrast, radiation damage from directly ionizing radiation is independent of cellular oxygen levels. The extent of DNA damage from indirectly ionizing radiation is dependent on the phase of the cell cycle. The most radiation-sensitive phases are G2 and M, whereas G1 and late S phases are less sensitive. Thus irradiation of a population of tumor cells results in killing of a greater proportion of cells in G2 and M phases. However, delivery of radiation in divided doses, a concept referred to as fractionation, allows the surviving G1 and S phase cells to progress to more sensitive phases, a process referred to as reassortment. In contrast to DNA damage after indirectly ionizing radiation, that after exposure to directly ionizing radiation is less dependent on the cell-cycle phase.159 Several chemicals can modify the effects of ionizing radiation. These include hypoxic cell sensitizers such as metronidazole and misonidazole, which mimic oxygen and increase cell kill of hypoxic cells.158 A second category of radiation sensitizers are the thymidine analogues iododeoxyuridine and bromodeoxyuridine. These molecules are incorporated into the DNA in place of thymidine and render the cells more susceptible to radiation damage; however, they are associated with considerable acute toxicity. Several other chemotherapeutic agents sensitize cells to radiation through various mechanisms, including VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 313 CHAPTER 10 ONCOLOGY Cellular and biochemical mechanisms Decreased drug accumulation Decreased drug influx Increased drug efflux Altered intracellular trafficking of drug Decreased drug activation Increased inactivation of drug or toxic intermediate Increased repair of drug-induced damage to: DNA Protein Membranes Alteration of drug targets (quantitatively or qualitatively) Alteration of cofactor or metabolite levels Alteration of gene expression DNA mutation, amplification, or deletion Altered transcription, posttranscription processing, or translation Altered stability of macromolecules Mechanisms relevant in vivo Pharmacologic and anatomic drug barriers (tumor sanctuaries) Host-drug interactions Increased drug inactivation by normal tissues Decreased drug activation by normal tissues Relative increase in normal tissue drug sensitivity (toxicity) Host-tumor interactions high-energy photons (gamma rays and X-rays) and charged particles (electrons). Gamma rays are photons that are released from the nucleus of a radioactive atom. X-rays are photons that are created electronically, such as with a clinical linear accelerator. Currently, high-energy radiation is delivered to tumors primarily with linear accelerators. X-rays traverse the tissue, depositing the maximum dose beneath the surface, and thus spare the skin. Electrons are used to treat superficial skin lesions, superficial tumors, or surgical beds to a depth of 5 cm. Gamma rays typically are produced by radioactive sources used in brachytherapy. The dose of radiation absorbed correlates with the energy of the beam. The basic unit is the amount of energy absorbed per unit of mass (joules per kilogram) and is known as a gray(Gy). One gray is equivalent to 100 rads, the unit of radiation measurement used in the past. 314 5-fluorouracil, actinomycin D, gemcitabine, paclitaxel, topotecan, doxorubicin, and vinorelbine.158 Radiation Therapy Planning PART I BASIC CONSIDERATIONS Radiation therapy is delivered in a homogeneous dose to a welldefined region that includes tumor and/or surrounding tissue at risk for subclinical disease. The first step in planning is to define the target to be irradiated as well as the dose-limiting organs in the vicinity.160 Treatment planning includes evaluation of alternative treatment techniques, which is done through a process referred to as simulation. Once the beam distribution that will best achieve homogeneous delivery to the target volume and minimize the dose to the normal tissue is determined, immobilization devices and markings or tattoos on the patient’s skin are used to ensure that each daily treatment is given in the same way. Conventional fractionation is 1.8 to 2 Gy/d, administered 5 days each week for 3 to 7 weeks. Radiation therapy may be used as the primary modality for palliation in certain patients with metastatic disease, primarily patients with bony metastases. In these cases, radiation is recommended for symptomatic metastases only. However, lytic metastases in weight-bearing bones such as the femur, tibia, or humerus also are considered for irradiation. Another circumstance in which radiation therapy might be appropriate is spinal cord compression due to metastases to the vertebral body that extend posteriorly to the spinal canal. The goal of adjuvant radiation therapy is to decrease localregional recurrence rates. Adjuvant radiation therapy can be given before surgery, after surgery, or, in selected cases, during surgery. Preoperative radiation therapy has several advantages. It may minimize seeding of the tumor during surgery and it allows for smaller treatment fields because the operative bed has not been contaminated with tumor cells. Also, radiation therapy for inoperable tumors may achieve adequate reduction to make them operable. The disadvantages of preoperative therapy are an increased risk of postoperative wound healing problems and the difficulty in planning subsequent radiation therapy in patients who have positive surgical margins. If radiation therapy is given postoperatively, it is usually given 3 to 4 weeks after surgery to allow for wound healing. The advantage of postoperative radiation therapy is that the surgical specimen can be evaluated histologically and radiation therapy can be reserved for patients who are most likely to benefit from it. Further, the radiation therapy can be modified on the basis of margin status. The disadvantages of postoperative radiation therapy are that the volume of normal tissue requiring irradiation may be larger owing to surgical contamination of the tissue planes and that the tumor may be less sensitive to radiation owing to poor oxygenation. Postlaparotomy adhesions may decrease the mobility of the small bowel loops, increasing the risk for radiation injury in abdominal or pelvic irradiation. Given the potential advantages and disadvantages of both approaches, the roles of preoperative and postoperative radiation therapy are being actively evaluated and compared for many cancer types. Another mode of postoperative radiation therapy is brachytherapy. In brachytherapy, unlike in external beam therapy, the radiation source is in contact with the tissue being irradiated. The radiation source may be cesium, gold, iridium, or radium. Brachytherapy is administered via temporary or permanent delivery implants such as needles, seeds, or catheters. Temporary brachytherapy catheters are placed either during open surgery or percutaneously soon after surgery. The implants are loaded interstitially, and treatment usually is given postoperatively for a short duration, such as 1 to 3 days. Although brachytherapy has the disadvantages of leaving scars at the catheter insertion site and requiring special facilities for inpatient brachytherapy the advantage of patient convenience owing to the shorter treatment duration, has made intracavitary treatment approaches very popular for the treatment of breast cancer. Another short delivery approach is intraoperative radiotherapy (IORT), often used in combination with external beam therapy. The oncologic consequences of the limited treatment volume and duration associated with brachytherapy and IORT are not well understood. Accelerated partial breast irradiation with interstitial brachytherapy, intracavitary brachytherapy (MammoSite), IORT, and three-dimensional conformal external beam radiotherapy is being compared with whole breast irradiation in an intergroup phase III trial (NSABP B-39/Radiation Therapy Oncology Group 0413). Several additional studies of adjuvant IORT also are ongoing internationally. There has also been increasing interest in utilizing intensity-modulated radiation therapy (IMRT). IMRT is a complex technique for the delivery of radiation therapy preferentially to target structures while minimizing doses to adjacent normal critical structures.161 It is widely utilized for the treatment of a variety of tumor types, including the central nervous system, head and neck, breast, prostate, gastrointestinal tract, and gynecologic organs, as well as in patients where previous radiation therapy has been delivered. It is thought that chemotherapy given concurrently with radiation improves survival rates. Chemotherapy before radiation has the advantage of reducing the tumor burden, which facilitates radiation therapy. On the other hand, some chemotherapy regimens, when given concurrently with radiation, may sensitize the cells to radiation therapy. Chemoradiation is being pursued in many tumor types, including rectal cancer, pancreatic cancer, and esophageal cancer.162-164 In a recent Cochrane review of six randomized controlled trials, it was demonstrated that in patients T3/4 rectal cancer, chemoradiation was associated with a significantly lower local recurrence rate compared with radiation therapy alone (OR 0.56, 95% CI 0.42-0.75, P<0.0001), but was not associated with improved survival.162 Side Effects Both tumor and normal tissue have radiation dose-response relationships that can be plotted as a sigmoidal curve (Fig. 10-16).160 A minimum dose of radiation must be given before any response is seen. The response to radiation then increases slowly with an increase in dose. At a certain dose level the curves become exponential, with increases in tumor response and normal tissue toxicity with each incremental dose increase. The side effects of radiation therapy can be acute, occurring during or 2 to 3 weeks after therapy, or chronic, occurring weeks to years after ­therapy. The side effects depend on the tissue included in the target ­volume. Some of the major acute and chronic sequelae of radiation are summarized in Table 10-13.160, 165 In addition to these effects, a small increase in the risk for secondary malignancies is attributable to radiation therapy. CANCER PREVENTION The truth of the old axiom, “An ounce of prevention is worth a pound of cure” is being increasingly recognized in oncology. Cancer prevention can be divided into three categories: (a) primary prevention (i.e., prevention of initial cancers in healthy VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ B Tumor control Complications Dose Figure 10-16. The probability of tumor control and of complications at different radiation doses. A. At lower doses, the probability of complications is low, with a moderate chance of tumor control. B. Increasing the dose may gain a higher chance of tumor control at the price of significantly higher complication risks. (Modified with permission from Eisbruch A, Lichter AS. With kind permission from Springer Science and Business Media.)160 individuals), (b) secondary prevention (i.e., prevention of cancer in individuals with premalignant conditions), and (c) tertiary prevention (i.e., prevention of second primary cancers in patients cured of their initial disease). The systemic or local administration of therapeutic agents to prevent the development of cancer, called chemoprevention, is being actively explored for several cancer types. In breast cancer, the NSABP Breast Cancer Prevention Trial demonstrated that tamoxifen administration reduces the risk of breast cancer by one half and reduces the risk of estrogen receptor-positive tumors by 69% in high-risk patients.166 Therefore, tamoxifen has been approved by the FDA for breast cancer chemoprevention. The subsequent NSABP P-2 trial demonstrated that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and is associated with a lower risk of thromboembolic events and cataracts but a non-statistically significant higher risk of noninvasive breast cancer; these findings led the FDA to approve raloxifene for prevention as well. Several other agents are also under investigation.167 Celecoxib has been shown to reduce polyp number and polyp burden in patients with FAP, which led to its approval by the FDA for these patients. In head and neck cancer, 13-cis-retinoic acid has been shown both to reverse oral leukoplakia and to reduce second primary tumor development.168, 169 Thus, the chemoprevention trials completed so far have demonstrated success in primary, secondary, and tertiary prevention. Although the successes of these chemoprevention studies are impressive, much remains to be done over the next few years to improve patient selection and decrease therapy-related toxic effects. It is important for surgeons to be aware of these preventive options, because they are likely to be involved in the diagnosis of premalignant and malignant conditions and will be the ones to counsel patients about their chemopreventive options. In selected circumstances, the risk of cancer is high enough to justify surgical prevention. These high-risk settings include hereditary cancer syndromes such as hereditary breast-ovarian cancer syndrome, hereditary diffuse gastric cancer, multiple endocrine neoplasia type 2, FAP, and hereditary nonpolyposis colorectal cancer, as well as some nonhereditary conditions such as chronic ulcerative colitis. Most prophylactic surgeries are large ablative surgeries (e.g., bilateral riskreducing mastectomy or total proctocolectomy). Therefore, it is important that the patient be completely informed about potential surgical complications as well as long-term lifestyle consequences. Further, the conservative options of close surveillance and chemoprevention need to be discussed. The patient’s cancer risk needs to be assessed accurately and implications for survival discussed. Ultimately, the decision to proceed with surgical prevention should be individualized and made with caution. Table 10-13 Local effects of radiation ORGAN ACUTE CHANGES CHRONIC CHANGES Skin Erythema, wet or dry desquamation, epilation Telangiectasia, subcutaneous fibrosis, ulceration GI tract Nausea, diarrhea, edema, ulceration, hepatitis Stricture, ulceration, perforation, hematochezia Kidney — Nephropathy, renal insufficiency Bladder Dysuria Hematuria, ulceration, perforation Gonads Sterility Atrophy, ovarian failure Hematopoietic tissue Lymphopenia, neutropenia, thrombocytopenia Pancytopenia Bone Epiphyseal growth arrest Necrosis Lung Pneumonitis Pulmonary fibrosis Heart — Pericarditis, vascular damage Upper aerodigestive tract Mucositis, xerostomia, anosmia Xerostomia, dental caries Eye Conjunctivitis Cataract, keratitis, optic nerve atrophy Nervous system Cerebral edema Necrosis, myelitis VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 315 CHAPTER 10 ONCOLOGY Percent A 316 TRENDS IN ONCOLOGY Cancer Screening and Diagnosis PART I BASIC CONSIDERATIONS It is clear that the practice of oncology will change dramatically over the next few decades, because our understanding of the molecular basis of cancer and available technologies are evolving rapidly. One of the critical changes expected is earlier detection of cancers. With improvements in available imaging modalities and development of newer functional imaging techniques, it is likely that many tumors will be detected at earlier, more curable stages in the near future. Another area of rapid development is the identification of serum markers. High-throughput technologies such as matrixassisted laser desorption ionization time-of-flight mass spectroscopy and liquid chromatography ion-spray tandem mass spectroscopy have revolutionized the field of proteomics and are now being used to compare the serum protein profiles of patients with cancer with those of individuals without cancer. Identification of unique proteins as well as unique proteomic profiles for most cancer types is being pursued actively by many researchers and, if successful, could dramatically enhance our ability to detect cancers early.170 In addition, there is greater interest placed in leveraging circulating free DNA as a potential approach for cancer screening. Surgical Therapy The current trend in surgery is toward more conservative resections. With earlier identification of tumors, more conservative operations may be possible. The goal, however, is always to remove the tumor en bloc with wide negative margins. Another interesting area being explored is the destruction of tumors by techniques such as radiofrequency ablation, cryoablation, and heat-producing technologies like lasers, microwaves, or focused ultrasound. Pilot studies have demonstrated that radiofrequency ablation is effective for destruction of small primary breast cancers. Although this approach remains experimental and potentially of limited applicability because of the need for expertise in breast imaging, the development of imaging technologies that can accurately map the extent of cancer cells, these types of noninvasive interventions are likely to come to the forefront. However, use of these techniques will be limited to treatment of cancers not involving hollow viscera. The debate over how to manage the regional lymph node basins for certain cancer types continues. With an increasing understanding of the metastatic process, surgeons may be able to stratify patients on the basis of the likelihood that their disease will spread metastatically, based on the gene expression profile of their primary tumors, and offer regional therapy accordingly. There is also a growing interest in minimally invasive surgical treatments for a variety of cancer types. Systemic Therapy The current trend in systemic therapy is toward individualized therapy. It is now presumed that all cancers of a certain cell origin are the same. Thus all patients are offered the same systemic therapy. Not all patients respond to these therapies; however, this emphasizes the biologic variability within the tumor groups. Therefore, the intent is to determine the underlying biology of each tumor to tailor therapy accordingly. Genomic, transcriptional, and proteomic profiling approaches are being used to identify molecular signatures that correlate with response to certain agents. It is likely that in the near future all tumors can be tested and treatments individualized. Patients who will respond to conventional therapies can be treated with these regimens, whereas patients who will not respond will not, which spares them the toxicity. Instead, the latter patients can be offered novel therapies. 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Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. sharp mesorectal excision and preoperative combinedmodality­ therapy. Ann Surg Oncol. 2003;10:80-85. Kapiteijn E, van de Velde CJ. The role of total mesorectal excision in the management of rectal cancer. Surg Clin North Am. 2002;82:995-1007. Meric F, Hunt KK. Surgical options for breast cancer. In: Hunt KK, Robb GL, Strom EA, Ueno NT, eds. M D Anderson Cancer Care Series-Breast Cancer. New York Springer-Verlag; 2001:187-222. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456-466. Querzoli P, Pedriali M, Rinaldi R, et al. Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients. 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European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216. Page R. Principles of Chemotherapy. In: Pazdur R, Hoskins W, Coia L, eds. Cancer Management: A Multidisciplinary Approach. Melville PRR Inc; 2001:21. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207-214. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. McAuliffe PF, Meric-Bernstam F, Mills GB, GonzalezAngulo AM. Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer. 2010;10 Suppl 3:S59-S65. Mocellin S, Rossi CR, Lise M, Marincola FM. Adjuvant immunotherapy for solid tumors: from promise to clinical application. Cancer Immunol Immunother. 2002;51:583-595. Perales MA, Wolchok JD. Melanoma vaccines. Cancer Invest. 2002;20:1012-1026. Lizee G, Cantu MA, Hwu P. Less yin, more yang: confronting the barriers to cancer immunotherapy. Clin Cancer Res. 2007;13:5250-5255. Dermime S, Armstrong A, Hawkins RE, Stern PL. Cancer vaccines and immunotherapy. Br Med Bull. 2002;62:149-162. Berinstein NL. Enhancing cancer vaccines with immunomodulators. Vaccine. 2007;25 Suppl 2:B72-B88. Cranmer LD, Hersh E. The role of the CTLA4 blockade in the treatment of malignant melanoma. Cancer Invest. 2007;25:613-631. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. The N Engl J Med. 2010;363:711-723. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 319 CHAPTER 10 ONCOLOGY 105. Wender R, Fontham ET, Barrera E, Jr., et al. American Cancer Society lung cancer screening guidelines. Cancer J Clin. 2013;63:106-117. 106. Jacobs TW, Connolly JL, Schnitt SJ. Nonmalignant lesions in breast core needle biopsies: to excise or not to excise? Am J Surg Pathol. 2002;26:1095-1110. 107. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287-5312. 108. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24:5313-5327. 109. Way BA, Kessler G. Tumour marker overview. Lab Med Newsletter. 1996;4:1-7. 110. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. 111. van ‘t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530-536. 112. Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:120-134. 113. Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. Cancer J Clin. 2010;60:70-98. 114. http://www.labcorp.com/datasets/labcorp/html/chapter/mono/ ri000600.htm: Alpha-Fetoprotein (AFP), Serum, Tumor Marker (Serial Monitor), Laboratory Corporation of America. Accessed December 26, 2008. 115. Nguyen MH, Keeffe EB. Screening for hepatocellular carcinoma. J ClinGastroenterol. 2002;35:S86-S91. 116. Chan DW, Beveridge RA, Muss H, et al. Use of Truquant BR radioimmunoassay for early detection of breast cancer recurrence in patients with stage II and stage III disease. J Clin Oncol. 1997;15:2322-2328. 117. Outcomes of cancer treatment for technology assessment and cancer treatment guidelines. American Society of Clinical Oncology. J Clin Oncol. 1996;14:671-679. 118. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781-791. 119. Lucci A, Hall CS, Lodhi AK, et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. LancetOncol. 2012;13:688-695. 120. Scoggins CR, Ross MI, Reintgen DS, et al. Prospective multiinstitutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol. 2006;24:2849-2857. 121. Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005; 353:793-802. 122. Giuliano AE, Hawes D, Ballman KV, et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011;306:385-393. 123. Janni W, Rack B, Lindemann K, Harbeck N. Detection of micrometastatic disease in bone marrow: is it ready for prime time? Oncologist. 2005;10:480-492. 124. Grau A, Spitz F, Bouvet M. Pancreatic adenocarcinoma. In: Feig B, Berger D, Fuhrman G, eds. The M D Anderson Surgical Oncology Handbook. Philadelphia Lippincott Williams & Wilkins; 2003:303. 125. Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8:101-108. 126. Moore HG, Riedel E, Minsky BD, et al. Adequacy of 1-cm distal margin after restorative rectal cancer resection with 320 PART I BASIC CONSIDERATIONS 149. Cusack JC, Jr., Tanabe KK. Introduction to cancer gene therapy. Surg Oncol Clin N Am. 2002;11:497-519. 150. Morrow C, Cowan K. Drug resistance and its clinical circumvention. In: Bast R, Kufe D, Pollock R, eds. Cancer Medicine. Hamilton: B.C. Decker, Inc; 2000:539. 151. Mittendorf EA, Wu Y, Scaltriti M, et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res 2009;15:7381-7388. 152. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73. 153. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-1043. 154. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 2007;104:20932-20937. 155. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. 156. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2012;2: 922-933. 157. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532-536. 158. Mundt A, Roeske J, Weichelbaum R. Principles of Radiation Oncology. In: Bast R, Kuff D, Pollock R, eds. Cancer Medicine. Hamilton B.C. Decker Inc; 2000:465. 159. Raju MR, Carpenter SG. A heavy particle comparative study. Part IV: acute and late reactions. Br J Radiol. 1978;51:720-727. 160. Eisbruch A, Lichter AS. What a surgeon needs to know about radiation. Ann Surg Oncol. 1997;4:516-522. 161. Hartford AC, Galvin JM, Beyer DC, et al. American College of Radiology (ACR) and American Society for 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. Radiation Oncology (ASTRO) Practice Guideline for Intensity-modulated Radiation Therapy (IMRT). Am J Clin Oncol. 2012;35:612-617. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3496-3502. Courrech Staal EF, Aleman BM, Boot H, van Velthuysen ML, van Tinteren H, van Sandick JW. Systematic review of the benefits and risks of neoadjuvant chemoradiation for oesophageal cancer. BrJSurg. 2010;97:1482-1496. Daly J, Bertagnolli M, DeCosse J. Oncology. In: Schwartz S, Spencer F, Galloway A, eds. Principles of Surgery. New York: McGraw-Hill; 1999:297. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-2741. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med. 1993;328:15-20. Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;323:795-801. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2:210-219. Meric-Bernstam F, Hung MC. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res. 2006;12:6326-6330. Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med. 2012;18:349-351. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 11 chapter Background Definitions History Transplant Immunobiology Transplant Antigens Allorecognition and Lymphocyte Activation Clinical Rejection 321 321 322 323 324 324 324 Hyperacute / 324 Acute / 324 Chronic / 324 Clinical Immunosuppression Induction 324 325 325 Corticosteroids / 325 Azathioprine / 326 Mycophenolate Mofetil / 326 Sirolimus / 327 Cyclosporine / 328 Tacrolimus / 328 Belatacept / 328 Humoral Rejection Rituximab / 328 Bortezomib / 329 Angelika C. Gruessner, Tun Jie, Klearchos Papas, Marian Porubsky, Abbas Rana, M. Cristy Smith, Sarah E. Yost, David L. Dunn, and Rainer W.G. Gruessner Islet versus Pancreas Transplants / 344 Eculizumab / 329 Infections and Malignancies Organ Procurement and Preservation 330 Deceased Donors / 330 Living Donors / 332 Organ Preservation / 332 334 Introduction / 334 Pretransplant Evaluation / 334 Medical Evaluation / 335 Surgical Evaluation / 336 Recipient Operation / 336 Grafts with Multiple Renal Arteries / 337 En Bloc Grafts / 338 Perioperative Care / 338 Results / 339 Pancreas Transplantation 328 329 Infections / 329 Malignancies / 330 Kidney Transplantation Depleting Antibodies / 325 Nondepleting Antibodies / 325 Maintenance Transplantation 340 Donor Operation / 340 Back Table Preparation of the Pancreas Graft / 341 Recipient Operation / 341 Complications / 343 Living Donor Pancreas Transplants / 343 Results / 344 BACKGROUND Organ transplantation is a relatively novel field of medicine that has made significant progress since the second half of the twentieth century. Advances in surgical technique and 1 a better understanding of immunology are the two main reasons that transplants have evolved from experimental procedures, just several decades ago, to a widely accepted treatment today for patients with end-stage organ failure. Throughout the world, for a variety of indications, kidney, liver, pancreas, intestine, heart, and lung transplants are now the current standard of care. But the success of transplantation has created new challenges. A better understanding of the pathophysiology of endstage organ failure as well as advances in critical care medicine and in the treatment of various diseases led to expanding the criteria for, and decreasing the contraindications to, transplants. Islet Transplantation Liver Transplantation 344 345 History / 345 Indications / 346 Recipient Selection / 347 Contraindications / 348 Surgical Procedure / 348 Pediatric Transplants / 349 Deceased Donor Split-Liver Transplants / 349 Living Donor Transplants / 349 Postoperative Care / 349 Evaluation of Graft Function / 351 Complications / 351 Intestine and Multivisceral Transplantation 352 Indications and Recipient Selection / 352 Surgical Procedure / 352 Postoperative Care / 353 Heart and Lung Transplantation 354 History / 354 Heart Transplants / 355 Lung Transplants / 356 Heart-Lung Transplants / 358 Xenotransplants 358 As a result, the discrepancy between the ever-growing number of patients awaiting a transplant and the limited number of organs available is one of the biggest challenges (Fig. 11-1). In 2009 alone, according to the United Network for Organ Sharing (UNOS), about 105,000 patients in the United States were awaiting a transplant, yet the number of transplants performed was only about 28,000 (Fig. 11-2). DEFINITIONS In addition to being the overall name of this relatively new field of medicine, transplantation is the process of transferring an organ, tissue, or cell from one place to another. An organ transplant is a surgical procedure in which a failing organ is replaced by a functioning one. The organ is transplanted either orthotopically (implanted in the same anatomic location in the recipient as it was in the donor) or heterotopically (implanted in VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 The field of transplantation has made tremendous advances in the last 50 years, mainly due to refinements in surgical technique and development of effective immunosuppressive medications. Although immunosuppressive medications are essential for transplantation, they are associated with significant short- and long-term morbidity. Opportunistic infections can be significantly lowered by the use of appropriate antimicrobial agents. Kidney transplantation represents the treatment of choice for almost all patients with end-stage renal disease. The gap another anatomic location). Orthotopic transplants require the removal of the diseased organ (heart, lungs, liver, or intestine); in heterotopic transplants, the diseased organ is kept in place (kidney, pancreas). According to the degree of immunologic similarity between the donor and recipient, transplants are divided into three main categories: (a) An autotransplant is the transfer of cells, tissue, or an organ from one part of the body to another part in the same person, so no immunosuppression is required. This type of transplant includes skin and vein, bone, cartilage, nerve, and islet cell transplants. (b) An allotransplant is the transfer of cells, tissue, or an organ from one person to another of the same species. The immune system of the recipient recognizes the donated organ as a foreign body, so immunosuppression is required in order to avoid rejection. (c) A xenotransplant is the transfer of cells, tissue, or an organ from one organism to another from a different species. To date, animal-to-human transplants are still experimental procedures, given the very complex immunologic and infectious issues that have yet to be solved. HISTORY Over the centuries, multiple references to transplantation can be found in the literature. Yet transplantation as a recognized scientific and medical field began to emerge only in the middle of the twentieth century. Two major events preceded the rise of transplantation. 5 6 7 between demand (patients on the waiting list) and supply (available kidneys) continues to widen. Pancreas transplantation represents the most reliable way to achieve euglycemia in patients with poorly controlled diabetes. The results of islet transplantation continue to improve but still trail those of pancreas transplantation. Liver transplantation has become the standard of care for many patients with end-stage liver failure and/or liver cancer. First, the surgical technique of the vascular anastomosis was developed by French surgeon Alexis Carrel.1 This led to increased transplant activity, especially in animal models. Russian surgeon Yu Yu Voronoy was the first to report a series of human-to-human kidney transplants in the 1940s.2 But the outcomes were dismal, mainly because of the lack of understanding of the underlying immunologic processes. Second, the findings of British scientist Sir Peter B. Medawar in the 1940s were also key.3 In his work with skin grafts in animal models and in human burn patients, he learned that the immune system plays a crucial role in the failure of skin grafts. His research led to a better understanding of the immune system and is considered to be the birth of transplant immunobiology. The first human transplant with long-term success was performed by Joseph Murray in Boston, Massachusetts, in 1954.4 Because it was a living related kidney transplant between identical twins, no immunosuppression was required; the recipient lived for another 8 years before he died of issues unrelated to the transplanted kidney. Other centers performed similar transplants and could reproduce the good results. Ultimately, attempts were made to perform kidney transplants between nonidentical individuals. For immunosuppression, total-body radiation and an anticancer agent called 6-mercaptopurine were used; given the profound toxicity of both those methods of immunosuppression, results were discouraging. A breakthrough was achieved in the early 1960s with 110,000 100,000 90,000 Number of patients 80,000 70,000 60,000 # Waiting 50,000 # Transplanted 40,000 30,000 20,000 10,000 0 322 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 11-1. Patients on the waiting list and the number of organ transplants performed, 2000 to 2009. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr. org) # Waiting Lu ng Figure 11-2. Patients on the waiting list and the number of organ transplants performed, 2009. KP = kidney and pancreas. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr.org) H ea r t/ Lu ng s ea rt H Ki Pa dn nc ey re as an d KP Li ve r In te st in e To ta l # Transplanted the introduction of maintenance immunosuppression through a combination of corticosteroids and a less toxic derivative of 6-mercaptopurine, azathioprine.5,6 Increasing experience with kidney transplants and the better results achieved with maintenance immunosuppression paved the way for the era of extrarenal transplants (Table 11-1). In 1963, the first liver transplant was performed by Thomas Starzl in Denver, Colorado, and the first lung transplant was performed by James Hardy in Jackson, Mississippi. In 1966, the first pancreas transplant was performed by William Kelly and Richard Lillehei in Minneapolis, Minnesota. In 1967, the first successful heart transplant was performed by Christiaan Barnard in Cape Town, South Africa. The early years of transplantation were marked by high mortality, mainly because of irreversible rejection. Dramatic changes occurred with the further development of immunosuppression. The groundbreaking event was the introduction of the first anti-T lymphocyte (T cell) drug, cyclosporine, in the early 1980s.7 Since then, with an even better understanding of immunologic processes, many other drugs have been introduced that target specific pathways of rejection. As a result, rejection rates have decreased substantially, allowing a 1-year graft survival rate in excess of 80% in all types of transplants. The gradual increase in the organ shortage led to innovative surgical techniques. For example, deceased donor split-liver transplants and living donor liver transplants have helped expand the liver donor pool. Similarly, living donor intestine and pancreas techniques have been developed. The evolution of donor nephrectomy from an open to a minimally invasive procedure (laparoscopic or robotic) has helped increase the pool of living kidney donors. TRANSPLANT IMMUNOBIOLOGY The outcomes of early transplants were unsatisfactory. The limiting factor was the lack of understanding of immunologic processes. Irreversible rejection was the reason for graft loss in the vast majority of recipients. A better understanding of transplant immunobiology led to significant improvements in patient and graft survival rates.8,9 The immune system is designed as a defense system to protect the body from foreign pathogens, such as viruses, bacteria, and fungi, but it also acts to reject transplanted cells, tissues, and organs, recognizing them as foreign. It mediates other complex processes as well, such as the body’s response to trauma or to tumor growth. No matter what the pathogen is, the immune system recognizes it as a foreign antigen and triggers a response that eventually leads either to death or to rejection of the pathogen. Table 11-1 Transplant history Organ Year Surgeon Location Kidney 1954 Joseph E. Murray Boston, MA Liver 1963 Thomas E. Starzl Denver, CO Lung 1963 James D. Hardy Jackson, MS Pancreas 1966 Richard C. Lillehei Minneapolis, MN Heart 1967 Christiaan N. Barnard Cape Town, South Africa Small intestine 1967 Richard C. Lillehei Minneapolis, MN Heart/lung 1981 Bruce Reitz Stanford, CA Multivisceral 1989 Thomas E. Starzl Pittsburgh, PA VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 11 Transplantation Number of patients 323 110,000 100,000 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 324 TRANSPLANT ANTIGENS PART I BASIC CONSIDERATIONS Transplants between genetically nonidentical persons lead to recognition and rejection of the organ by the recipient’s immune system, if no intervention is undertaken. The main antigens responsible for this process are part of the major histocompatibility complex (MHC). In humans, these antigens make up the human leukocyte antigen (HLA) system. The antigen-encoding genes are located on chromosome 6. Two major classes of HLA antigens are recognized. They differ in their structure, function, and tissue distribution. Class I antigens (HLA-A, HLA-B, and HLA-C) are expressed by all nucleated cells. Class II antigens (HLA-DR, HLA-DP, and HLA-DQ) are expressed by antigenpresenting cells (APCs) such as B lymphocytes, dendritic cells, macrophages, and other phagocytic cells. The principal function of HLA antigens is to present the fragments of foreign proteins to T lymphocytes. This leads to recognition and elimination of the foreign antigen with great specificity. HLA molecules play a crucial role in transplant recipients as well. They can trigger rejection of a graft via two different mechanisms. The most common mechanism is cellular rejection, in which the damage is done by activated T lymphocytes. The process of activation and proliferation is triggered by exposure of T lymphocytes to the donor’s HLA molecules. The other mechanism is humoral rejection, in which the damage is done by circulating antibodies against the donor’s HLA molecules. The donor-specific antibodies can be present either pretransplant, due to previous exposure (because of a previous transplant, pregnancy, blood transfusion, or immunization), or posttransplant. After binding to the donor’s HLA molecules, the complement cascade is activated, leading to cellular lysis. ALLORECOGNITION AND LYMPHOCYTE ACTIVATION The immune system of each person is designed to discriminate between self and nonself cells and tissues. This process is called allorecognition, with T cells playing the crucial role. The recognition of foreign HLA antigens by the recipient’s T cells may occur by either a direct or an indirect pathway. Direct recognition occurs when the recipient’s T cells are activated by direct interaction with the donor’s HLA molecules. Indirect recognition occurs when the recipient’s T cells are activated by interaction with APCs that have processed and presented the foreign antigen. The foreign antigen can be shed from the graft into the circulation, or it can be identified by the APCs in the graft itself. Independent of the pathway of foreign HLA antigen presentation, the ensuing activation of T cells is similar. A two-signal model, T-cell activation begins with the engagement of the T-cell receptor (TCR)/CD3 complex with the foreign molecule. This interaction causes transmission of the signal into the cell, named signal 1. However, this signal alone is not sufficient to activate the T cell. An additional costimulatory signal is required, named signal 2. Two well-characterized costimulatory interactions are the CD40/CD154 and B7/CD28 pathways. The “master switch” is turned on by the interaction of CD40 protein with APCs, along with the interaction of CD154 protein with T cells; this ligation induces the upregulation of other costimulatory molecules. Transmission of signal 1 and signal 2 into the cell nucleus leads to upregulation of the transcription of genes for several cytokines, including the T-cell growth factor interleukin-2 (IL-2). In turn, IL-2 activates a number of pathways, leading to proliferation and differentiation of T cells. Rejection is a result of an attack of activated T cells on the transplanted organ. Although T-cell activation is the main culprit in rejection, B-cell activation and subsequent antibody production also play a role. After the foreign HLA antigen is processed by B cells, it interacts with activated helper T cells, leading to differentiation of B cells into plasma cells and subsequently to their proliferation and antibody production. CLINICAL REJECTION Graft rejection is due to a complex interaction of different parts of the immune system, including B and T lymphocytes, APCs, and cytokines. The end result is graft damage caused by inflammatory injury. According to its onset and pathogenesis, rejection is divided into three main types: hyperacute, acute, and chronic (each described in the following sections). Hyperacute Hyperacute rejection, a very rapid type of rejection, results in irreversible damage and graft loss within minutes to hours after organ reperfusion. It is triggered by preformed antibodies against the donor’s HLA or ABO blood group antigens. These antibodies activate a series of events that result in diffuse intravascular coagulation, causing ischemic necrosis of the graft. Fortunately, pretransplant blood group typing and cross-matching (in which the donor’s cells are mixed with the recipient’s serum, and then destruction of the cells is observed) have virtually eliminated the incidence of hyperacute rejection. Acute Acute rejection, the most common type of rejection, usually occurs within a few days or weeks posttransplant. According to the mechanism involved, it is further divided into cellular (T-cell–mediated) rejection, humoral (antibody-mediated) rejection, or a combination of both. The diagnosis is based on the results of biopsies of the transplanted organ, special immunologic stains, and laboratory tests (such as elevated creatinine levels in kidney transplant recipients, elevated liver function values in liver transplant recipients, and elevated levels of glucose, amylase, and lipase in pancreas transplant recipients). Chronic Chronic rejection is a slow type of rejection. It can manifest within the first year posttransplant, but most often progresses gradually over several years. The mechanism is not well understood, but the pathologic changes eventually lead to fibrosis and loss of graft function. With advances in immunosuppression, this relatively rare form of rejection is becoming more common. CLINICAL IMMUNOSUPPRESSION A successful transplant is a balance between the recipient’s immune response, the donor’s allograft, and pharmacologic immunosuppression. Immunosuppressive regimens are very important to graft and patient survival posttransplant. 2 Immunosuppression has evolved from the use of azathioprine and steroids in the 1960s and 1970s to the development, in the 1980s, of cyclosporine, which increased allograft survival.10,11 The introduction of tacrolimus and mycophenolate mofetil (MMF) in the 1990s further changed the field of transplantation, enabling a variety of combinations to be used for immunosuppression (Table 11-2). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Immunosuppressive drugs by grouping Immunophilin binders Calcineurin inhibitors   Cyclosporine   Tacrolimus Noninhibitors of calcineurin   Sirolimus Antimetabolites Inhibitors of de novo purine synthesis   Azathioprine   Mycophenolate mofetil Biologic immunosuppression Polyclonal antibodies   Atgam   Antithymocyte immunoglobulin Monoclonal antibodies   Muromonab-CD3   Basiliximab   Belatacept   Alemtuzumab   Rituximab   Bortezomib   Eculizumab Other Corticosteroids Nondepleting Antibodies Immunosuppressants usually are used in multidrug regimens, aimed at increasing efficacy by targeting multiple pathways to lower the immune response and to decrease the toxicity of individual agents. Certain regimens may involve withdrawal, avoidance, or minimization of certain classes of drugs. Transplant centers generally institute their immunosuppressive protocols based on experience, risk profiles, cost considerations, and outcomes. Immunosuppression is delivered in two phases: induction (starting immediately posttransplant, when the risk of rejection is highest) and maintenance (usually starting within days posttransplant and continuing for the life of the recipient or graft). Thus, the level of immunosuppression is highest in the first 3 to 6 months posttransplant; during this time, prophylaxis against various bacterial, viral, or even antifungal opportunistic infections is also given.12,13 A conventional immunosuppressive protocol might include (a) induction with anti-T-lymphocyte–depleting or nondepleting antibodies and (b) maintenance with calcineurin inhibitors, antiproliferative agents, and corticosteroids. Characteristics of the most common immunosuppressive agents are listed in Table 11-3. INDUCTION Induction includes the use of depleting (polyclonal) antibodies or nondepleting antibodies within the first month posttransplant. Studies have shown that induction with antibody regimens may prevent acute rejection, potentially leading to improved graft survival and the use of less maintenance immunosuppression. Depleting Antibodies Rabbit antithymocyte globulin (Thymoglobulin) is a purified gamma globulin obtained by immunizing rabbits with human Basiliximab (Simulect) is an anti-CD25 monoclonal antibody. The alpha subunit of the IL-2 receptor, also known as Tac or CD25, is found exclusively on activated T cells. Blockade of this component by monoclonal antibody selectively prevents IL-2–induced T-cell activation. No lymphocyte depletion occurs with basiliximab; it is not designed to be used to treat acute rejection. Its selectivity in blocking IL-2–mediated responses makes it a powerful induction agent without the added risks of infections, malignancies, or other major side effects. Currently, basiliximab is the only available anti-CD25 monoclonal antibody approved for clinical use. Usually, it is followed by the use of calcineurin inhibitors, corticosteroids, and MMF as maintenance immunosuppression.16 Alemtuzumab (Campath), another anti-CD52 monoclonal antibody, was initially used to treat chronic lymphocytic leukemia. The use of alemtuzumab has grown in the field of transplantation, given its profound lymphocyte-depleting effects. It causes cell death by complement-mediated cytolysis, antibody-mediated cytotoxicity, and apoptosis. One dose alone (30 mg) depletes 99% of lymphocytes. Monocyte recovery can be seen at 3 months posttransplant; B-cell recovery at 12 months; and T-cell recovery, albeit only to 50% of baseline, at 36 months. Alemtuzumab causes a significant cytokine release reaction and often requires premedications (steroids and antihistamines). Because of the long-lasting T-cell depletion, the risks of infection and posttransplant lymphoproliferative disorder remain. Currently, alemtuzumab is available only through a limited distribution program, not through commercial medication distributors.17,18 MAINTENANCE Corticosteroids Corticosteroids have had a role in immunosuppression since the beginning of the field of transplantation. Despite numerous attempts to limit or discontinue their use, they remain an integral component of most immunosuppressive protocols, for both induction and maintenance. Moreover, they are often the first-line agents in the treatment of acute rejection. Steroids bind to glucocorticoid-responsive elements in DNA that prevent the transcription of cytokine genes and cytokine receptors. In addition, steroids have an impact on lymphocyte depletion, on decreases in cell-mediated immunity, and on T-cell activation of many phases of rejection. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 325 CHAPTER 11 Transplantation thymocytes. Atgam, which has largely been replaced by Thymoglobulin, is a purified gamma globulin obtained by immunizing horses with human thymocytes. These agents contain antibodies to T cells and B lymphocytes (B cells), integrins, and other adhesion molecules, thereby resulting in rapid depletion of peripheral lymphocytes. Typically, the total dose of Thymoglobulin is roughly 6 mg/kg, a dose that has been shown to confer adequate lymphocyte depletion and better allograft survival. Doses of 3 mg/kg may not effectively prevent acute rejection, but more doses and prolonged duration increase the risk of infection and the potential occurrence of lymphoma. Thymoglobulin administration causes a cytokine release syndrome, so premedications (acetaminophen and diphenhydramine) are usually given. The principal side effects of Thymoglobulin include fever, chills, arthralgias, thrombocytopenia, leukopenia, and an increased incidence of a variety of infections.14,15 Table 11-2 326 Table 11-3 Summary of the main immunosuppressive drugs PART I BASIC CONSIDERATIONS Drug Mechanism of Action Adverse Effects Clinical Uses Dosage Cyclosporine (CSA) Binds to cyclophilin Inhibits calcineurin and IL-2 synthesis Nephrotoxicity Tremor Hypertension Hirsutism Improved bioavailability of microemulsion form Oral dose 5 mg/kg per day (given in two divided doses) Tacrolimus (FK506) Binds to FKBP Inhibits calcineurin and IL-2 synthesis Nephrotoxicity Hypertension Neurotoxicity GI toxicity (nausea, diarrhea) Improved patient and graft survival in (liver) primary immunosuppression and rescue therapy Used as mainstay of maintenance protocols IV 0.015 mg/kg per day as continuous infusion PO 0.05 mg/kg per day (given every 12 h) Mycophenolate mofetil Antimetabolite Leukopenia Inhibits enzyme GI toxicity necessary for de novo purine synthesis Effective for primary immunosuppression in combination with tacrolimus 1 g bid PO Sirolimus Inhibits lymphocyte Thrombocytopenia effects driven by IL-2 Increased serum receptor cholesterol/LDL Poor wound healing May allow early withdrawal of steroids and decreased calcineurin doses 2–4 mg/d, adjusted to trough drug levels Corticosteroids Multiple actions Anti-inflammatory Inhibits lymphokine production Cushingoid state Glucose intolerance Osteoporosis Used in induction, maintenance, Varies from milligrams to and treatment of acute several grams per day rejection Maintenance doses, 5–10 mg/d Azathioprine Antimetabolite Interferes with DNA and RNA synthesis Thrombocytopenia Neutropenia Liver dysfunction Used in maintenance protocols or if intolerance to mycophenolate mofetil 1–3 mg/kg per day for maintenance Belatacept T-cell blocker Increased risk of bacterial infections New drug for maintenance immunosuppression in renal transplants only 5–10 mg/kg per day infusion FKBP = FK506-binding protein; GI = gastrointestinal; IL = interleukin; IV = intravenous; LDL = low-density lipoprotein; PO = oral Nonetheless, the numerous adverse effects of steroid therapy contribute significantly to morbidity in transplant recipients.19 Common side effects include acne, increased appetite and associated weight gain, mood changes, diabetes, hypertension, and impaired wound healing. One of the most common maintenance immunosuppressive regimens consists of triple-drug therapy: prednisone, a calcineurin inhibitor, and an antimetabolite. Large doses of steroids are usually given perioperatively and in the immediate postoperative period. Protocols vary by center, but the steroid dose is usually tapered to an adult dose of roughly 5 to 15 mg daily, or completely stopped at some point. Steroids are substrates for CYP3A4, CYP3A5, and P-glycoprotein pathways where drug interactions might need to be monitored.20,21 decreased significantly. However, it is preferred in recipients who are considering conceiving a child, because MMF is teratogenic in females and can cause birth defects. AZA might be an option for recipients who cannot tolerate the gastrointestinal (GI) side effects of MMF. The most significant side effect of AZA, often doserelated, is bone marrow suppression. Leukopenia is often reversible with dose reduction or temporary cessation of the drug. Other significant side effects include hepatotoxicity, pancreatitis, neoplasia, anemia, and pulmonary fibrosis. Its most significant drug interaction is with allopurinol, which blocks AZA’s metabolism, increasing the risk of pancytopenia. Recommendations are to not use AZA and allopurinol together, or if doing so is unavoidable, to decrease the dose of AZA by 75%.22 Azathioprine Mycophenolate Mofetil An antimetabolite, azathioprine (AZA) is converted to 6-mercaptopurine and inhibits both the de novo purine synthesis and salvage purine synthesis. AZA decreases T-lymphocyte activity and decreases antibody production. It has been used in transplant recipients for more than 40 years, but became an adjunctive agent after the introduction of cyclosporine. With the development of newer agents such as MMF, the use of AZA has Approved in May 1995 by the U.S. Food and Drug Administration (FDA) for preventing acute rejection after kidney transplants, MMF has now been incorporated into routine maintenance regimens after many solid organ transplants. Mycophenolate is the prodrug of mycophenolate acid, derived from Penicillium fungi. Mycophenolate acid is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) involved in VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ additive toxicities with other medications that might lead to leukopenia and thrombocytopenia. Sirolimus The first mammalian target of rapamycin (mTOR) inhibitors to enter clinical use was sirolimus (Rapamune). A key regulatory kinase, mTOR changes cells from the G1 to S phase in the cell cycle, in response to proliferation signals provided by cytokines like IL-2. The mTOR inhibitors bind to FK506-binding protein (FKBP), and the sirolimus-FKBP complex binds to mTOR. Sirolimus also inhibits proliferation of vascular smooth muscle cells, possibly easing the vasculopathy and progressive fibrosis that can affect allografts. Sirolimus is a substrate for CYP3A4/4 and has many significant drug interactions (see Table 11-4). To date, sirolimus has been used in a variety of combinations for maintenance immunosuppression, alone or in conjunction with one of the calcineurin inhibitors. In such combinations, sirolimus usually is used to help withdraw, or completely avoid the use of, steroids. It also has been used as an alternative to Table 11-4 Side effects and drug interactions of the main immunosuppressive drugs Common Side Effects Other Medications That Increase Blood Levels Other Medications That Decrease Blood Levels Other Medications That Potentiate Toxicity Cyclosporine (CSA) Hypertension, nephrotoxicity, hirsutism, neurotoxicity, gingival hyperplasia, hypomagnesemia, hyperkalemia Verapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juice Isoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort Nephrotoxicity: ganciclovir, aminoglycosides, NSAIDs, ACE-Is, and ARBs Tacrolimus (FK506) Hypertension, nephrotoxicity, alopecia, hyperglycemia, neurotoxicity, hypomagnesemia, hyperkalemia Verapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juice Isoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort Nephrotoxicity: ganciclovir, aminoglycosides, NSAIDs, ACE-Is, and ARBs Sirolimus Thrombocytopenia and neutropenia, elevated cholesterol, extremity edema, impaired wound healing Verapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juice Isoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort — Mycophenolate mofetil Leukopenia, thrombocytopenia, GI upset — Cholestyramine, antacids Bone marrow suppression: valganciclovir, ganciclovir, TMP-SMX Corticosteroids Hyperglycemia, osteoporosis, cataracts, myopathy, weight gain — — — Azathioprine Leukopenia, anemia, thrombocytopenia, neoplasia, hepatitis, cholestasis — — Bone marrow suppression: allopurinol, sulfonamides ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; NSAID = nonsteroidal anti-inflammatory drug; TMP-SMX = trimethoprim-sulfamethoxazole VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 327 CHAPTER 11 Transplantation the de novo pathway of purine synthesis.23 MMF is available in capsules (250 and 500 mg); the starting dose is 1 g twice daily. In hopes of decreasing the GI side effects, an entericcoated formulation called Myfortic was developed; its benefits have not been clearly demonstrated in studies, but in some conversion studies, patients did report less GI intolerance. The pharmacokinetics of MMF are complex; mycophenolic acid (MPA) levels are not routinely performed at most transplant centers. Studies have shown that MPA levels and the incidence of rejection are not significantly correlated.24 The most common side effects of MMF are GI in nature, most commonly diarrhea, nausea, dyspepsia, and bloating. Esophagitis and gastritis occur in roughly 5% of recipients and may represent a cytomegalovirus (CMV) or herpesvirus family infection. The other important side effects are leukopenia, anemia, and thrombocytopenia (Table 11-4). Leukopenia can sometimes be reversed by lowering the MMF dose and discontinuing other agents like valganciclovir. MMF does not have any significant drug interactions, but clinicians should be careful to avoid 328 PART I tacrolimus or cyclosporine, in a calcineurin-sparing protocol. One of the most significant side effects of sirolimus is hypertriglyceridemia, a condition that may be resistant to statins and fibrates. Impaired wound healing (immediately posttransplant in particular), thrombocytopenia, leukopenia, and anemia also are associated with sirolimus, and these problems are exacerbated when it is used in combination with MMF.25,26 Cyclosporine BASIC CONSIDERATIONS The introduction of cyclosporine in the early 1980s dramatically altered the field of transplantation by significantly improving outcomes after kidney transplantation. Cyclosporine binds with its cytoplasmic receptor protein, cyclophilin, which subsequently inhibits the activity of calcineurin, thereby decreasing the expression of several critical T-cell activation genes, the most important being for IL-2. As a result, T-cell activation is suppressed.27 Many formulations of cyclosporine exist, so it is important to know which one the transplant recipient is taking. Sandimmune, an older, oil-based formulation, has poor bioavailability and variable absorption. The newer formulations, Gengraf and Neoral, are microemulsified with improved bioavailability. Cyclosporine can be given intravenously or orally to maintain trough levels of 250 to 350 ng/mL for the first 3 months posttransplant; then it can be tapered to 150 to 250 ng/mL.28 The metabolism of cyclosporine is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4). Calcineurin inhibitors are nephrotoxic and constrict the afferent arteriole in a dose-dependent, reversible manner (Table 11-5). They also can cause hyperkalemia and hypomagnesemia. Several neurologic complications, including headaches, tremor, and seizures, also have been reported.29 Cyclosporine has several undesirable cosmetic effects, including hirsutism and gingival hyperplasia. It is associated with a higher incidence of hypertension and hyperlipidemia than is tacrolimus. Tacrolimus The calcineurin inhibitor tacrolimus (Prograf) is now the backbone of most immunosuppressive regimens. Tacrolimus Table 11-5 Drug interactions and side effects associated with calcineurin inhibitors Interactions Medications Inhibition of metabolism Clarithromycin, erythromycin, azole antifungals, diltiazem, verapamil, nicardipine, amiodarone, grapefruit juice, ritonavir, azithromycin Induction of metabolism Nevirapine, rifampin, St. John’s wort, carbamazepine, phenobarbital, phenytoin, caspofungin Hyperkalemia Potassium-sparing diuretics, angiotensinconverting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), β-blockers, trimethoprim-sulfamethoxazole Nephrotoxicity Nonsteroidal anti-inflammatory drugs, aminoglycosides, amphotericin, ACE-Is, ARBs acts by binding FKBPs, causing roughly 10 to 100 times more potent inhibition of IL-2 production than cyclosporine (which acts by binding cyclophilins). It can be given intravenously, orally, or sublingually to maintain trough levels of 8 to 12 ng/mL for the first 3 months posttransplant; then it can be tapered to 6 to 10 ng/mL. The metabolism of tacrolimus is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4). Tacrolimus causes a higher incidence of new-onset diabetes posttransplant than does cyclosporine. Other side effects include alopecia, nephrotoxicity, neurotoxicity, hypertension, hyperkalemia, hypomagnesemia, and an increased incidence of certain types of infection.30 Belatacept The best-characterized pathway of T-cell costimulation includes CD28; its homologue, the cytotoxic T-lymphocyte–associated protein 4 (CTLA4); and their ligands, CD80 and CD86. Belatacept (also known as LEA29Y) was developed through two amino acid substitutions to abatacept (also known as CTLA4-Ig), a fusion protein consisting of the extracellular domain of CTLA4 and the Fc domain of immunoglobulin G (IgG). It is a highavidity molecule with slower dissociation rates. Recent trials have compared the use of belatacept vs. a standard cyclosporine protocol in recipients of living donor, deceased donor, and extended-criteria donor kidneys. Belatacept was not inferior to cyclosporine in both patient and allograft survival rates, but was associated with a higher rate of biopsyproven acute cellular rejection. In terms of adverse effects, belatacept differs from standard calcineurin-based regimens because of an increased risk of posttransplant lymphoproliferative disorder (PTLD); the greatest risk is in recipients who are Epstein-Barr virus (EBV)seronegative pretransplant. The FDA recommends the use of belatacept only in seropositive recipients. Studies in liver transplant recipients were halted early because of increased mortality rates. However, belatacept does have a lower incidence of cardiovascular risk factors including metabolic lipid disorders, hypertension, neurotoxicity, glucose abnormalities, and adverse cosmetic effects. Except for the increased risk of malignancy, the more favorable adverse effect profile of belatacept and its convenient monthly dosing schedule may make it an attractive option for maintenance of immunosuppression, possibly improving compliance.31,32 HUMORAL REJECTION Rituximab A chimeric anti-CD20 (anti-B cell) monoclonal antibody, rituximab is currently FDA approved for treating lymphoma. The CD20 antigen is expressed early in the B-cell cycle but is absent on mature plasma cells. The variable region binds to CD20 through three different mechanisms: (a) antibodydependent cell cytotoxicity, (b) complement-dependent cell killing, and (c) induction of apoptotic cell death. The use of rituximab has grown to include the treatment of antibody-mediated rejection and use in desensitization protocols. Studies so far have been small, with rituximab usually used in conjunction with plasmapheresis, steroids, and intravenous immunoglobulin (IVIG).33-35 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Bortezomib Eculizumab A humanized monoclonal antibody with high affinity for C5, eculizumab is a first-in-class, FDA-approved agent for treating paroxysmal nocturnal hemoglobinuria and hemolytic uremic syndrome. It blocks the activation of the terminal complement cascade. Most antibody-mediated rejection episodes are associated with early complement activation as evidenced on renal transplant biopsies by the presence of C4d+ staining of the peritubular capillaries. Given its highly selective mechanism of action, this agent is predicted to be useful to treat antibodymediated rejection and to desensitize patients pretransplant. However, its serious adverse effects include an increased risk of infections, especially due to encapsulated bacteria such as Neisseria meningitidis. Patients should be immunized with meningococcal vaccine at least 2 weeks before the administration of eculizumab.34,38,39 INFECTIONS AND MALIGNANCIES Advances in immunosuppression have led to improved graft survival rates. However, the growing population of immunosuppressed patients, in turn, has led to an increased incidence of opportunistic infections and malignancies. Such posttransplant complications have become important barriers to long-term disease-free survival. Infections Transplant recipients are predisposed to a variety of infections. Immunosuppression is the obvious reason. Moreover, such patients have already endured end-stage organ disease pretransplant and then the stress of an invasive transplant operation. Posttransplant, they continue to have significant comorbid conditions. Early. Early infections (i.e., infections occurring within 1 month posttransplant) can be due to a wide spectrum of pathogens (bacterial, viral, and fungal). In the immediate postoperative period, recipients are significantly compromised from the stress of the operation, from induction immunosuppression, and often from initially impaired graft function. Infections during this period can be devastating. It is imperative to differentiate between medical and surgical infections. Surgical infections are the most common and require expedient surgical intervention. Typical examples include generalized peritonitis, intra-abdominal abscesses, and wound infections. In liver and pancreas recipients, surgical infections are most severe. The incidence of intra-abdominal infections is decreasing, but they remain a significant problem: they are the second most common reason (after vascular thrombosis) for graft loss in pancreas recipients. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 329 CHAPTER 11 Transplantation A proteasome inhibitor, bortezomib is FDA approved for treating multiple myeloma. It can directly target plasma cells. Traditional treatments have been successful in removing antibodies, inhibiting antibody activity, or lowering antibody production; however, targeting mature antibody production in plasma cells has not met with success. Bortezomib has been shown to cause apoptosis of normal plasma cells, thereby decreasing alloantibody production in sensitized patients. Several case reports and series have described the use of bortezomib for the treatment of antibodymediated rejection and in desensitization protocols.34,36,37 Lengthy operations with significant blood loss, prolonged warm and cold ischemic times, and spillage of contaminated fluid (bile, urine, or bowel contents) predispose patients to intrainfections. Other prominent risk factors are the 3 abdominal high level of induction immunosuppression immediately posttransplant and anastomotic leaks. Furthermore, pretransplant infections can re-emerge or worsen. The signs and symptoms of intra-abdominal infections are those of peritonitis: fever, hypotension, ileus, and abdominal pain, although the latter can be masked by immunosuppression. Treatment entails a prompt return to the operating room. Intra-abdominal infections are usually polymicrobial, involving several bacterial and fungal species. Common bacterial isolates include Escherichia coli, as well as Enterococcus, Klebsiella, and Pseudomonas species. Common fungal isolates are Candida albicans, Candida krusei, and Candida glabrata. Localized infections or abscesses can be treated with percutaneous drainage and antibiotics. Medical infections include respiratory, urinary tract, and bloodstream infections. Medical treatment should also be aggressive, often including empiric antibiotics and antifungal medications even before culture results are available. Recipients of organs from infected donors should be treated per the results of donor culture speciation and the antibiotic sensitivity profile. Late. Late infections primarily are due to chronic immunosuppression, specifically the depression of cell-mediated immunity that renders recipients susceptible to viruses, fungi, and parasites. Members of the herpesvirus group are the most common etiologic agents of viral infections posttransplantation, with herpes simplex virus (HSV), CMV, and EBV being the most prominent. Pretransplant exposure to viruses may confer immunity. Recipients who are seronegative for HSV, CMV, and/or EBV have a higher incidence of posttransplant infections, especially if they receive donor allografts from seropositive donors. CMV is a latent infection that can be transmitted to seronaive recipients by donor organs from seropositive individuals, can reactivate during immunosuppression, or both. Infections usually occur 3 to 6 months posttransplant or during treatment for rejection. The incidence of CMV has been greatly reduced with 12-week acyclovir prophylaxis.40 CMV infections range from an asymptomatic or mild flu-like syndrome to tissue-invasive disease resulting in pneumonitis, hepatitis, and GI ulcerations. Symptomatic infections and all tissue-invasive CMV disease should be treated with intravenous (IV) ganciclovir, a reduction in immunosuppression, or both, although successful treatment of mild to moderate rejection and concurrent mild to moderate CMV disease has been described. EBV infections range from a mild mononucleosis syndrome to severe hepatitis and highly morbid PTLD. PTLD ranges from a localized tumor to a progressive, diffuse infiltration of various organs including the brain. It results from the proliferation of EBV-positive B cells in immunosuppressed patients. The main risk factors are a high degree of immunosuppression and a predisposing EBV serostatus (seronaive recipient, seropositive donor). Among patients with early lesions, the first line of treatment is to reduce immunosuppression. For those with more advanced PTLD, rituximab is used. After 6 months posttransplant, the risk of invasive fungal infections is closely associated with environmental exposures. Blastomyces dermatitidis grows in moist soil in the Midwest and Southeast regions of the United States. Diagnosis is confirmed by biopsy; the preferred treatment is IV amphotericin B. 330 PART I BASIC CONSIDERATIONS Coccidioides immitis can cause invasive coccidioidomycosis after inhalation of aerosolized infectious particles. It is endemic in the Southwest, Northern Mexico, and various parts of Central and South America. This infection can be resilient and difficult to treat. The first line of treatment is high-dose amphotericin B. Histoplasma capsulatum is found in chicken and bat droppings in the Ohio River and Mississippi River valleys. Dissemination is commonplace; up to a quarter of patients have central nervous system (CNS) involvement. Treatment consists of prolonged (3 to 13 months) administration of oral itraconazole. Opportunistic infections with Aspergillus, Cryptococcus, Mucor, and Rhizopus species are rare but can cause serious infections. Patients with invasive Candida or Aspergillus infections have a 20% mortality rate. Prophylaxis with fluconazole has been shown to reduce invasive fungal infections in liver recipients.41 Pneumocystis jiroveci (also known as PCP) is ubiquitous and can cause pulmonary disease in immunocompromised patients. However, trimethoprim-sulfamethoxazole (TMPSMX) is effective prophylaxis against PCP, and daily, lifelong administration has virtually eliminated this infection among transplant recipients. Malignancies Chronic immunosuppression increases the risk of developing certain types of malignancies. The most extensive data, from a cohort study involving more than 175,000 solid organ transplant recipients, showed that 10,656 of them developed malignancies. The standardized incidence ratio was 2.10 (as compared with the general population). Recipients had at least a fivefold increase (as compared with the general population) in these types of malignancies: Kaposi’s sarcoma, nonmelanoma skin cancer, non-Hodgkin’s lymphoma, and cancer of the liver, anus, vulva, and lip. In addition, recipients had a statistically significant increase (as compared with the general population) in melanoma, Hodgkin’s lymphoma, and cancer of the lung, kidney, colon, rectum, and pancreas.42 ORGAN PROCUREMENT AND PRESERVATION Organ procurement is a key element in organ transplantation. Currently, 58 organ procurement organizations (OPOs) exist in the United States, all members of the Organ Procurement and Transplantation Network (OPTN), which is a federally mandated network created by and overseen by UNOS. Each OPO is responsible for evaluating and procuring deceased donor organs for transplantation in a specific geographic region. Hospitals receiving any type of federal reimbursement for their services (whether transplant-related or not) are required to report all deaths to their OPO in a timely manner. Each OPO then determines the medical suitability of the deceased for organ donation; requests consent for donation from family members; if consent is given, contacts the OPTN to analyze and identify potential recipients whose HLA antigens most closely match those of the donor; and arranges for the recovery and transport of any donated organs. Strategies to increase organ donation and utilization have been successfully implemented in the last 10 years. The nationwide “Organ Donation Breakthrough Collaborative,” sponsored by the U.S. Department of Health and Human Services in 2003, brought the OPOs and transplant communities into a single concerted program to develop best practices guidelines. However, a severe donor shortage remains. The number of living organ donors peaked in 2007 and has declined since. Alternative options include tissue engineering and stem cell research, but those fields are in their infancy in terms of producing fully functional and vascularized human organs. With the development of genetic knockout pigs, xenotransplantation still shows promise, but two problems in particular—immunologic barriers and xenosis (also known as zoonosis) of endogenous porcine retroviruses—have yet to be satisfactorily addressed. Today, the gap between patients waiting for organ transplants and the number of organs available continues to widen. More than 110,000 patients are on the waiting list for solid organ transplants, but only 28,456 transplants were performed in 2011. Deceased Donors Most transplants today utilize organs from deceased donors. Formerly, death was determined by the cessation of both cardiac and respiratory function. Donation after Brain Death. In 1968, the concept of “irreversible coma” was introduced by an ad hoc committee report at Harvard Medical School; that concept was pivotal to the final acceptance, in 1981, of “brain death” as a legal definition in the United States. The legal language states that the declaration of brain death should be in accordance with acceptable medical standards, but does not specify clinical methodology. It is customary for hospitals to establish their own policies to declare brain death, according to their standards of care and local regulations. Typically, brain death is defined as the irreversible cessation of brain function, including the brainstem. The presence of medical conditions that mimic brain death—such as drug overdose, medication side effects, severe hypothermia, hypoglycemia, induced coma, and chronic vegetative state—need to be excluded. The latest evidence-based guideline on determining brain death in adults reaffirmed the validity of current clinical practice.43 Briefly, the clinical diagnosis of brain death consists of four essential steps: (a) establishment of the proximate cause of the neurologic insult; (b) clinical examinations to determine coma, absence of brainstem reflexes, and apnea; (c) utilization of ancillary tests, such as electroencephalography (EEG), cerebral angiography, or nuclear scans, in patients who do not meet clinical criteria; and (d) appropriate documentation. A similar guideline on determining brain death in pediatric patients was recently developed.44 Once the diagnosis of brain death has been established, the local OPO assumes the care of the potential donor and initiates the process of donor evaluation and organ donation, and the potential donor is screened for contraindications to donation. The medical history and social history are obtained from the available family members. A battery of tests, including serologic or molecular detection of human immunodeficiency virus (HIV) and viral hepatitis, are performed. The exact medical conditions that preclude donation vary; nonetheless, in the United States, infections and other medical conditions that determine eligibility are dictated by UNOS bylaws and routinely reviewed and updated. The OPO focuses on preserving organ function and optimizing peripheral oxygen delivery until organ procurement commences.45 In all deceased donors, core temperature, systemic arterial blood pressure, arterial oxygen saturation, and urine output must be determined routinely and frequently. Arterial blood gases, serum electrolytes, blood urea nitrogen, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ preserved. Lateral to the SMA is the inferior mesenteric vein (IMV), which can be cannulated for portal flushing. Dissection of the hepatic hilum and the pancreas should be limited to the common hepatic artery (CHA), and branches of the CHA (e.g., splenic, left gastric, and gastroduodenal arteries) are exposed. The gastrohepatic ligament is carefully examined to preserve a large anomalous or replaced left hepatic artery, if present. The supraceliac aorta can be exposed by dividing the left triangular ligament of the liver and the gastrohepatic ligament. The common bile duct is transected at the superior margin of the head of the pancreas. The gallbladder is incised and flushed with ice-cold saline to clear the bile and sludge. If the pancreas is to be procured, the duodenum is flushed with antimicrobial solution. Before the cannulation of the distal aorta, systemic heparinization (300 units/kg) is administered. The supraceliac aorta is clamped; cold preservation fluid is infused via the aortic (systemic) and IMV (portal) cannulas. The thoracic organs, liver, pancreas, and kidneys are then removed. Donation after Cardiac Death. Given the severe shortage of donor organs, donation after cardiac death (DCD)—also known as donation by non–heart-beating donors (NHBDs)—was reintroduced to the transplant community in the 1990s.51 The category of DCD (Maastricht classification) was initially proposed at an international workshop and is now widely adopted for organ procurement.52 Currently, most NHBDs in the United States meet Maastricht classification III; that is, they have suffered a devastating injury with no chance of a meaningful recovery but do not meet the criteria for brain death. After consent for donation is obtained from the next of kin, the donor’s life support is removed. After the cessation of cardiac and respiratory function, organ procurement commences. DCD procurement protocols vary between states; religious and cultural differences need to be taken into consideration. The surgical team must be familiar with, and respect, the local protocol. With cardiac death (as opposed to brain death), warm ischemic injury to organs can occur during the period between circulatory cessation and rapid core cooling through perfusion of preservation solution. However, the difference in long-term outcomes is negligible for recipients of organs from either type of donor. Still, a significant percentage of liver grafts procured after cardiac death, especially those with more than 25 minutes of warm ischemic time, develop devastating ischemic cholangiopathy and fail.53 A new development to minimize ischemic injury to organs procured after cardiac death has been the application of extracorporeal membrane oxygenation (ECMO). With ECMO, DCD differs in two key ways: (a) cannulation occurs before withdrawal of life support and (b) organs are perfused via ECMO with warm oxygenated blood after declaration of cardiac death. The initial experience with organs procured using ECMO has been encouraging. Surgical Technique. Surgeons who perform multiple organ Figure 11-3. Exposure for thoracic and abdominal organ procurement. retrieval should be familiar and experienced with the superrapid technique described by the Pittsburgh group.54 Preferably, NHBDs undergo withdrawal of life support in the operating room after the surgical site is prepped and draped, as soon as the surgical team is ready. Alternatively, the NHBD is transported to the operating room after declaration of cardiac death. A midline incision is used to rapidly gain entry into the abdominal cavity. An assistant retracts the small bowel and the sigmoid colon laterally, so that the bifurcation of the aorta can VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 331 CHAPTER 11 Transplantation serum creatinine, liver enzyme, hemoglobin, and coagulation tests need to be monitored regularly. In all brain-dead donors, elevated intracranial pressure triggers a compensatory catecholamine response to maintain cerebral profusion pressure. Ischemic injury to the spinal cord and the sympathetic system may lead to a profound vasodilation. As a result, brain-dead donors frequently have severe hemodynamic and metabolic derangements, so aggressive monitoring and intervention are required to prevent loss of precious organs. Previous studies of deceased donor care focused on organspecific resuscitation protocols that resulted in only marginal gains in the number of organs transplanted. The latest developments center on multisystem protocols to increase the number of organs transplanted per donor (OTPD).46,47 The goals are to maintain a core temperature between 36.0 and 37.5°C, a mean arterial pressure >70 mmHg or a systolic pressure >100 mmHg, and a hemoglobin level between 7 and 10 g/dL; hormonal therapy and aggressive treatment of arrhythmias and metabolic derangements are also called for.47 Surgical Technique. Procurement of multiple organs (heart, lungs, kidney, liver, pancreas, and/or small bowel), or multivisceral procurement, was first described by the Pittsburgh group in 1987.48 Since then, most centers have incorporated changes, especially with regard to the timing and location of dissection and flushing.49,50 The basic steps involve a long incision to provide wide exposure of all thoracic and abdominal organs (Fig. 11-3). A Cattell-Braasch maneuver (complete mobilization of the distal small bowel, right colon, and duodenum) is performed to allow for identification of the distal aorta, iliac bifurcation, and distal inferior vena cava (IVC). The infrarenal aorta is the site for inserting the cannula that will allow for flushing of the organs with cold preservation solution. Sometimes, division of the inferior mesenteric artery is necessary to facilitate the exposure of the distal aorta. The third portion of the duodenum is retracted cephalad to expose the root of the superior mesenteric artery (SMA). Limited dissection is performed at the root of the SMA, which is encircled with a vessel loop to enable its temporary occlusion at the time of flushing, thus reducing the incidence of overperfusion injury to the pancreas. A large anomalous or replaced right hepatic artery typically rises from the SMA, and this should be identified and 332 PART I BASIC CONSIDERATIONS be easily identified on the left side of the vertebral column. A short segment of the distal aorta is dissected out from the retroperitoneum. A moist umbilical tape is passed around the aorta, which is used to secure a cannula. The distal aorta is clamped. Next, a cannula is passed cephalad through an aortotomy and secured. Flushing with cold preservation solution is started at once, followed by cross-clamping the aorta proximally (thoracic aorta) and venting through the vena cava. The portal flush is then instituted. The rest of the procedure is similar to procurement after brain death, with two noticeable differences. First, to avoid injury to a large anomalous or replaced left hepatic artery, the gastrohepatic ligament and the left gastric artery are separated from the stomach at the lesser curvature. Second, to avoid injury to a large anomalous or replaced right hepatic artery, the SMA is examined before it is divided. If the pancreas is not procured, a common aortic patch encompassing both the SMA and the celiac artery can be procured with the liver. Living Donors The maxim of medical ethics is “primum non nocere” (above all, do no harm), and for that reason, living organ donation presents unique ethical and legal challenges. Performing potentially harmful operations to remove organs from healthy individuals seems, at first glance, to contradict that maxim. But in fact, the ethical framework of living organ donation rests on three guiding principles respected in all discussions of medical practice: beneficence to the recipient, nonmaleficence to the donor, and the donor’s right to autonomy.55 In order to achieve optimal outcomes (the common good), transplant professionals should focus on maximizing the benefits for the recipient and minimizing the damage to the donor. The Uniform Anatomical Gift Act adopted by all states in the United States (with slight variations) provides the legal framework for competent adult living donors to decide whether or not to donate. It is the fiduciary duty of transplant professionals to explain the risks of organ donation. Any decision to donate should be uncoerced, and no enticements should be offered. The use of living donors offers numerous advantages for recipients in need. First and foremost is the availability of lifesaving organs for those who would otherwise succumb to the progression of their end-stage disease. In certain parts of the world, such as East Asia, the concept of brain death and the use of deceased donors conflict with the prevailing culture or religion. Even in countries where the use of deceased donors is accepted, the use of living donors may significantly shorten the waiting time for recipients. A shorter waiting time generally implies a healthier recipient—one whose body has not been ravaged by prolonged end-stage organ failure. Moreover, with the use of living donors, transplants are planned (rather than emergency) procedures, allowing for better preoperative preparation of the recipient. Receiving an organ from a closely matched relative may also have immunologic benefits. And long-term results may be superior with the use of living donors, as is certainly the case with kidney transplants. The major disadvantage is the risk to the living donor. Medically, there is no possibility of benefit to the donor, only the potential for harm. The risk of death associated with donation depends on the organ being removed. For a nephrectomy, the estimated mortality risk is less than 0.05%; for a partial hepatectomy, about 0.2%. The risk of surgical and medical complications also depends on the procedure being performed. In addition, long-term complications may be associated with a partial loss of organ function after donation. The guiding principle should be minimization of risk to the donor. All potential risks must be carefully explained to the potential donor, and written informed consent must be obtained.56 Surgical Technique. The kidney, the first organ to be transplanted from living donors, is still the most common organ donated by these individuals. The donor’s left kidney is usually preferable because of the long vascular pedicle. Use of living donor kidneys with multiple renal arteries should be avoided, in order to decrease the complexity of the vascular reconstruction and to help avoid graft thrombosis. Most donor nephrectomies are now performed via minimally invasive techniques, that is, laparoscopically, whether hand-assisted or not. With laparoscopic techniques, an intraperitoneal approach is most common: it involves mobilizing the colon, isolating the ureter and renal vessels, mobilizing the kidney, dividing the renal vessels and the distal ureter[C6], and removing the kidney (Fig. 11-4). Extensive dissection around the ureter should be avoided, and the surgeon should strive to preserve as much length of the renal artery and vein as possible. Liver transplants with living donors are not as commonly performed, given the significantly higher rates of donor mortality and morbidity. Initially, only adult donors for pediatric recipients were selected, but now, living donor liver transplants also involve adult donors for adult recipients. In dual graft living donor liver transplants, segmental grafts from two living donors augment the recipient’s graft size.57 The donor hepatectomy is similar to a major lobar hepatectomy, except that it is important to preserve the integrity of the vascular structure until graft resection (Fig. 11-5). Living donor transplants of organs other than the kidney and liver are fairly uncommon, but certain centers do perform such transplants. Living donor pancreas transplants involve performing a distal pancreatectomy, with the graft consisting of the body and tail of the pancreas; vascular inflow and outflow are provided by the splenic artery and splenic vein. Living donor intestinal transplants usually involve removal of about 200 cm of the donor’s ileum, with inflow and outflow provided by the ileocolic vessels. Living donor lung transplants involve removal of one lobe of one lung from each of two donors; both grafts are then transplanted into the recipient. Organ Preservation The development and continuing refinement of organ preservation methods have completely revolutionized the transplant field. Extending the time that organs can be safely stored after procurement has enabled better organ utilization and better recipient outcomes.58,59 Hypothermia and pharmacologic inhibition are the two most frequent methods. Both slow—yet cannot completely shut down—the removed organ’s metabolic activity, so both have adverse effects, such as cellular swelling and degradation. Cold storage solutions were introduced to mitigate some of the adverse effects of hypothermia or pharmacologic inhibition alone. Such solutions help prevent cellular swelling and the loss of cellular potassium. One, and perhaps the most effective, preservation solution was developed at the University of Wisconsin and remains in wide use.60 Its ingredients include lactobionate (which helps prevent cellular swelling and reperfusion injury), raffinose, and hydroxyethyl starch (which helps reduce swelling of endothelial VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 333 B C D E F CHAPTER 11 Transplantation A Figure 11-4. Laparoscopic left donor nephroureterectomy. A. Takedown of splenic flexure of colon to expose the left renal hilum. B. Dissection of left ureter off the psoas muscle. C. Dissection of left renal vein and gonadal vein. Left ureter seen lateral to the dissection. D. Dissection of left renal artery. Lumbar veins clipped and divided. E. Endo-TA stapler transection of the left renal artery. F. Placement of ports and Pfannenstiel incision for the donor kidney extraction. A B Figure 11-5. Donor hepatectomy (right hepatectomy). A. The liver parenchymal transection line (c, the Cantlie line) marked with cautery. Right portal vein (p) and right hepatic artery (a) isolated. b = bile duct. Cystic duct was cannulated for intraoperative cholangiography. B. Exposure of hepatic veins after transection of the parenchyma. IVC = inferior vena cava; L = left hepatic vein; M = middle hepatic vein; R = right hepatic vein VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 334 PART I BASIC CONSIDERATIONS cells, thereby decreasing edema). Histidine-tryptophanketoglutarate solution is also currently in wide use.61 Despite enhancements in preservation methods, the amount of time that an organ can be safely stored remains relatively short (hours, not days), particularly with organs from marginal donors. Among kidney recipients, delayed graft function becomes significantly more frequent after cold ischemic times of more than 24 hours, necessitating temporary dialysis, which is associated with increased risks of graft loss and higher costs.62 Among liver recipients, primary nonfunction and biliary complications ensue after prolonged cold ischemic times. In the case of heart and lung recipients, ischemic times should be under 6 hours. All of those times assume the use of normal donors. There is revived interest in the use of the pulsatile perfusion pump, a kidney graft preservation method that has been available for more than 40 years.63 With the increasing shortage of available donor organs and the rise in the use of organs after cardiac death, the pulsatile perfusion pump is garnering renewed enthusiasm as an adjunct method of preservation, even for donor organs other than kidneys.64,65 KIDNEY TRANSPLANTATION Introduction Ullman reported the first attempted human kidney transplant in 1902.66 For the next 50 years, sporadic attempts all ended in either technical failure or in graft failure from rejection. Joseph Murray performed the first successful kidney transplant in 1954, an epochal event in the history of organ transplantation. In that first case, the immunologic barrier was circumvented by transplanting a kidney between identical twins.67 For his pivotal contribution, Murray shared the Nobel Prize in Physiology or Medicine in 1990 with E. Donnall Thomas for their discoveries concerning “organ and cell transplantation in the treatment of human disease.” The introduction of AZA (Imuran) in 1960 marked the beginning of a new era in kidney transplantation. With the combination of steroids and AZA for maintenance immunosuppression, the 1-year graft survival rate with a living related donor kidney approached 80%; with a deceased donor kidney, the rate was 65%.68 In the ensuing years, major milestones included the introduction of more effective immunosuppressive medications with lower toxicity profiles, such as polyclonal antilymphocyte globulin in the 1970s, cyclosporine in the 1980s, tacrolimus in the 1990s, and biologics in the first decade of the twenty-first century, as previously mentioned. Parallel to the developments in medical science were the transplant community’s concerted efforts to improve use of healthcare resources. In the United States, the Social Security amendments of 1972 provided Medicare coverage for patients with end-stage renal disease (ESRD). The National Organ Transplant Act of 1984 initiated the process of creating what later became UNOS, an umbrella organization to ensure access to organs by patients in need, to enhance organ procurement and allocation, and to improve posttransplant outcomes. This infrastructure later became the blueprint for other countries to follow. As a result, organ transplantation is the most transparent field of medicine. Data such as transplant center performance are readily available on public websites; penalties for violation of regulations and for underperformance often result in transplant programs being shut down. Today, a kidney transplant remains the most definitive and durable renal replacement therapy for patients with ESRD. It offers better survival and improved quality of life and is considerably more cost-effective than dialysis.69,70 According 4 to the 2010 Scientific Registry of Transplant Recipients (SRTR) annual report, a total of 84,614 adult patients were on the kidney transplant waiting list, including 33,215 added just that year.71 Yet in 2009, only 15,964 adult kidney transplants were performed in the United States (9912 with a deceased donor and 6052 with a living donor). Of note, the number of patients added to the kidney transplant waiting list has increased every year, but the number of kidney transplants performed has been declining since 2006. On the positive side, posttransplant outcomes have continued to improve: in 2009, the 1-year graft survival rate with a living donor kidney was 96.5%; with a deceased donor kidney, the rate was 92.0%. The advantages of a living donor kidney transplant include better posttransplant outcomes, avoidance of prolonged waiting time and dialysis, and the ability to coordinate the donor and recipient procedures in a timely fashion. Living donor kidney recipients enjoy better long-term outcomes, a low incidence of delayed graft function, and reduced risks of posttransplant complications. Furthermore, the elective nature of living donor kidney transplants provides unique opportunities for recipient desensitization treatment if the donor and recipient are ABOincompatible or if the HLA cross-match results are positive. Some of the challenges transplant professionals face today are closing the growing gap between supply and demand and thereby reducing the current prolonged waiting times; refining immunosuppressive medications to achieve better outcomes with reduced toxicity; and caring for patients who develop rejection, especially antibody-mediated rejection. Pretransplant Evaluation Active infection or the presence of a malignancy, active substance abuse, and poorly controlled psychiatric illness are the few absolute contraindications to a kidney transplant. Studies have demonstrated the overwhelming benefits of kidney transplants in terms of patient survival, quality of life, and cost-effectiveness, so most patients with ESRD are referred for consideration of a kidney transplant. However, to achieve optimal transplant outcomes, the many risks (such as the surgical stress to the cardiovascular system, the development of infections or malignancies with long-term immunosuppression, and the psychosocial and financial impacts on compliance) must be carefully balanced. Any problems detected during the evaluation of transplant candidates are communicated to their referring physician and/or to a specialist if advanced evaluation and treatment are needed, ultimately improving overall care. Essentially, the pretransplant evaluation is a multifaceted approach to patient education and disease management. Before the pretransplant medical evaluation begins, kidney transplant candidates are encouraged to attend a group meeting focused on patient education. The meeting is coordinated by a transplant physician or surgeon. The intent is to familiarize patients with the pretransplant evaluation process and with pertinent medical concepts and terms. In an open forum format, important decisions such as type of donor (living vs. deceased) are discussed. The group meeting empowers patients to fully participate in their care and serves as an impetus for a meaningful dialogue with healthcare professionals. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Medical Evaluation Malignancies. Because of the long-term use of immunosuppressive medications, transplant recipients are at increased risk for development of malignancies. Untreated and/or active malignancies are absolute contraindications to a transplant (with two exceptions: nonmelanocytic skin cancer and incidental renal cell cancer identified at the time of concurrent nephrectomy [i.e., for polycystic kidney disease] and renal transplantation). For most patients who have undergone treatment of low-grade tumors with a low risk of recurrence (e.g., completely locally excised low-grade squamous cell cancer of the skin, colon cancer in a polyp absent stalk invasion), a wait of at least 2 years after successful treatment is recommended before a kidney transplant can be considered. However, for certain types of tumors, especially at advanced stages or those with a high risk of recurrence (e.g., melanoma, lymphoma, renal cell cancer, breast cancer, colon cancer), a delay of at least 5 years is advisable. According to the Israel Penn International Transplant Tumor Registry, tumor recurrence posttransplant is not infrequent: the recurrence rate is 67% in patients with multiple myeloma, 53% in nonmelanocytic skin cancer, 29% in bladder cancer, and 23% in breast cancer.75 Infections. A thorough history of infections and immunizations should be obtained from transplant candidates, who need all recommended age-appropriate vaccinations according to the Centers for Disease Control and Prevention (CDC) guidelines. Ideally, vaccinations should be completed at least 4 to 6 weeks before the kidney transplant takes place. Immunosuppressive medications blunt the immune response and reduce the effectiveness of vaccinations; even more important, with attenuated vaccines, vaccine-derived infections could occur. If a splenectomy is anticipated (e.g., in recipients whose donor is ABOincompatible or whose HLA cross-match results are positive), Kidney Disease. The third most common cause of graft loss in kidney transplant recipients is recurrence of glomerular diseases such as focal segmental glomerulosclerosis (FSGS), immunoglobulin A (IgA) nephropathy, hemolytic uremic syndrome, systemic lupus erythematosus, and membranoproliferative glomerulonephritis. FSGS deserves special mention for its frequent occurrence and dramatic presentation of early graft loss. An estimated 30% to 40% of FSGS patients develop recurrent disease posttransplant; of those, up to half eventually VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 335 CHAPTER 11 Transplantation Cardiovascular Disease. Diabetes and hypertension are the leading causes of chronic renal disease. Concomitant cardiovascular disease (CVD) is a common finding in this population. An estimated 30% to 42% of deaths with a functioning kidney graft are due to CVD.72,73 Therefore, assessment of the potential kidney transplant candidate’s cardiovascular status is an important part of the pretransplant evaluation. In fact, the American Heart Association and the American College of Cardiology Foundation recently published their expert consensus on CVD evaluation and management for solid organ transplant candidates.74 The process should focus on careful screening for the presence of significant cardiac conditions (e.g., angina, valvular disease, and arrhythmias) and for a prior history of congestive heart failure, coronary interventions, or valvular surgery. The perioperative risk assessment is based on patient symptoms and exercise tolerance. For all kidney transplant candidates, a resting 12-lead electrocardiogram (ECG) should be obtained. In addition, in this population, the use of echocardiography to analyze left ventricular function and to assess for pulmonary hypertension is useful. Stress testing may be considered in patients with no active cardiac condition but with risk factors such as diabetes, hemodialysis for more than 1 year, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia. The utility of noninvasive stress testing (as compared with angiographic studies) for evaluating coronary artery disease is controversial; an additional prognostic marker is the troponin T (cTnT) level. then they should be immunized against encapsulated organisms (such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) well in advance of the splenectomy. Transplant candidates should undergo routine tuberculosis (TB) screening. According to the latest CDC report, in 2011, 3929 TB cases were diagnosed in persons born in the United States and 6546 were diagnosed in foreign-born persons.76 Serologic screening combined with a chest roentgenogram for fungal infections such as coccidioidomycosis or histoplasmosis, in patients who either have a history of those infections or are from an endemic area, are recommended. Chronic infections such as osteomyelitis or endocarditis must be fully treated; a suitable waiting period after successful treatment must occur, in order to ensure that relapse does not occur. Hepatitis can be caused by five different type of viruses, hepatitis virus A, B, C, D, and E, with the first three being the most common. Acute viral hepatitis is a contraindication to a kidney transplant; however, chronic viral hepatitis (most commonly caused by hepatitis B [HBV] or C [HCV]) does not preclude a recipient from undergoing a kidney transplant. In such candidates, obtaining a liver biopsy is essential to assess the disease severity. Recipients infected with HBV should undergo antiviral treatment (e.g., lamivudine) to prevent reactivation and progression of liver disease. Note that HBV is a noncytopathic virus; the liver damage is the result of an immune-mediated process.77 Moreover, the presence of normal liver enzymes in patients with HBV antigenemia does not predict the severity of parenchymal damage. Transplant candidates with chronic HCV infection often have HCV-related glomerulonephritis. As with HBV infection, the clinical presentation and biochemical findings with HCV infection are often unreliable in predicting liver damage. In patients with evidence of cirrhosis, a combined liver-kidney transplant should be considered. In appropriate candidates, pretransplant antiviral treatment with interferon-α may be considered. However, after a kidney transplant, interferon treatment is not recommended, because it may precipitate graft rejection. Thanks to the excellent outcomes of highly active antiretroviral therapy (HAART), infection with HIV is no longer considered a contraindication to a kidney transplant. Kidney transplant candidates with HIV must have an undetectable HIV viral load and a CD4 lymphocyte count greater than 200/mm3; in addition, they must not have had any opportunistic infection in the previous year.78 Latent viral infections such as CMV and EBV are of particular interest, given the risks of reactivation posttransplant and the detrimental effects on graft and patient survival. Knowing the serologic status of CMV and EBV infections helps transplant professionals gauge the risk of immunosuppressive regimens and the impact of the donor’s viral status, thereby guiding plans for posttransplant antiviral prophylaxis treatment or, as noted earlier, avoiding transplants between a seropositive donor and a seronaive recipient. 336 PART I lose their graft.79 In recipients with a history of FSGS, posttransplant nephrotic proteinuria should be promptly investigated; if diagnosis is confirmed by kidney biopsy, rescue plasmapheresis should be instituted at once. Adjuvant therapy with rituximab recently has been proposed.80 BASIC CONSIDERATIONS Hypercoagulopathy. Kidney transplant candidates with a history of thrombotic events, repeated miscarriages, or a family history of thrombophilia should be screened for the following coagulopathic disorders: activated protein C resistance ratio, factor V Leiden mutation, factor II 20210 gene mutation, antiphospholipid antibody, lupus anticoagulation, protein C or S deficiency, antithrombin III deficiency, and hyperhomocysteinemia. In recipients at risk for hypercoagulopathy, pediatric kidney grafts should be avoided; so should any kidney allografts with a complex vascular anatomy.81 A perioperative anticoagulation protocol is recommended in this population. Surgical Evaluation Urologic Evaluation. Kidney transplant candidates (pediatric patients, in particular) with chronic kidney disease as a result of congenital or genitourinary abnormalities should undergo a thorough urologic evaluation. A voiding cystourethrogram and a complete lower urinary tract evaluation to rule out outlet obstruction are essential. Indications for a native nephrectomy include chronic pyelonephritis, large polycystic kidneys with loss of intra-abdominal domain, significant vesicoureteral reflux, or uncontrollable renovascular hypertension. Vascular Evaluation. The potential implant sites for a kidney graft include the recipient’s aorta, vena cava, and iliac vessels. Careful physical examination often reveals significant central and/or peripheral vascular disease. Findings such as a pulsatile intra-abdominal mass, diminished or absent peripheral pulse, claudication, rest pain, and tissue loss in lower extremities should be further evaluated by abdominal computed tomography scan or ultrasound, Doppler studies, and/or angiography. With the popularity of endovascular interventions, transplant surgeons should also be familiar with such technology and have detailed anatomic studies of patients with vascular stents. Immunologic Evaluation. ABO blood typing and HLA typing (HLA-A, -B, and -DR) are required before a kidney transplant. The method of screening for preformed antibodies against HLA antigens (because of prior transplants, blood transfusions, or pregnancies) is evolving. The panel-reactive antibody (PRA) assay is a screening test that examines the ability of serum from a kidney transplant candidate to lyse lymphocytes from a panel of HLA-typed donors. A numeric value, expressed as a percentage, indicates the likelihood of a positive cross-match with a donor. A higher PRA level identifies patients at high risk for a positive cross-match and therefore serves as a surrogate marker to measure the difficulty of finding a suitable donor and the risk of graft rejection. The latest development in anti-HLA antibody screening is Luminex technology, using HLA-coated fluorescent microbeads and flow cytometry. In theory, this technology pinpoints donor-specific antibodies (DSAs) in the serum of a kidney transplant candidate with a high PRA level. Since all organ donors must undergo HLA typing, a negative cross-match for recipients with a high PRA level can be ensured by avoiding the selection of donors carrying unacceptable antigens (i.e., a virtual cross-match).82 Kidney transplant candidate data (including ABO blood types, HLA types, and DSAs) are now entered into a nationwide central database to facilitate deceased donor kidney allocation, as described earlier. Psychosocial Evaluation. Psychiatric disorders have been recognized as important contributing factors to poor outcomes posttransplant. Patients with uncontrolled psychiatric disorders are at high risk for noncompliance with treatment, impaired cognitive function, and the development of substance abuse. The psychosocial evaluation is essential to ensure that transplant candidates understand the risks and benefits of the procedure and that they adhere to the lifetime immunosuppressive medication regimen. Recipient Operation Kidney allografts usually are transplanted heterotopically. The iliac fossa is recognized as the ideal position because of its proximity to the recipient’s bladder and iliac vessels.83,84 Retroperitoneal allograft placement also allows easy access for percutaneous biopsies and interventions for ureteral complications. The right iliac fossa is the preferred site because of its easy access to the recipient’s iliac vessels. However, if a pancreas transplant is anticipated in the future or if now failed kidney grafts have been placed at the right iliac fossa, then the left iliac fossa is used for implantation. The current surgical technique for kidney transplants was developed and popularized in the 1950s and 1960s and has changed little since.85 A large-bore three-lumen urinary catheter is inserted after the recipient is anesthetized, and it is occluded with a clamp beneath the surgical drapes. Recipients whose native kidneys produce urine will naturally fill up the urinary bladder; those individuals whose kidneys do not will require insufflation of saline prior to creation of the ureteral anastomosis. Exposure of the operative field starts with a curvilinear skin incision, one to two finger widths above the midline pubic bone and the lateral edge of the rectus sheath. Superiorly, the extension of the incision depends on the recipient’s body habitus and the size of the donor kidney. The anterior rectus sheath is incised, medially to laterally, until the lateral edge of the rectus sheath is exposed. The posterior rectus sheath is missing below the arcuate line, thus providing direct access to the extraperitoneal space. The rectus muscle can be easily mobilized medially without being divided. The remainder of the fascial incision is along the lateral edge of the rectus sheath until the desired exposure is achieved (Fig. 11-6). The retroperitoneal space of the iliac fossa is entered by mobilizing the peritoneum medially. The inferior epigastric vessels, the round ligament (in females), and the spermatic cord and its vasculature (in males) are encountered in this space; the former two structures are divided, while the latter is retracted with a vascular loop. A self-retained retractor is used to expose the surgical field. The iliac vessels should be dissected with great care. To minimize the risk of lymphocele development postoperatively, dissection of the iliac artery should be limited; the intertwining lymphatics around the iliac vessels should be ligated. In general, the donor’s renal artery and vein are anastomosed to the recipient’s external iliac vessels in an end-to-side fashion (Fig. 11-7). In recipients with a severely calcified iliac artery, the internal iliac artery can be used as an alternative, and in select cases, an endarterectomy must be performed. After restoring the circulation to the donor’s kidney, urinary continuity can be established via several approaches. The approach chosen depends on such factors as the length of the donor ureter and a recipient history of bladder surgery, native VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 337 B C Figure 11-6. Incision and exposure for kidney transplant. A. Mark for the skin incision. B. Anterior rectus sheath incised obliquely. The abdominal muscle transected lateral to the rectus muscle. C. External iliac artery and vein dissected. nephrectomy, or pelvic radiation. The two most common procedures to restore urinary continuity are the Leadbetter-Politano and a modification of the Lich (e.g., extravesical) ureteroneocystostomy, which actually was designed to avoid ureteral reimplantation. During the former procedure, a large cystotomy is created in the dome of the bladder, and the donor ureter is brought through a lateral and somewhat inferior 1-cm submucosal tunnel into the bladder, the end of which is spatulated and then sewn in place without tension with interrupted absorbable sutures placed through the mucosa and submucosa on the inside of the bladder. An extravesical ureteroneocystostomy is performed by careful dissection of a 1-cm portion of the muscular layers on the anterolateral portion of the bladder until a “bubble” of mucosa is exposed. The donor ureter is spatulated in a diamond-shaped fashion, the bladder mucosa is incised, absorbable interrupted sutures are placed in four quadrants, and a mucosa-to-mucosa anastomosis is created using running absorbable sutures with a temporary ureteral stent in place of the first three-quarters of A the anastomosis. The muscular layers of the bladder are then carefully approximated over the anastomosis to prevent reflux. The decision to place a ureteral stent depends on the surgeon, who must try to balance the risk of infectious complications with the possible technical complications of a ureteral anastomosis, but in general, this is not required except during the rarely performed donor ureter to recipient ureter anastomosis or in the case of a pediatric kidney transplant. Fixation of the donor’s kidneys is not necessary, except in the case of small kidneys (usually from a pediatric donor) or en bloc kidneys. Grafts with Multiple Renal Arteries In 10% to 30% of donor kidneys, multiple renal arteries are encountered. Unless kidney transplant candidates have hypercoagulopathy, grafts with multiple renal arteries fare as well as those with single vessels.86 Vascular reconstruction options include implanting the donor’s arteries separately, reconstructing the multiple arteries into a common channel, or combining multiple arteries into a common Carrel patch (Fig. 11-8). B Figure 11-7. Vascular anastomoses of kidney transplant. A. Arterial anastomosis: donor renal artery with Carrel patch to recipient external iliac artery, end-to-side. B. Venous anastomosis: donor renal vein with caval extension conduit to recipient external iliac vein, end-to-side. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 11 Transplantation A 338 PART I BASIC CONSIDERATIONS A B Figure 11-8. Arterial and venous reconstruction. A. Two renal arteries combined into a single Carrel patch (arrow). Right renal vein extension conduit constructed with stapled caval patch. IVC = inferior vena cava; R = right renal vein. B. Three renal arteries anastomosed to external iliac artery separately. En Bloc Grafts clearly marked, in order to avoid torsion of the anastomosis. If the color of the two kidneys looks different after reperfusion, repositioning should be attempted to rule out vascular torsion; fixation of the en bloc kidneys to the retroperitoneum is often necessary. The donor’s ureters are implanted to the recipient’s bladder, either as two separate anastomoses or as a common patch (Fig. 11-9). Only a handful of centers have performed en bloc kidney transplants, but the long-term outcomes are encouraging.87,88 Debate persists about whether to implant kidneys obtained from young donors (<5 years or whose body weight is under 20 kg) as a single en bloc unit into one recipient or separately into two recipients. The underlying issues are the shortage of donor organs, the complexity of the surgical procedure, the risks of graft thrombosis, ureteral complications, and long-term outcomes. In en bloc kidney transplants, the donor aorta and vena cava are used as the vascular inflow and outflow conduits. Therefore, reconstruction of the en bloc graft pretransplant is key to a successful transplant. The donor’s suprarenal vena cava and aorta are oversewn. The lumbar branches of the cava and aorta are ligated. Dissection around the renal hilum should be avoided. The orientation of the cava and aorta should be A Perioperative Care Preoperatively, a thorough history and physical examination should be performed. Any changes in transplant candidates’ recent medical history should be investigated in great detail. B Figure 11-9. En bloc kidney transplant (3-month-old donor kidneys). A. En bloc kidneys benched. Vascular integrity tested with methylene blue (blue hue look of the kidneys). B. En bloc kidneys transplanted in to a 62-year-old woman. Donor aorta anastomosed to recipient’s external iliac artery; donor cava, to recipient’s external iliac vein. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ treatments are at increased risk. Signs and symptoms (such as an expanding hematoma over the surgical site, increased pain over the graft, a falling hemoglobin level, hypotension, and tachycardia) should arouse suspicion of hemorrhage. Doppler ultrasound is useful to establish the underlying cause. Surgical exploration seldom is required, because the accumulated hematoma tamponades the bleed. Indications for surgical exploration include ongoing transfusion requirement, hemodynamic instability, and graft dysfunction from hematoma compression. For recipients on anticoagulation or antiplatelet treatments, the threshold for surgical exploration is lower. Small unligated vessels at the donor’s renal hilum or recipient’s retroperitoneum are likely sources of bleeding. One of the most devastating postoperative complications in kidney recipients is graft thrombosis. It is rare, occurring in fewer than 1% of recipients. The recipient risk factors include a history of recipient hypercoagulopathy and severe peripheral vascular disease; donor-related risk factors include the use of en bloc or pediatric donor kidneys, procurement damage, technical factors such as intimal dissection or torsion of vessels, and hyperacute rejection. Graft thrombosis usually occurs within the first several days posttransplant. Acute cessation of urine output in recipients with brittle posttransplant diuresis and the sudden onset of hematuria or graft pain should arouse suspicion of graft thrombosis. Doppler ultrasound may help confirm the diagnosis. In cases of graft thrombosis, an urgent thrombectomy is indicated; however, it rarely results in graft salvage. Urologic complications are seen in up to 5% of recipients. The cause is often related to ureteral ischemia, damage during procurement of the donor’s distal ureter, or technical errors. Symptoms of urine leak include fever, pain, swelling at the graft site, increased creatinine level, decreased urine output, and cutaneous urinary drainage. Diagnosis can be confirmed by a combination of ultrasound, nuclear renography, drainage of perinephric fluid collection, and comparison of serum and fluid creatinine levels. Depending on the location and volume of the urine leak, satisfactory results can be achieved by surgical exploration and repair or by percutaneous placement of a nephrostomy and ureteral stenting. Early urinary obstruction can be due to edema, blood clots, torsion of the ureter, or compression from a hematoma. Late urinary obstruction is often related to ischemia. The appearance of hydronephrosis on ultrasound is a good initial indicator. Treatment includes percutaneous placement of a nephrostomy and ureteral stenting. If transluminal intervention fails, surgical intervention (such as ureteral reimplantation or a ureteropyelostomy) can be undertaken. Results A kidney transplant remains the most common solid organ transplant in the world today. With the introduction of induction immunosuppressive therapy and ever-improving, less toxic immunosuppressive medications, posttransplant outcomes have become better and better. According to a recent analysis of more than 250,000 U.S. adult kidney transplant recipients, the actual half-life (50% graft survival) of a deceased donor kidney was 6.6 years in 1989, 8 years in 1995, and 8.8 years in 2005. Interestingly, during that same period—though with a much better overall outcome—the half-life of a living donor kidney has essentially remained the same: 11.4 years in 1989 and 11.9 years in 2005.89 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 339 CHAPTER 11 Transplantation In those recipients with a historically negative PRA level who have recently undergone blood transfusions, a prospective tissue cross-match is necessary to avoid graft rejection. Electrolyte panels should be checked. Emergency dialysis may be necessary for transplant candidates experiencing hyperkalemia or fluid overload. For dialysis-dependent transplant candidates, the catheter sites should be examined preoperatively to rule out infections. Vascular access for hemodialysis is essential to avoid complications related to posttransplant acute tubular necrosis (ATN). Vascular evaluation is mandatory; any changes in results should be investigated by appropriate imaging studies. As is routine for other major surgical procedures, transplant candidates should preoperatively undergo a chest x-ray, a 12-lead ECG, blood typing, cross-match tests, and prophylaxis against surgical site infection (by administration of a nonnephrotoxic antibiotic with activity against both common skin microflora and gram-negative pathogens); candidates should receive nothing to eat or drink. Intraoperatively, transplant recipients should be kept well-hydrated to avoid ATN and should receive heparin prior to vascular occlusion. Before reperfusion of the transplanted kidney, the desired central venous pressure should be maintained at around 10 mmHg, and the systolic blood pressure should be above 120 mmHg. In pediatric recipients of an adult graft, a superphysiologic condition may be necessary to avoid ATN or graft thrombosis. Mannitol often is administered before reperfusion as a radical scavenger and diuretic agent, and a diuretic such as furosemide is administered as well. Postoperatively, the guiding principles for the care of kidney transplant recipients are the same as for other surgical patients. The crucial elements include hemodynamic stability and fluid and electrolyte balance. To achieve a euvolemic state, the recipient’s urine output is replaced with either an equal or a reduced volume of IV fluid on an hourly basis, depending on the medical status. In recipients undergoing brisk dieresis, aggressive replacement of electrolytes (including calcium, magnesium, and potassium) may be necessary. In recipients experiencing ATN, fluid overload, or hyperkalemia, however, fluid restriction, treatment for hyperkalemia, and even hemodialysis may be necessary. Hypotension is an unusual event immediately posttransplant. The differential diagnoses include hypovolemia, vasodilation, and myocardial infarction with cardiac failure. Immediate action should be taken to avoid life-threatening complications. Posttransplant hypertension can be mediated by catecholamines, fluid overload, or immunosuppressive agents. Postoperatively, urine output is used as a surrogate marker to monitor graft function. Among recipients whose native kidneys produce significant amounts of urine, normal or increased urine output can be misleading; for them, serum blood urea nitrogen and creatinine levels are more reliable indicators of kidney graft function. Suddenly decreased or minimal urine output requires immediate attention. A change in volume status is the most common cause, but other culprits include blockage of the urinary catheter, urinary leak, vascular thrombosis, hypotension, drug-related nephrotoxicity, ATN, and rejection (all of which must be thoroughly investigated). Diagnostic studies such as Doppler ultrasound, nuclear renograms, or biopsies should be considered. Postoperative bleeding is an uncommon event after a kidney transplant. Recipients on anticoagulation or antiplatelet 340 PART I BASIC CONSIDERATIONS The biggest improvements have been in the reduction of 1-year graft failure. With a deceased donor kidney, the 1-year graft failure rate dropped from 20% in 1989 to less than 7% in 2009; with a living donor kidney, the rate dropped from 8.5% in 1989 to less than 3% in 2009.89 Furthermore, steroid-free protocols90 and calcineurin-free protocols91 have been validated and implemented in the last two decades, further reducing medicationrelated side effects and vastly improving the quality of life for tens of thousands of recipients. Currently, the most common cause of graft loss is recipient death (usually from cardiovascular causes) with a functioning graft. The second most common cause is chronic allograft nephropathy; characterized by a slow, unrelenting deterioration of graft function, it likely has multiple causes (both immunologic and nonimmunologic).92,93 The graft failure rate due to complications related to surgical technique has remained at about 2%. PANCREAS TRANSPLANTATION A successful pancreas transplant is currently the only definitive long-term treatment for patients with insulin-dependent diabetes mellitus (IDDM) that (a) restores normal glucose hemostasis without exposing patients to the risk of severe hypoglycemia and (b) prevents, halts, or reverses the development or pro5 gression of secondary complications of diabetes.94 Given its vast medical, social, and financial implications, diabetes mellitus is a huge burden to patients and to society as a whole. An estimated 10% to 15% of the U.S. population is affected by it; of all diabetic patients, 10% have early-onset disease. In the United States, diabetes mellitus is the most common cause of end-stage kidney disease, blindness, impotence, major limb amputations, and coronary or peripheral vascular bypass procedures. It is one of the most common causes of death, along with myocardial infarction and stroke. Diabetes significantly decreases not only the quality of life but also life expectancy. Despite improvements in exogenous insulin administration (including the use of devices such as insulin pumps), wide fluctuations in glucose levels and the risk of hypoglycemic episodes are common. The Diabetes Control and Complications Trial (DCCT) demonstrated in the late 1990s that intensive insulin therapy may slow the rate of secondary complications of diabetes—yet at the expense of (life-threatening) iatrogenic hypoglycemia. The annual mortality rate of patients with insulin-induced inadvertent hypoglycemia is estimated to be as high as 2% to 3%. Since the first pancreas transplant in December 1966, performed by William Kelly and Richard Lillehei at the University of Minnesota, more than 25,000 pancreas transplants in the United States and more than 10,000 pancreas transplants from all over the world have been reported to the International Pancreas Transplant Registry (IPTR), which is maintained at the University of Arizona.94,95 Pancreas transplants are performed in three recipient categories: • S imultaneous pancreas and kidney (SPK) transplant in diabetic and uremic patients. Almost 80% of pancreas transplants are performed in this category. The recipient is already obligated to lifelong immunosuppressive therapy, due to the need for a kidney transplant, so only the surgical risk of a pancreas transplant is added. A successful SPK transplant renders the recipient dialysis-free and insulinindependent. • Pancreas after kidney (PAK) transplant in diabetic and posturemic patients. Approximately 15% of all pancreas transplants fall into this category. These patients previously underwent a kidney transplant with either a living or deceased donor, but are candidates for a subsequent pancreas transplant because of poor glucose control or because of progression of secondary diabetic complications (which may include the development of diabetic nephropathy in the transplanted kidney). • Pancreas transplant alone (PTA) in nonuremic patients with brittle diabetes mellitus. Only about 8% of all pancreas transplants are in this category. These patients have not yet developed advanced diabetic nephropathy, but their glucose levels are extremely labile despite best efforts to control it. Because of the lifelong need for immunosuppressive therapy, the surgical risk has to be balanced with the medical risks of brittle diabetes (e.g., frequent episodes of hypoglycemia and hypoglycemic unawareness). In SPK recipients, a plethora of literature exists that demonstrates significant improvements in secondary diabetic complications (across all organ systems) posttransplant. Improvements have been reported in diabetic nephropathy, neuropathy (autonomic and peripheral), micro- and macrovascular disease, retinopathy, gastroparesis, and other secondary complications.96 Currently, more than 1000 pancreas transplants are performed annually in the United States, with the goal of conferring the following benefits: excellent glucose control (similar to that of a functioning native pancreas), prevention or improvement of secondary diabetic complications, and increased quality of life and life expectancy. In addition, pancreas transplants can be successfully performed in patients who have undergone a total pancreatectomy for benign disease (such as chronic pancreatitis) to treat both endocrine and exocrine deficiency after surgery.97 Donor Operation The general criteria for selecting deceased donors for pancreas procurement are similar to those for other solid organs; a history of type 1 diabetes mellitus obviously is a contraindication. Relative contraindications include previous pancreatic procedure(s), as well as pancreatic disorders, such as chronic pancreatitis and intraductal papillary mucinous neoplasm. Hyperglycemia in itself is not a contraindication to pancreas procurement, because its cause in brain-dead donors usually is severe insulin resistance, which is rarely observed in recipients. In light of better anatomic understanding and improved surgical skills, all three abdominal organs that share a common blood supply (pancreas, liver, and intestine) can be procured at the same time and transplanted into three different recipients (Fig. 11-10). During pancreas procurement, a “no-touch” technique of the gland is preferred; dissection of the pancreas is carried out in a way that avoids direct manipulation of the organ such that simultaneous procurement of the spleen, duodenum, and surrounding connective tissues occurs. In contrast to the liver and kidneys, the pancreas should not be extensively flushed at the end of the procurement. To minimize the amount of preservation fluid that reaches the pancreas, the splenic artery and SMA can be temporarily clamped at their origin from the aorta. Usually, the celiac axis with an VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ RHV MHV 341 LHV CHAPTER 11 Transplantation IPDA MCA Figure 11-10. Simultaneous pancreas, in situ split-liver, and intestine procurement. IPDA = inferior pancreaticoduodenal artery; LHV = left hepatic vein; MCA = middle cerebral artery; MHV = middle hepatic vein; RCA = right coronary artery; RHV= right hepatic vein. (Reproduced from Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer, 2004; Color Plate VI, Figure 8.1.3.11. With kind permission of Springer Science + Business Media.) RCA aortic Carrel patch is retained with the liver. The splenic artery is divided close to its origin and is retained with the pancreas. The SMA is also procured with an aortic Carrel patch and is retained with the pancreas. In case of a replaced or aberrant right hepatic artery, this first branch off of the SMA is carefully dissected out from the posterior surface of the pancreas. A replaced or aberrant right hepatic artery does not transverse the pancreas and is not a contraindication to combined pancreas and liver procurement. But with this anatomic variant, an aortic Carrel patch with the proximal SMA and replaced or aberrant right hepatic artery remains with the liver; the distal SMA with the inferior pancreaticoduodenal artery remains with the pancreas. In the relatively rare event that the liver is not procured, then neither the splenic nor the gastroduodenal arteries need to be divided at their respective takeoff; the donor’s celiac axis and the SMA are included on a common Carrel patch. This technique allows a single arterial anastomosis to be performed in the recipient without reconstruction. At the end of the procurement, the pancreas is attached to the spleen, duodenum, and proximal jejunum, which is stapled at both ends.98 Back Table Preparation of the Pancreas Graft Back table preparation of the pancreas graft consists of four steps: (a) removal of the spleen; (b) shortening, restapling, and/ or suture reinforcement of the mesenteric root; (c) trimming of any excess distal and proximal duodenum, along with reinforcement of the proximal staple line; and (d) arterial reconstruction. Back table preparation is carried out in a basin filled with chilled preservation solution. The most common technique to create a single arterial inflow to the pancreas graft is the “Y-graft” reconstruction, using a resected segment of the donor iliac artery bifurcation. In this technique, the donor external iliac artery is anastomosed end-to-end to the donor SMA, and the donor internal iliac artery is anastomosed end-to-end to the splenic artery (Fig. 11-11). This procedure allows the donor common iliac artery to be anastomosed as a single vessel to the recipient’s common iliac artery. For venous outflow, the portal vein is kept relatively short, in order to avoid the risk of venous thrombosis by kinking or impingement.98 Recipient Operation Over the years, different surgical techniques have been described for (a) the management of exocrine pancreatic secretions and (b) the type of venous drainage. For the secretions, the two most common techniques are drainage of the duodenal segment to the bladder (bladder drainage) or to the small bowel (enteric drainage) (Figs. 11-12 and 11-13). For venous drainage, systemic venous drainage is preferred over portal venous drainage. The pancreas graft is usually placed intra-abdominally and preferably on the right side, because the iliac vessels are in a more VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 342 IIA SA PART I EIA SMA BASIC CONSIDERATIONS Figure 11-11. Posterior view of the pancreas graft with Y-graft reconstruction. EIA = external iliac artery; IIA = internal iliac artery; SA = splenic artery; SMA = superior mesenteric artery. (Reproduced from Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer, 2004; Color Plate VII, Figure 8.1.3.13[B]. With kind permission of Springer Science + Business Media.) shallow position on the right than on the left side; moreover, the vessels are already appropriately aligned for the vascular anastomoses (i.e., a lateral position for the common iliac vein, a medial position for the common iliac artery). Venous and arterial anastomoses are performed end-to-side. After restoration of blood flow to the graft, hemostasis must be meticulously maintained. Because the donor portal vein purposely is kept short, ligation and transection of all of the recipient’s internal iliac vein branches are frequently performed, in order to prevent tension on the venous anastomosis. The pancreas usually is placed with the pancreatic head and duodenum pointing caudally. Bladder drainage is performed using either a hand-sewn or a stapled anastomosis in which the antimesenteric side of the donor duodenum is sewn to the superior portion of the dome of the bladder. The stapled technique requires that a circular cutting stapler be inserted through the open distal end of the donor duodenum, which is subsequently closed. Bladder drainage has two main advantages. First, rejection of the exocrine pancreas precedes rejection of the endocrine pancreas by 5 to 7 days. Amylase levels are measured routinely in the recipient’s urine. With bladder drainage, antirejection treatment can successfully be implemented when the recipient is still normoglycemic and only hypoamylasuric. In the absence of hyperglycemia, more than 90% of pancreas rejection episodes are reversible. Second, bladder drainage avoids the bacterial contamination that occurs with enteric drainage. If an anastomotic leak occurs, it is easier to treat, because the infection usually remains localized to the right lower quadrant. Enteric drainage is more physiologic and has advantages as well. The antimesenteric side of the donor’s duodenum is anastomosed to the antimesenteric portion of the recipient’s jejunum in a side-to-side fashion. The enteric anastomosis can also involve a defunctionalized Roux-en-Y loop, which minimizes the potential complications if an enteric leak occurs. 98 Currently, in the United States, more than 80% of all pancreas transplants are performed with enteric drainage for the exocrine pancreatic secretions, and more than 90% employ systemic venous drainage.95 Figure 11-12. Whole-organ transplant with systemic vein and bladder exocrine drainage. (Reproduced from Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer, 2004; Color Plate XIV, Figure 8.2.2.2[B]. With kind permission of Springer Science + Business Media.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Complications The technical complication rate for pancreas transplants is higher than for any other solid organ transplant. Four factors contribute to the high surgical complication rate99: (a) the nature of the organ itself with inherent organ-specific surgical complications (e.g., pancreatitis, abscesses, necrosis, fistulas, and pseudocysts) and its low blood flow (which significantly increases the risk of thrombosis, as compared with a kidney or liver transplant); (b) the risk of a leak or infection after connecting two hollow viscera (the duodenum and either the bladder or small intestine); (c) the increased incidence of rejection episodes, because the pancreas is one of the most immunogenic solid organs; and (d) the underlying disease of diabetes mellitus, predisposing patients not only to infections but also to cardiovascular and other complications. The most common surgical complications are thrombosis (an incidence of 5%–15%), intra-abdominal abscesses (5%–10%), and bleeding (6%–8%). Other pancreas-specific complications include graft pancreatitis (frequently due to procurement or reperfusion injury), pancreatic fistulas, and pancreatic pseudocysts. Anastomotic leaks do not always require a graft pancreatectomy, but arterial pseudoaneurysms, arteriovenous fistulas, and wound dehiscence may. Bleeding frequently requires relaparotomy. Thrombosis usually occurs within the first week posttransplant. It manifests as a sudden increase in insulin requirements or as a sharp drop in urinary amylase levels. Venous thrombosis, which is more common than arterial thrombosis, is associated with distinct clinical symptoms, including a swollen and tender graft, hematuria, lower extremity edema, and deep vein thrombosis, the latter two occurring ipsilaterally. Arterial thrombosis is less symptomatic and may not initially cause pain; its diagnosis is usually confirmed by Doppler ultrasonography. Surgical exploration in recipients with thrombosis usually requires a graft pancreatectomy. Living Donor Pancreas Transplants Pancreas transplants using living donors also can be performed safely and successfully in select donors and recipients. Since 1979, about 150 such transplants have been performed worldwide, with 1-year graft survival rates in excess of 85% over the last decade. A meticulous donor evaluation using standard criteria remains key to a low donor metabolic and surgical complication rate. The concept of procuring the distal pancreas from a living donor is based on the observation that patients with benign or malignant pancreatic disorders can undergo a distal hemipancreatectomy without any serious change in endocrine function. Living donor pancreas transplants are ideal for patients with an identical twin, but other relatives can be suitable donors as well. In particular, patients with high PRA levels should be considered for a living donor transplant. Living donor pancreas transplants decrease the number of deaths of diabetic patients on the waiting list, help overcome the organ shortage, reduce mortality and morbidity, and improve the quality of life for patients with debilitating side effects of diabetes. The use of living donors also reduces the risk of graft rejection, as compared with the use of deceased donors. Yet living donor pancreas transplants remain relatively rare, performed under very selective circumstances. In terms of surgical technique, the donor splenic artery and vein are anastomosed to the recipient’s external iliac artery and vein in an end-to-side fashion, and exocrine drainage can occur via an anastomosis VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 343 CHAPTER 11 Transplantation Figure 11-13. Whole-organ transplant with systemic vein and enteric exocrine drainage. (Reproduced from Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer, 2004; Color Plate XIV, Figure 8.2.2.2[A]. With kind permission of Springer Science + Business Media.) With the advent of advanced interventional radiologic procedures to drain intra-abdominal abscesses, the reoperation rate has markedly decreased. Pancreas transplant recipients are usually kept on broad-spectrum antimicrobial agents for the first 7 days posttransplant. The most common nonsurgical complication posttransplant is rejection. The incidence of rejection is about 30% within the first year. The diagnosis is usually based on an increase in serum amylase and lipase levels and, in bladder-drained recipients, a decrease in urinary amylase levels. A sustained drop in urinary amylase levels greater than 25% from baseline should prompt a pancreas graft biopsy to rule out rejection. In entericdrained recipients, one must rely on serum amylase and lipase levels only. Other signs and symptoms of rejection include tenderness over the graft, unexplained fever, and hyperglycemia, which usually is a late finding; fewer than 5% of all rejection episodes can be reversed in its presence. The diagnosis of rejection should be confirmed by a percutaneous pancreas graft biopsy. Other nonsurgical complications include infections with CMV, HCV, or extra-abdominal bacteria or fungi; malignancies, such as PTLD; and, rarely, graft-versus-host disease. For such complications, the diagnosis and treatment are similar to what is recommended after other solid organ transplants. Bladder-drained pancreas recipients may experience an array of unique urologic complications. Usually the result of the irritating nature of pancreatic enzymes on the urothelium in the bladder and urethra, these urologic complications can lead to cystitis, hematuria, and dysuria. With the loss of bicarbonate from pancreatic secretions, dehydration and metabolic acidosis are not uncommon. Many of these complications are chronic, such that approximately 20% to 30% of all bladder-drained recipients require conversion to enteric drainage within the first 5 years posttransplant.100 Significant improvements have been noted not only in 1-year pancreas graft function but also in long-term success rates. The most recent 5-, 10-, and 20-year pancreas graft function rates are 80%, 68%, and 45% for SPK recipients; 62%, 46%, and 16% for PAK recipients; and 59%, 39%, and 12% for PTA recipients, respectively. The quality of the deceased donor graft is of paramount importance. The use of anti–T-cell induction therapy has had a significant impact on long-term graft survival, specifically in PTA recipients. IPTR data show significant improvements in patient survival and pancreas graft function rates since the inception of UNOS, over a course of 24 years.92,95,99,102 Clearly, pancreas transplants now offer excellent outcomes for patients with IDDM. 344 PART I BASIC CONSIDERATIONS Islet vs. Pancreas Transplants Figure 11-14. Segmental transplant with systemic vein and bladder exocrine drainage. The donor splenic artery and splenic vein are anastomosed end-to-side to the recipient’s external iliac artery and vein. The splenic artery anastomosis is lateral and proximal to the splenic vein anastomosis. A two-layer ductocystostomy is constructed. (Reproduced from Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer, 2004; Color Plate XVI, Figure 8.2.2.4. With kind permission of Springer Science + Business Media.) of the pancreatic duct and transected end of the pancreas to the bladder or bowel101 (Fig. 11-14). Results As of December 2010, more than 35,000 pancreas transplants had been reported to the IPTR: more than 25,000 transplants in the United States and more than 10,000 in other countries According to IPTR data, recipient age at the time of the transplant has increased significantly, and so has the number of transplants for patients with type 2 diabetes. The trend over time has been toward stricter donor criteria, with a concentration on younger donors, preferably trauma victims, and on short pancreas graft preservation time. Drainage techniques have changed over time, too: enteric drainage of exocrine pancreatic secretions is now predominant, in combination with systemic drainage of the venous effluent of the pancreas graft. Immunosuppressive protocols have developed toward antibody induction therapy, followed by administration of tacrolimus and MMF for maintenance. Steroid avoidance has increased over time in all three recipient categories. These changes have led to improved patient and graft survival rates. In all three recipient categories, early technical graft loss rates have decreased significantly to about 8%. Likewise, the 1-year immunologic graft loss rate has also decreased, ranging from 2% to 6%. The 1-year patient survival rates now exceed 90% in all three recipient categories. The highest 1-year pancreas graft survival rate is in SPK recipients: 86% for the pancreas and 93% for the kidney. The 1-year pancreas graft survival rate is 80% in PAK recipients and 78% in PTA recipients. Pancreas transplants are frequently compared with islet transplants, which are less invasive and, therefore, more appealing. It is important to emphasize that these two types of transplants are not mutually exclusive but rather complementary. The results of islet transplants have improved over the past decade, but overall islet graft function, specifically long-term function, still significantly trails overall pancreas graft function.103 Islet trans6 plants involve pancreas procurement (as described earlier) and then separation of islets from the exocrine pancreatic tissues using proteolytic enzymes (as described later). The human pancreas contains about one million islets, of which half are lost during the isolation process. About 10,000 islets per kilogram of body weight are needed to achieve insulin independence when transplanted into the liver. Frequently, one donor pancreas does not suffice; in fact, up to four donor pancreases have been used for one islet recipient. Because of the relatively disappointing long-term outcomes, insurance providers in the United States do not provide reimbursement for islet transplants. Transplant centers with both pancreas and islet transplant programs follow an algorithm that favors islet transplants in patients with a high surgical risk and pancreas transplants in patients with a low surgical risk. Although solitary donor pancreases are not in short supply, only one donor pancreas is required for a successful pancreas transplant; in contrast, two to four donor pancreases are commonly used for one islet recipient with less favorable long-term outcomes. Of note, the primary goal of current islet transplant trials is not insulin independence but rather a reduction in the incidence and severity of hypoglycemic events, a reduction in exogenous insulin requirements, and an amelioration of hemoglobin A1c levels. Islet transplants rarely maintain long-term insulin independence. A recent study showed a higher rate of insulin independence in PTA recipients than in recipients of an islet transplant alone, despite the use of up to three donor pancreases in each of the islet recipients.104 Until islet transplant results significantly improve and include long-term insulin independence, a pancreas transplant remains the treatment of choice for β-cell replacement therapy in patients with IDDM. ISLET TRANSPLANTATION Transplanting islets of Langerhans isolated from deceased donor pancreases is an appealing option for patients with type 1 diabetes. An islet transplant involves the procurement of a donor pancreas and its transportation to a specialized islet VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ islet recipients were C-peptide positive and retained hypoglycemia awareness, indicating residual islet function and benefit. In fact, at 9 years posttransplant, 15% remained insulinindependent, and 73% had hypoglycemia awareness and corrected hemoglobin A1c levels.115 In the mid-2000s, new trials began with the goal of establishing protocols that enable insulin independence, using islets from a single donor pancreas; the results were good, especially with strict donor and recipient selection.116,117 In the most experienced centers, long-term rates of diabetes reversal are now about 50% at 5 years posttransplant. The reasons include refinements in pancreas preservation, islet isolation, and culture protocols, as well as the use of newer induction immunosuppressive agent combinations, such as a T-cell–depleting antibody (antiCD3 antibody, alemtuzumab, or antithymocyte globulin) and a tumor necrosis factor-alpha (TNF-α) inhibitor (etanercept or infliximab). Presumably, viable β-cell mass is now preserved, both pre and posttransplant.116-120 Thus, islet transplant results are approaching those of whole-pancreas transplants; however, because islets from more than one pancreas are typically needed, those results cannot be directly compared with the results of whole-pancreas transplants.121,122 In the United States, an islet transplant is still officially deemed an experimental procedure. In contrast, since 2001, it has been considered a standard of care and is fully reimbursed in Canada and, more recently, in the United Kingdom, Sweden, Switzerland, France, and Italy as well. Worldwide, since 2000, more than 750 patients with diabetes have undergone an islet transplant, and 80 ongoing trials have enrolled up to 1500 islet recipients.118 One of the U.S. trials (a multicenter phase 3 registration trial sponsored by the National Institutes of Health) aims to collect the necessary data for submitting a biological license application (BLA) to the FDA. A successful BLA would open the road for islet transplants to become a standard of care and thus reimbursable by the Centers for Medicare and Medicaid Services. The full potential of islet transplants remains to be realized, but the future is exciting. As the latest improvements in pancreas preservation, islet isolation and purification, islet culture, and islet immunoisolation are implemented clinically, the hope is that sustained insulin independence will become consistently possible with a single pancreas donor and without the need for systemic immunosuppression. LIVER TRANSPLANTATION The first attempts at liver transplants in the late 1960s through the 1980s were largely experimental endeavors, with a 1-year survival rate of only 30%. But breakthroughs in immunosuppression, surgical technique, organ preservation, anesthesia, and critical care have improved that rate to approximately 85% today. Liver transplants remain daunting, especially in the face of an organ shortage that results in sicker potential candidates. Unfortunately, the perioperative mortality rate and the 1-year mortality rate are among the highest of any surgical operation currently performed. History The first experimental liver transplants in dogs are often attributed to C. Stuart Welch in 1955 and then Jack Cannon in 1956. However, current scholarship reveals that Vittorio Staudacher first described the technique in 1952.123 A series of canine VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 345 CHAPTER 11 Transplantation isolation facility, where the pancreas is enzymatically digested; then, the islets are purified from the rest of the digested pancreas using density gradients. The purified islets are then cultured and evaluated for their identity, viability, and potency, before being infused into the portal vein of a diabetic recipient. When the procedure is successful, these islet cells engraft into the recipient and secrete insulin, providing excellent momentto-moment control of blood glucose, as is seen with a wholepancreas transplant. A successful islet transplant offers advantages over exogenous insulin injections—advantages that are similar to those of a whole-pancreas transplant. These advantages include restoring β-cell secretory capacity, improving glucose counterregulation, restoring hypoglycemia awareness, providing perfect or near-perfect glucose homeostasis, and, potentially, preventing secondary diabetic complications. Unlike a whole-pancreas transplant, an islet transplant does not involve a major surgical procedure with its associated mortality and morbidity. Instead, it can generally be performed as an outpatient procedure using percutaneous catheter-based therapy to cannulate a branch of the portal vein, with minimal recovery time for the recipient. Potential complications associated with islet injection include portal hypertension, portal vein thrombosis, hepatic abscesses, and bacteremia. Theoretically, islet transplants could have wider application (as compared with current practice and with whole-pancreas transplants), given the significantly lower surgical risk, the relatively small tissue volume transplanted, and the potential for islet immunomodulation or immunoisolation, which could minimize or eliminate the need for immunosuppression. The first reported attempt at an islet transplant was in 1893 by Watson-Williams and Harsant: they transplanted a sheep’s minced pancreas into the subcutaneous tissue of a young boy with ketoacidosis.105 The discovery of insulin may have reduced interest in islet transplants as a treatment for diabetes, at least until the realization that insulin could not provide perfect glycemic control and that, therefore, patients ultimately suffered devastating secondary complications. Several milestones ensued: the first whole-pancreas transplants,106 early success with rodent islet transplants,107 and then, in the 1970s, human islet autotransplants after pancreatectomy, in order to address the intractable pain associated with chronic pancreatitis, by Sutherland, Najarian, and colleagues in Minnesota.108 Until recently, attempts to extend those trailblazing findings of clinical islet autotransplants to clinical islet allotransplants in patients with type 1 diabetes met with generally very poor success. For example, in 1995, a report of the International Islet Transplant Registry indicated that of 270 recipients, only 5% were insulin-independent at 1 year posttransplant. In 2000, Shapiro and colleagues reported the results of the Edmonton protocol, which enabled consistent diabetes reversal and short-term (<1 year) insulin independence.109-111 The Edmonton protocol prescribed transplanting a large number of freshly isolated islets (>10,000 islet equivalents per kilogram body weight, typically requiring the use of two to four pancreases) with a specialized “islet-sparing,” steroid-free immunosuppressive protocol consisting of low-dose tacrolimus, sirolimus, and IL-2 receptor antibody induction. Those results were replicated at other experienced transplant centers,112,113 but the rates of long-term (>5 year) insulin independence remained poor, well below those of whole-pancreas transplants.114 Still, despite the low rates of long-term insulin independence, most 346 PART I BASIC CONSIDERATIONS experiments followed, which refined the surgical technique to ensure perioperative survival. The next obstacle—immunologic rejection—was addressed by drug immunosuppression with AZA and prednisone. The first human liver transplant trials started in 1963 with Thomas Starzl, but a series of deaths led to a voluntary moratorium for 3.5 years. With the resumption of clinical transplants in 1967, Starzl performed the first successful liver transplant. Still, for the next decade, survival rates were dismal: only 20% of the 170 liver transplant recipients in Starzl’s program at the University of Colorado survived more than 5 years.124 Several innovations dramatically improved outcomes. The advent of better immunosuppressive drugs was instrumental. In 1978, cyclosporine was introduced clinically in England. It was soon combined with prednisone to great effect. The arrival of tacrolimus in the 1990s further improved graft survival. Technical advances were also significant. Donor procurement techniques and cold organ preservation protocols were standardized, and the recipient operation was also refined. Choledochocholedochostomy or choledochojejunostomy to a Roux-en-Y limb became standard and significantly decreased the frequency of biliary complications. Innovations, including living donor liver transplants and deceased donor split-liver transplants, enabled more pediatric recipients to be transplanted. Improvements in portosystemic shunting and perioperative critical care also were contributory. Indications In general, any form of irreversible liver disease is an indication a liver transplant. Chronic alcoholic disease and HCV 7 for are the most common indications in the United States. An extensive list of acute and chronic diseases of the liver that are treatable by a liver transplant is provided in Table 11-6. Offering transplants to alcoholic patients has always drawn some opposition, because of the perception of it being a self-inflicted illness, as well as concerns about recidivism and the recipient’s possible inability to maintain postoperative immunosuppression and care. Yet studies have shown that such patients have excellent outcomes and that liver transplants for them are cost-effective.125-127 Because patients who drink 4 to 8 ounces of liquor daily for 10 to 15 years have an increased risk of developing cirrhosis, the general requirement for acceptance as a transplant candidate is 6 months of abstinence. Furthermore, most transplant centers recommend rehabilitation and Alcoholics Anonymous programs. Transplants for HCV have yielded worse outcomes than transplants for other diseases.128 The reason is the universal recurrence of the virus posttransplant. Viral levels reach pretransplant levels as early as 72 hours posttransplant.129 The course of the viral infection is often accelerated posttransplant: 10% to 20% of recipients develop cirrhosis after just 5 years.130 Studies have suggested that use of older donors may increase the chance of aggressive recurrence.131 The best method to prevent recurrence would be to eradicate the infection pretransplant, but doing so is not always possible because patients with decompensated cirrhosis often cannot tolerate treatment. Once recurrence occurs, treatment methods are limited. One study found that pegylated interferon and ribavirin therapy achieved a sustained viral response in 44% of patients.132 A substantial number of patients undergo liver transplants for cholestatic disorders. Primary biliary cirrhosis, an autoimmune disease, is characterized by damage to the intralobular bile Table 11-6 Diseases amenable to treatment by a liver transplant Autoimmune liver diseases Autoimmune hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Congenital Biliary atresia Viral hepatitis Hepatitis B Hepatitis C Alcoholic liver disease Metabolic diseases α1-Antitrypsin deficiency Cystic fibrosis Hemochromatosis Tyrosinemia Wilson’s disease Hepatic malignancy Hepatocellular carcinoma Neuroendocrine tumor metastatic to liver Fulminant hepatic failure Other Alagille syndrome Cryptogenic cirrhosis Budd-Chiari syndrome Polycystic liver disease Amyloidosis ducts that progresses to liver cirrhosis. Trends toward earlier treatment may explain the slight decrease in liver transplants for this disorder.133 Posttransplant outcomes in patients with this disorder have been excellent, with many centers achieving 1-year survival rates of 90% to 95%. Recurrence is relatively uncommon: a large series reported a 30% recurrence rate at 10 years posttransplant.134 The second most common cholestatic disorder among liver transplant candidates is primary sclerosing cholangitis. It is characterized by inflammation and fibrosis of large intraand extrahepatic biliary ducts; 70% of such patients also have inflammatory bowel disease. Recurrent cholangitis is common and increases mortality rates beyond what would be expected on the basis of laboratory values. On behalf of such patients, appeals can often be made for priority in allocation to the UNOS regional review boards. Posttransplant outcomes for such patients have been excellent. Primary sclerosing cholangitis is a significant risk factor for cholangiocarcinoma, so annual screenings (including imaging and measurement of serum CA 19-9 levels) should be carried out. Recurrence is fairly uncommon: studies have reported a recurrence rate of up to 20% at 10 years posttransplant.135 Progressive metabolic disorders also are treatable with liver transplants. Hemochromatosis, an inherited disorder, results in excessive intestinal iron absorption. Iron deposition can cause cirrhosis and severe cardiomyopathy. Careful cardiac evaluation is necessary pretransplant. Another metabolic disorder, α1-antitrypsin deficiency, is characterized by insufficient levels of a protease inhibitor, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Recipient Selection The diagnosis of cirrhosis itself is not an indication for a transplant. Patients may have compensated cirrhosis for years such that the traditional indication for a transplant is decompensated cirrhosis, manifested by hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, portal hypertensive bleeding, and hepatorenal syndrome (each described below). Hepatic encephalopathy is an altered neuropsychiatric state caused by metabolic abnormalities resulting from liver failure. The early stages result in sleep disturbances and depression. As the liver disease progresses, patients can become somnolent and confused and, in the end stages, comatose. Ammonia is produced by enterocytes from glutamine and from colonic bacterial catabolism, and the use of serum ammonia levels as a marker of encephalopathy is controversial because a variety of factors can influence levels. Hyperammonemia suggests worsening liver function and bypass of portal blood flow around the liver. GI bleeding and infection can exacerbate hepatic encephalopathy. Ascites (the accumulation of fluid in the abdominal cavity) that is caused by cirrhosis is a transudate with a high serum-ascites gradient (>1.1 g/dL). Associated with portal hypertension, it is treated initially with sodium restriction and diuretics. Refractory ascites necessitates large-volume paracentesis and eventually a transjugular intrahepatic portosystemic shunt (TIPS). Contraindications to TIPS placement include significant hepatic encephalopathy, advanced liver disease, congestive heart failure, renal insufficiency, and severe pulmonary hypertension.141 Spontaneous bacterial peritonitis, an infection of the ascitic fluid without an evident intra-abdominal source, is characterized by fever, abdominal pain, and an ascitic fluid polymorphonuclear count ≥250 cell/mm3 on paracentesis. The first line of empiric treatment is with a third-generation cephalosporin because the majority of cases are caused by aerobic gram-negative microbes such as E. coli, although Gram stain and culture results should be used to guide therapy. Portal hypertensive bleeding can be a devastating event for patients with cirrhosis. Each bleeding event carries a 30% mortality rate and accounts for a third of all deaths related to cirrhosis. Only 50% of bleeding events cease spontaneously, so treatment must be expedient. The initial medical treatment is with vasopressin and octreotide. The initial intervention is endoscopy with sclerotherapy and band ligation of bleeding varices. If those initial attempts fail, more aggressive treatment is necessary with a balloon tamponade (using a SengstakenBlakemore tube) and with emergent TIPS placement. The last line of treatment is emergency surgery to place a portosystemic shunt, transect the esophagus, or devascularize the gastroesophageal junction (Sugiura procedure). Preventing variceal bleeding is essential and can be achieved, with some success, using β-blockers. Hepatorenal syndrome is a form of acute renal failure that develops as liver disease worsens. The etiology is unclear, but splanchnic vasodilation from portal hypertension and increased production of circulating vasodilators result in a decline in renal perfusion. Characterized by oliguria (<500 mL of urine/day) and low urine sodium levels (<10 mEq/L), hepatorenal syndrome is often reversed by a liver transplant, even after dialysis dependence. Pretransplant, other causes of renal failure need to be excluded, including ATN, drug nephrotoxicity, and chronic renal disease. The initial medical therapy includes octreotide, midodrine, and vasopressin analogs, but the syndrome often progresses to dialysis dependence. The Model for End-Stage Liver Disease (MELD) was originally developed to assess risk for TIPS placement.142 Later analysis revealed it to be an excellent model to predict survival among patients with cirrhosis, especially those on the waiting list for a liver transplant.143 In 2002, liver graft allocation was restructured to be based on the MELD score. Although the historic indication for a liver transplant is decompensated cirrhosis, a landmark analysis comparing waiting list mortality with posttransplant mortality established that a minimum MELD score of 18 is necessary to have a survival benefit posttransplant. A MELD score between 15 and 18 does VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 347 CHAPTER 11 Transplantation resulting in early-onset emphysema and cirrhosis. Careful pulmonary evaluation is necessary pretransplant. Wilson’s disease, an autosomal recessive disorder characterized by impaired cellular copper transport, leads to copper accumulation in the liver, brain, and cornea. Patients can develop significant neurologic complications and cirrhosis. Several reports suggest improvement of neurologic deficiencies posttransplant.136,137 Transplants can also be performed in patients with hepatic malignancies, but only in accordance with strict criteria. Hepatocellular carcinoma (HCC), a complication of cirrhosis, is the most common type of hepatic malignancy. Resection is the first line of treatment if possible, but often, cirrhosis is too advanced. If the tumor meets the Milan criteria, a liver transplant can be performed. These criteria were established by a landmark paper in 1996 showing that patients with a single tumor under 5 cm in diameter, or with three tumors under 3 cm in diameter, in the absence of vascular invasion, had a 4-year survival rate of 85%.138 Patients with such tumors receive exception points, based on their UNOS region, allowing for a timely transplant before their tumors spread. Transplants for cholangiocarcinoma are still in the experimental stages but may be performed if the center has an experimental protocol in place. The Mayo Clinic protocol, which uses neoadjuvant therapy and strict exclusion criteria, has resulted in a 5-year survival rate of 82%.139 Acute fulminant hepatic failure also is an indication for a liver transplant; in fact, such patients are the highest priority for the next available liver in their UNOS region. This devastating illness is defined by acute and severe liver injury with impaired synthetic function and encephalopathy in a person who had normal liver function. It is often caused by acetaminophen overdose; acute fulminant viral hepatitis A, B, and E; other viral infections; drug toxicity; ingestion of Amanita mushrooms; acute fatty liver of pregnancy; or Wilson’s disease. A significant number of patients will recover with supportive care. The difficulty lies in predicting who will not recover and therefore would benefit from a liver transplant. The King’s College criteria were developed for this purpose: patients with acetaminopheninduced disease, a pH <7.3 or grade III/IV encephalopathy, a prothrombin time >100 seconds, and serum creatinine >3.4 mg/ dL meet those criteria.140 Management of acute liver failure is very intensive. Such patients suffer from severe coagulopathy, hypoglycemia, lactic acidosis, and renal dysfunction. They are susceptible to infections, which are frequently overwhelming. Cerebral edema, a serious complication of acute liver failure, is a leading cause of death from brain herniation. Intracranial pressure monitoring and serial imaging are often necessary; if a patient develops irreversible brain damage, a transplant is not performed. 348 PART I not confer a survival advantage, but a transplant may be justified if the patient has significant morbidity from cirrhosis.144 Acute liver failure itself is an indication for a liver transplant. To qualify for Status 1 (first priority for a donor liver within the UNOS region), the transplant candidate must meet the following criteria: (a) onset of hepatic encephalopathy within 8 weeks after the first symptoms of liver disease; (b) absence of pre-existing liver disease; and (c) ventilator dependence, dialysis, or an international normalized ratio (INR) >2.0. BASIC CONSIDERATIONS Contraindications In general terms, contraindications to a liver transplant include insufficient cardiopulmonary reserve, uncontrolled malignancy or infection, and refractory noncompliance. Older age is only a relative contraindication: carefully selected recipients over the age of 70 years can achieve satisfactory outcomes.145 Patients with reduced cardiopulmonary reserve are unlikely to survive a liver transplant. Candidates should have a normal ejection fraction. If coronary arterial disease is present, they should undergo revascularization pretransplant. Severe chronic obstructive pulmonary disease (COPD) with oxygen dependence is a contraindication. Severe pulmonary hypertension with a mean pulmonary artery pressure greater than 35 mmHg that is refractory to medical therapy is also a contraindication. Candidates with pulmonary hypertension should be evaluated with a right heart catheterization. For candidates with alcoholic liver disease, few reliable predictors of posttransplant relapse exist.146 Most centers require 6 months of abstinence from drugs and alcohol. Insurance companies often make more stringent demands, including random drug screening and 1 year of abstinence. Uncontrolled infections pretransplant are a substantial risk posttransplant when the patient becomes significantly immunosuppressed. Fungal and multidrug-resistant bacterial infections are relative contraindications. Some centers require an extended period of treatment and documented eradication pretransplant. HIV infection is a relative contraindication; some centers have strict protocols that exclude patients with a history of acquired immunodeficiency syndrome (AIDS)-related illnesses as well as those who are coinfected with HCV. Ideally, patients with a history of malignancy (with the exception of HCC) should be cured of the cancer pretransplant. In most cases, this means eradication, completion of curative therapy, and absence of recurrence over a certain period of time, which varies by the tumor type, but can be up to 5 years or longer for aggressive tumors (see earlier Malignancy section). Figure 11-15. Cirrhotic liver immobilized in preparation for complete hepatectomy. portal vein. Significant hemodynamic instability and increased variceal bleeding can occur. Patients who are unable to tolerate this phase can be placed on venovenous bypass, with cannulas drawing blood from the IVC via the femoral vein and via the portal vein, returning it to the systemic circulation via the subclavian vein. Venovenous bypass itself can cause complications, including air embolism, thromboembolism, and trauma to the cannulated vessels. The donor liver is placed in the orthotopic position. The suprahepatic vena caval anastomosis is performed first in an end-to-end fashion, followed by the infrahepatic vena caval and portal anastomosis, both also end-to-end. The liver is then reperfused, often leading to a period of hemodynamic instability and cardiac arrhythmias due to the release of byproducts of ischemia from the donor liver. Coagulopathy also can worsen because of these byproducts as well as fibrinolysis. The arterial anastomosis between the donor common hepatic or celiac trunk is most often performed with the recipient CHA in an end-to-end fashion. Of course, many variations are possible. After arterial reperfusion, the bile duct anastomosis Surgical Procedure A liver transplant is among the most extensive operations performed, and it can be associated with considerable blood loss. A bilateral subcostal incision with midline extension is used. Mechanical retraction spreads the rib cage to allow access. The ligamentous attachments of the liver are dissected free. The vascular structures are isolated, including the suprahepatic and infrahepatic vena cava, the portal vein, and hepatic artery (Fig. 11-15). The bile duct, portal structures, and vena cava are divided, completing the hepatectomy (Fig. 11-16)—often the bloodiest and most difficult part of the operation, particularly in the presence of extensive varices and severe coagulopathy. After the liver is removed, the anhepatic phase begins. This phase is characterized by the absence of inferior vena caval return to the heart and by portal congestion due to clamping of the Figure 11-16. Isolation and division of the hilar structures to diseased liver-hepatic artery, portal vein, and common bile duct. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 349 Donor Left hepatic vein Left portal vein Left hepatic artery Pediatric Transplants Outcomes after pediatric liver transplants are among the best after any type of transplant, with a 1-year survival rate of 90%. The most common indication is biliary atresia. After diagnosis is confirmed, a Kasai procedure is promptly carried out: a Roux-en-Y loop of bowel is directly anastomosed to the hilum of the liver. The Kasai procedure often allows time for the children to grow in size, reducing the risk of a transplant when it is required, as it eventually is in 75% of such children. The other common indication for a pediatric liver transplant is a metabolic disorder, such as α1-antitrypsin deficiency, tyrosine metabolism deficiencies, and primary oxalosis. Since the MELD score was developed for adults, pediatric liver allocation is based on an analogous model, the Pediatric End-Stage Liver Disease (PELD) score, which incorporates bilirubin levels, INR, albumin levels, age, and growth failure. The surgical procedure is similar to the adult procedure. Graft implantation is more challenging, given the pediatric recipient’s smaller vascular structures. As a result, surgical complications are much more common in pediatric recipients. Hepatic artery thrombosis is about three times more common. Donor size matching is very important in the pediatric population and often limits the donor pool for pediatric recipients. To address this issue, deceased donor split-liver transplants and living donor transplants (both described in the following sections) have been developed. Deceased Donor Split-Liver Transplants A deceased donor allograft can be split into two grafts, most frequently into a left lateral segment for a child and an extended right segment for an adult (Fig. 11-17). It can be done in vivo (during the donor operation) or ex vivo (on the back table after the donor liver is removed). Both techniques have similar outcomes. Increased morbidity is associated with splitting allografts, whether for adult or pediatric recipients; however, the technique is justified given the donor shortage and has been important for improving access to transplants for pediatric recipients.147 Living Donor Transplants Donation by an adult living donor to an adult recipient requires either the right or left lobe of the liver (Fig. 11-18). Donation by an adult living donor to a pediatric recipient requires the left lateral lobe (Fig. 11-19). Donor safety is paramount. The donor operation has a 0.2% mortality rate and significant morbidity rates, including rehospitalization (8.5%), bile leak or stricture Recipient Hepatic artery Roux limb Portal vein Figure 11-17. Donor and recipient procedure for living donor liver transplant into a pediatric recipient. (6.0%), reoperation (4.5%), and major postoperative infections (1.1%).148 Careful donor selection is vital. Potential donors should be medically and psychologically healthy, their hepatic anatomy should be amenable to donation, and absolutely no coercion can occur. A separate donor team should serve as the donor advocate and thoroughly explain all risks. Careful recipient selection is essential. Transplant candidates also must qualify for a deceased donor liver transplant, because a significant number of living donor transplant recipients will eventually require a retransplant. Transplant candidates should be medically fit enough to withstand the rigors of the operation and of the postoperative course with a partial graft. An absolute contraindication is a critical illness: the limited success of such transplants does not justify the risks to the living donor. The obvious advantages of a living donor transplant are that it can be done expediently (avoiding the waiting list mortality associated with candidates for a deceased donor transplant) and that it can be planned. Postoperative Care A liver transplant imposes significant trauma on the major organ systems. Immediately posttransplant, the first goal is to stabilize those systems. Acid-base equilibrium and hemodynamic stability are often difficult to maintain but are essential. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 11 Transplantation is performed between the donor and recipient common ducts, also in an end-to-end fashion. If necessary for technical reasons, the recipient common duct can be joined to a Roux-en-Y limb. Some surgeons choose to insert a T-tube or place internal stents in the common bile duct to protect the anastomosis. The piggyback technique is a common variation of the standard technique. The recipient’s IVC is preserved by carefully dissecting off the posterior aspect of the liver. This added dissection is a disadvantage of this variation, often increasing hepatectomy time and blood loss. The recipient’s liver is removed by dividing it at the confluence of the hepatic veins. The preserved IVC is an advantage of this variation, allowing venous return from the lower body to the heart during the anhepatic phase and improving renal perfusion. No randomized studies, however, have demonstrated the superiority of the piggyback technique over the standard technique. 350 PART I BASIC CONSIDERATIONS IVC M H LHV RHV V S2 S4 IVC RHD R.P.V. R.P.A. LH D LH A LP V FL MPV C B PHA C.D. D S3 C.A. A MHV LHV LHV RHV CHA MPV B Figure 11-18. A. Hepatic transection completed for right lobe removal. CA = cystic artery; CBD = common bile duct; CD = cystic duct; FL = falciform ligament; IVC = inferior vena cava; LHD = left hepatic duct; LHV= left hepatic vein; MHV = middle hepatic vein; MPV = main portal vein; PHA = proper hepatic artery; RHA = right hepatic artery; RHV = right hepatic vein; RPV = right portal vein; S2, S3, S4 = segments 2, 3, and 4. B. Implantation of the donor right lobe with the MHV. CHA = common hepatic artery. (Reproduced with permission from Gruessner RWG, Benedetti E, eds. Living Donor Organ Transplantation. New York: McGraw-Hill, 2008. © 2008 by The McGraw-Hill Companies, Inc.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ A Complications B Figure 11-19. A. Hepatic transection completed for removal of left lateral segments (S2 and S3). Bile ducts to segments 2 and 3 divided; vascular structures still intact. B. Implantation of the donor left lobe. (Reproduced with permission from Gruessner RWG, Benedetti E, eds. Living Donor Organ Transplantation. New York: McGraw-Hill, 2008. © 2008 by The McGraw-Hill Companies, Inc.) Periods of hypotension can increase the risk of hepatic artery thrombosis. Careful attention needs to be paid to ongoing bleeding. Appropriate hemoglobin levels should be maintained. Ongoing bleeding mandates a return trip to the operating room; the rate of reoperation can be as high as 25% among high-risk patients. Transfusion of platelets and fresh frozen plaza must be done prudently, because theoretically their administration can increase the risk of hepatic artery thrombosis. Graft function should be evaluated frequently; if it is impaired, an ultrasound is urgently required to assess for the presence of vascular complications. Evaluation of Graft Function Evaluation of the graft begins in the operating room. Its appearance overall, any swelling, and the quantity and quality of bile production after reperfusion can help assess function. In the intensive care unit, hemodynamic stability, correction of coagulopathy, euglycemia, successful temperature regulation, clearance of lactic acid, and restoration of neurologic status Vascular complications occur in about 8% to 12% of recipients and include thrombosis, stenosis, and pseudoaneurysm formation. The most common vascular complication is hepatic artery thrombosis. Recent reviews suggest that its incidence is between 1.6% and 4%152; the mortality rate is 50%, even after definitive therapy.153 Early presentation can be quite dramatic, with fulminant hepatic necrosis, primary nonfunction, transaminitis, or fever. Late presentation, however, can be asymptomatic or subtle, with cholangitis, bile leak, mild transaminitis, hepatic abscesses, or failure to thrive. Diagnostic imaging with ultrasound has more than 90% sensitivity and specificity. If hepatic artery thrombosis is identified, urgent re-exploration is needed. A thrombectomy or revision of an anastomosis may be successful, but with significant hepatic necrosis, a retransplant is necessary. Thrombosis of the portal vein is very uncommon. Signs of early thrombosis include liver dysfunction, ascites, and variceal bleeding. Upon diagnosis, an operative thrombectomy should be attempted. Biliary complications remain the Achilles’ heel of liver transplantation, affecting 10% to 35% of these organ recipients. Signs include fever and abdominal pain, with bilious drainage from surgical drains. Diagnosis is made with cholangiography. Complications manifest themselves as leaks or strictures. Leaks require a reoperation and surgical correction, whereas strictures can most often be managed with radiologic or endoscopic interventions. Two common reconstructions are choledochostomy and choledochojejunostomy. Some centers also routinely use T-tube stents or internal stents. Consensus has not been reached as to which reconstruction technique is superior. Early infectious complications are often associated with initial graft function and pretransplant risk factors. Intraabdominal infections should raise concerns of a possible bile leak. Fungal infections are often associated with poor graft function. Given the immunosuppressed and compromised state of liver recipients, early infectious complications can be devastating. The types of opportunistic infections that occur in liver transplant recipients are similar to those that occur in other types of solid organ transplant recipients and are due to suppression of cell-mediated immunity by chronic immunosuppressive drug administration. Acute rejection occurs in approximately 20% of liver recipients. The first line of treatment is with a high dose of a corticosteroid, which is usually effective; if not, antilymphocyte therapy is initiated. Rejection of the liver (unlike other transplanted organs) does not adversely affect patient or graft VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 351 CHAPTER 11 Transplantation S2 + 3 are all signs of a functioning graft, even before the first set of liver function test results are obtained. Transaminases usually peak by postoperative day 2. An aspartate transaminase (AST) level greater than 2500 IU/L is suggestive of significant injury. Cholestasis usually peaks from postoperative day 7 to 12. The INR should improve shortly after reperfusion. In 3% to 4% of patients undergoing a liver transplant, the graft does not function for any identifiable reason, a condition termed primary nonfunction; in such cases, a retransplant is the only option. Some studies suggest that a peak AST level of 5000 IU/L may be predictive of primary nonfunction.149-151 Factors associated with primary nonfunction include donor macrosteatosis, prolonged cold and warm ischemic times, and prolonged donor hospital stay.151 352 PART I BASIC CONSIDERATIONS survival rates. Maintenance immunosuppression consists of a corticosteroid, tacrolimus, and mycophenolate. Table 11-7 INTESTINE AND MULTIVISCERAL TRANSPLANTATION Children Adults Gastroschisis Visceral ischemia secondary to SMA/SMV thrombosis Midgut volvulus Crohn’s disease Intestinal atresia Trauma After the introduction of long-term total parenteral nutrition (TPN) in the late 1970s and the early success of liver, kidney, and heart transplants, the first attempts at intestine transplants were made. Over the first two decades, the results were dismal. But the introduction of the immunosuppressive drug tacrolimus in the late 1980s led to significant improvement in graft and patient survival rates. Nonetheless, intestine transplants remain the least frequently performed of all transplants, with the lowest graft survival rates. The main obstacle is the high immunogenicity of the intestine, caused by its abundant lymphoid tissue. High levels of immunosuppression are needed, yet the rejection rate is still high. The microbial colonization of the intestine confers the risk of translocation of pathogenic microorganisms into the recipient’s circulation, causing severe systemic infections. Through the first decade of the twenty-first century, the survival of patients on long-term TPN was superior to the survival of intestine transplant recipients, so a transplant was considered only as rescue therapy for patients with life-threatening TPN-related complications. Over the last several years, improvements in surgical techniques, in perioperative and postoperative care, and particularly in immunosuppressive protocols have led to significantly better patient and graft survival rates posttransplant.154 Recent data indicate that survival rates after an intestine transplant often are better than, or at least similar to, survival rates among patients receiving chronic TPN in the home setting.155 Today, an intestine or multivisceral transplant is recognized as a feasible treatment. Indications and Recipient Selection An intestine transplant is indicated for patients with irreversible intestine failure in combination with TPN failure. The definition of intestine failure does not specify the exact length of the remaining intestine. Intestine failure is typically multifactorial. Variables include what part of the small intestine is absent, whether or not the ileocecal valve is present, whether or not the patient underwent an ostomy, and how long the remaining colon is. TPN failure is defined as significant biochemical or pathologic evidence of liver injury, loss of central vein access with thrombosis of at least two central veins, frequent indwelling catheter infection or a single episode of fungal infection, and recurrent episodes of severe dehydration despite IV fluid supplementation. Indications for a transplant differ between the adult and pediatric population. The leading causes of intestine failure are summarized in Table 11-7. The disease involvement of organs other than the intestine dictates the extent of the operation required. Liver failure is often seen in patients on long-term TPN. If pathologic or biochemical evidence of severe liver damage is combined with signs of portal hypertension, then a combined liver-intestine transplant is the treatment of choice. However, a multivisceral transplant (liver, pancreas, stomach, duodenum, and/or small intestine) might be necessary among children who suffer diffuse intestinal dysmotility syndromes and adults who develop diffuse portomesenteric thrombosis, extensive intra-abdominal desmoid disease encasing the main Leading causes of intestine failure Necrotizing enterocolitis Mesenteric desmoid tumors Microvillus involution disease Radiation enteritis Hirschsprung’s disease Massive resection secondary to tumors Crohn’s disease Chronic intestinal pseudoobstruction Pseudo-obstruction Autoimmune enteropathy SMA = superior mesenteric artery; SMV = superior mesenteric vein visceral vascular structures with concurrent short gut syndrome, or massive abdominal trauma. Surgical Procedure For both the donor and recipient surgery, the key decision is which organs will be transplanted.156 For an isolated intestine transplant, the blood supply is based on the arterial inflow from the SMA and on the venous outflow from the superior mesenteric vein (SMV). Both vessels are isolated at the root of the mesentery. For a combined liver-intestine transplant, the blood supply is based on the arterial inflow from the celiac axis and SMA, which are procured en bloc with an aortic patch. The liver, duodenum, pancreas, and small intestine—because of their close anatomic relationship—are procured en bloc. If the hepatoduodenal ligament is left intact, no biliary reconstruction is necessary, which virtually eliminates the risk of postoperative biliary complications.157 Because the entire splanchnic system drains into the liver, venous drainage is achieved by anastomosis of the hepatic veins to the recipient’s vena cava. For both an isolated intestine transplant and a combined liver-intestine transplant, the proximal transection of the GI tract occurs at the first portion of the duodenum. For a multivisceral transplant, the stomach is part of the graft; hence, the transection of the GI tract occurs at the distal esophagus. Figs. 11-20 to 11-22 show these three main types of transplants. The vast majority of intestine transplants use a deceased donor organ. However, advances in surgical techniques have made the use of living donors a feasible alternative for either an isolated intestine transplant or a combined liver-intestine transplant. With a living donor, the donor operation is slightly different: for an isolated intestine transplant, 150 to 200 cm of the donor’s ileum, on a vascular pedicle comprising the ileocolic artery and vein, are used158 (Fig. 11-23); for a combined liverintestine transplant, performed almost exclusively for pediatric recipients, segments II and III of the donor’s liver are used, in addition to the intestine (Fig. 11-24). Similarly, the recipient operation also varies by the organs transplanted. Generally, the recipient’s infrarenal aorta is used to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 353 CHAPTER 11 Transplantation Figure 11-20. Isolated intestine transplant. Figure 11-22. Multivisceral transplant. achieve the arterial inflow to the graft. For an isolated intestine transplant, venous drainage is achieved via systemic or portomesenteric drainage; for a combined liver-intestine transplant or a multivisceral transplant, venous drainage is achieved via the hepatic veins. Systemic venous drainage, given its lesser technical difficulty, is preferred over portomesenteric drainage. The diversion of splanchnic flow into the systemic venous circulation can cause several metabolic abnormalities, but no hard evidence shows any negative impact clinically on the recipient. After the organs are perfused, the continuity of the recipient’s GI tract is restored, which includes the placement of a gastrostomy or jejunostomy feeding tube and an ileostomy. In the early postoperative period, the ileostomy enables regular endoscopic surveillance and biopsy of the intestinal mucosa. Once the recipient recovers, the ileostomy can be taken down. The last, but often the most difficult, part of the recipient operation is abdominal wall closure. It is especially challenging in intestine transplant recipients because they have usually undergone multiple previous procedures, resulting in many scars, ostomies, feeding tubes, and the loss of abdominal domain. To provide sufficient coverage of the transplanted organs, the use of prosthetic mesh often is necessary. Postoperative Care Figure 11-21. Combined liver-intestine transplant. Initial postoperative care for intestine transplant recipients does not significantly differ from that for other organ transplant recipients. In the intensive care unit, each recipient’s cardiovascular, pulmonary, and renal function is closely monitored; aggressive resuscitation with fluid, electrolytes, and blood products is performed. Broad-spectrum antibiotics are an integral component of care. Of all solid organ transplants, intestine transplants have the highest rate of rejection. With intestine transplants, no serologic marker of rejection is available, so frequent biopsies and histologic evaluation of the intestinal mucosa are of utmost importance. Rejection leads to structural damage of the intestinal mucosa. Translocation of endoluminal pathogens into the circulation can cause systemic infections. Thanks to the introduction of new immunosuppressive protocols, the rejection rates and the overall patient and graft VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 354 PART I BASIC CONSIDERATIONS A B Figure 11-23. A. Donor operation. About 180 to 200 cm of distal ileum on a vascular pedicle comprising the ileocolic artery and vein are removed. B. Recipient operation. The donor’s ileocolic artery and vein (or the terminal branches of the donor’s superior mesenteric artery and vein) are anastomosed end-to-side to the recipient’s infrarenal aorta and vena cava. (Reproduced with permission from Gruessner RWG, Benedetti E, eds. Living Donor Organ Transplantation. New York: McGraw-Hill, 2008. © 2008 by The McGraw-Hill Companies, Inc.) survival rates have improved significantly. Variations between the protocols exist, but the general concept is to induce immunosuppression with polyclonal T-cell antibody and high doses of a corticosteroid, followed by maintenance doses of corticosteroids and the calcineurin inhibitor tacrolimus. Immediately posttransplant, recipients are maintained on TPN. Enteral nutrition is initiated as early as possible, but is advanced very cautiously. It can take several weeks for the transplanted intestine to achieve structural integrity and functionality and for the recipient to tolerate the full strength of tube feeds. Despite all the recent advances, the complication rate posttransplant remains high. The most common complications include intra-abdominal abscesses, enteric leaks, intraabdominal sepsis, the need for a reoperation, graft thrombosis, life-threatening bleeding, and central line problems. Immunosuppression-specific complications include rejection, PTLD, graft-versus-host disease (GVHD), infections, and malignancies. Tailoring the recipient’s immunosuppression plays a critical role in preventing these complications: a low level of immunosuppression leads to graft rejection, but too much confers a high risk of infectious complications, PTLD, and, less commonly, GVHD—all of which are associated with a significantly increased risk of graft failure and mortality. The long-term results of intestine transplants have improved significantly, even though they still remain inferior to the results of other abdominal organ transplants.159,160 HEART AND LUNG TRANSPLANTATION History The first successful heterotopic heart transplant, in an animal model, was performed by Carrel and Guthrie in 1905.161 Subsequent progress with cardiopulmonary bypass and immunologic modulation facilitated the first successful adult human heart transplant, performed by Christiaan Barnard in 1967 in Cape Town, South Africa.162 However, it was Norman Shumway at Stanford who persisted with heart transplants, in the face of disappointing patient outcomes at a number of early centers. Thanks to the diligence of Shumway and colleagues in perfecting heart transplant techniques, along with the development, by Caves, of endomyocardial biopsy as a method of allograft rejection surveillance, human heart transplants began to reappear in the 1980s as a viable solution to end-stage heart failure. By 1981, the introduction of cyclosporin A finally created the necessary clinical immunologic modulation necessary to make long-term survival of heart recipients a reality.161 Lung transplants have a similar history. In the 1950s, Metras in France and Hardin and Kittle in the United States performed canine lung transplants, demonstrating that meticulous anastomotic technique could produce normal pulmonary pressures. Hardy performed the first human lung transplant in 1963, although the patient lived only 18 days. The first successful long-term lung transplant was performed in 1983 in Toronto. These early lung recipients, however, were plagued VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Heart Transplants 355 Indications. The most common diagnosis leading to a heart by infection, rejection, and, most significantly, bronchial anastomotic dehiscence. Cooper and colleagues soon determined that the high-dose corticosteroids used for immunosuppression were responsible for the frequent occurrence of dehiscence. The combination of high-dose corticosteroids and ischemic donor bronchi was deadly to lung recipients. Cooper, Morgan, and colleagues showed that the bronchial anastomosis could be protected by wrapping it with a vascular omental pedicle, which not only provided neovascularity but also offered a buttress against any partial dehiscence.163 Once cyclosporine became available for lung recipients, corticosteroid doses could be quickly tapered and stopped; cyclosporine poses no danger to the integrity of the bronchial anastomosis. In fact, the introduction of cyclosporine allowed the success of the first combined heart-lung transplant at Stanford in 1981 (after unsuccessful attempts by Cooley in 1969, Lillehei in 1970, and Barnard in 1981, all of whom used only high-dose corticosteroids for immunosuppression). The 1980s marked the start of the modern age of thoracic transplants. Procedure. Heart transplants are most often performed orthotopically (Fig. 11-25). The recipient’s native heart is removed, Figure 11-25. A donor’s heart brought forward for anastomosis. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 11 Transplantation Figure 11-24. Recipient operation. For a combined living donor liver-intestine transplant in a pediatric recipient, liver segments 2 and 3 are implanted in standard fashion (the donor’s left hepatic vein to the recipient’s vena cava, the donor’s left hepatic artery to the recipient’s proper or common hepatic artery, the donor’s left portal vein branch to the recipient’s portal vein trunk). The donor’s ileocolic artery and vein are anastomosed to the recipient’s infrarenal aorta and cava. In the recipient, a duodenum-to-donor ileum anastomosis and a distal Bishop-Coop ileostomy are constructed to re-establish bowel continuity. A very short Roux-en-Y loop (10 to 20 cm) is anastomosed to the donor’s bile duct(s). (Reproduced with permission from Gruessner RWG, Benedetti E, eds. Living Donor Organ Transplantation. Color Plates, Figure IN-6. New York: McGraw-Hill, 2008. © 2008 by The McGraw-Hill Companies, Inc.) transplant is ischemic dilated cardiomyopathy, which stems from coronary artery disease, followed by idiopathic dilated myopathy and congenital heart disease. About 3000 patients are added to the waiting list each year. Evaluation. Pretransplant, both candidates and potential donors are evaluated to ensure their suitability for the procedure. Transplant candidates undergo echocardiography, right and left heart catheterization, evaluation for any undiagnosed malignancies, laboratory testing to assess the function of other organs (such as the liver, kidneys, and endocrine system), a dental examination, psychosocial evaluation, and appropriate screening (such as mammography, colonoscopy, and prostate-specific antigen testing). Once the evaluation is complete, the selection committee determines, at a multidisciplinary conference, whether or not a heart transplant is needed and is likely to be successful. Transplant candidates who meet all of the center’s criteria are added to the waiting list, according to the UNOS criteria, which are based on health status. Once a potential deceased donor is identified, the surgeon reviews the status report and screening examination results. The donor is initially matched to the recipient per the recipient’s status on the UNOS waiting list, the size match, and the blood type. Results of the donor’s serologic testing, echocardiography, chest x-ray, hemodynamic testing, and possibly coronary artery evaluation are assessed, in order to determine whether or not the donor’s heart can withstand up to 4 hours of cold ischemic time during procurement, transport, and surgery. 356 PART I a c d BASIC CONSIDERATIONS b a Figure 11-26. Suture lines for bicaval anastomosis (a), biatrial anastomosis (b), aortic anastomosis (c), and pulmonary artery anastomosis (d). leaving the superior vena cava, the IVC, the left atrial cuff, the aorta, and the pulmonary artery in situ, in order to allow for anastomosis of the donor’s heart. Usually the left atrial cuff is anastomosed first, providing left heart inflow. Right heart inflow is achieved using a bicaval technique, by directly sewing the donor’s superior vena cava and IVC to the recipient’s venae cavae or by creating an anastomosis of the right atrium to a right atrial cuff. The donor’s main pulmonary artery is connected to the recipient’s pulmonary artery, and finally, the aortic anastomosis is completed (Fig. 11-26). Once the cross-clamp is removed, the heart is allowed to receive circulation from the recipient and begins to function normally. Inotropic support with isoproterenol, dobutamine, or epinephrine is often required for 3 to 5 days, in order to support recovery from the cold ischemia.164 On rare occasions, a heterotopic or “piggyback” heart can be transplanted, leaving the native heart in place. But this scenario is becoming very uncommon with the increasing use of mechanical circulatory support for single-ventricle failure. Posttransplant Care. Patient survival rates for heart recipients differ slightly after primary transplants vs. retransplants. After primary transplants, the patient survival rates at 1, 3, and 5 years are 87%, 79%, and 72%, respectively; after retransplants, the rates are 82%, 67%, and 58%.165 An increasing number of heart recipients have now survived more than 15 to 20 years with their first graft, especially those with no significant history of either cellular or antibody-mediated rejection. Heart recipients must be monitored for both early and late complications. Early complications include primary graft dysfunction, acute cellular or antibody-mediated rejection, right heart failure secondary to pulmonary hypertension, and infection. Hemodynamic values are monitored to assess early graft function; pharmacologic and sometimes mechanical support is instituted if needed. The goal of immunosuppression is to prevent rejection, which is assessed by immunosuppressive levels and, early on, by endomyocardial biopsy. Both T-cell–mediated (cellular) and B-cell–mediated (antibody-mediated) rejection are monitored. Most of the immunosuppression used is aimed at T cells; however, if the recipient has many preformed antibodies or develops donor-specific antibodies, other strategies (such as plasmapheresis or rituximab) are used to reduce the antibody load. Immunosuppressive regimens can vary by center, but most often consist of three categories of medications: a calcineurin inhibitor (usually tacrolimus or cyclosporine), an antiproliferative agent (MMF or AZA), and a corticosteroid (prednisone). Other immunosuppressive agents can be used, depending on the needs of individual recipients. Recipients are also assessed for any infections, with visual inspection of wound healing and with monitoring of the complete blood count and cultures as needed. Other common early sequelae include drug-induced nephrotoxicity, glucose intolerance, hypertension, hyperlipidemia, osteoporosis, malignancies, and biliary disease. Late complications include acquired transplant vasculopathy, progressive renal failure, and, most commonly, malignancies, especially skin cancer and PTLD. Accelerated coronary artery disease is the third most common cause of death posttransplant (after infections and acute rejection) and the most common cause after the first year. Coronary artery disease can begin to develop as early as 1 year posttransplant. Its pathogenesis is unknown, but it is believed to be immunologic. Because of these late complications, most transplant centers continue to perform screening tests and recipient examinations at least annually after the first year. Lung Transplants Indications. The indications for a lung transplant include congenital disease, emphysema, COPD, cystic fibrosis, idiopathic pulmonary fibrosis, primary pulmonary hypertension, α1-antitrypsin deficiency, and the need for a retransplant after primary graft failure. Each year in the United States, about 1600 patients are added to the waiting list; nearly a third of them have COPD and/or emphysema. The next most common diagnosis among patients on the waiting list is cystic fibrosis. A lung allocation score (LAS) was instituted in 2005. The average lung transplant candidate requires oxygen (often 4 L/min or more at rest) and has an extensively compromised quality of life, as documented by the results of pulmonary function and 6-minute walk tests. Evaluation. Evaluation for a lung transplant is very similar to evaluation for a heart transplant, except that lung transplant candidates undergo more extensive pulmonary function testing, a 6-minute walk test, chest computed tomography, ventilation-perfusion (V-Q) scanning, and arterial blood gas assessment. In addition, all lung transplant candidates must have adequate cardiac function and must meet psychosocial requirements. Potential lung donors are also screened for blood type and size match. Larger lungs are accepted for COPD patients; smaller lungs are chosen for the restricted chest cavity of fibrotic patients. Donors should have a partial pressure of oxygen in arterial blood (Pao2) value >300 mmHg on a fraction of inspired oxygen (Fio2) of 100% and a positive end-expiratory pressure (PEEP) value of 5. Ideally, donors will have normal chest x-ray results, but exceptions for isolated abnormalities that will not affect subsequent graft function can be made. Living donors can donate a single lobe to a smaller recipient, such as a child. Single-lung transplants are common in many centers and can VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 357 final anastomotic suture is tightened, with gentle lung insufflation. All clamps are removed, and the lung is aerated. At least two chest tubes are left in place. After the transplant is complete, a bronchoscopy is performed to clear the airway of blood and secretions. Figure 11-27. Clamshell incision. Bronchial anastomosis with ligated pulmonary arteries and veins. serve to increase the availability of lungs for multiple recipients. Newer concepts, such as “lung in the box” extracorporeal lung perfusion and stem cell technologies, may further improve the availability of donor lungs by optimizing the use of otherwise marginal grafts. Procedure. Lung transplants can be done either as (a) single-lung transplants (to either side via thoracotomy) or as (b) sequential bilateral-lung transplants (via bilateral thoracotomies or via a single clamshell incision that divides the sternum; Fig. 11-27). They can be done absent extracorporeal mechanical cardiopulmonary perfusion (bypass), with the lung with the worst function (as predicted by preoperative ventilation and perfusion scanning) transplanted first. Despite careful surgical technique and excellent anesthesia, the poor pulmonary reserve of some lung recipients may require the institution of cardiopulmonary bypass to complete the transplant. Bypass is initiated through the chest by direct cardiac cannulation or peripherally via the femoral vessels. Once the thoracotomy is made, a recipient pneumonectomy is performed with care, in order to avoid injury to the phrenic or recurrent laryngeal nerves. The pulmonary veins and main pulmonary artery are encircled outside the pericardium. At this point, once the main pulmonary vessels are occluded, the need for cardiopulmonary bypass can be assessed. The vessels and bronchus are ligated; the donor’s lung is prepared and brought to the table wrapped in cold iced gauze, in order to extend the cold preservation time. The bronchial anastomosis (Fig. 11-28) is performed first and then covered with peribronchial tissue or pericardium. The pulmonary artery and, finally, the vein are anastomosed. The lung is then deaired before the Posttransplant Care. Patient survival rates for lung recipients vary significantly after primary vs. redo transplants. After primary transplants, the patient survival rates at 1, 3, and 5 years are 83%, 62%, and 46%, respectively; after retransplants, the rates are 64%, 38%, and 28%. Postoperative care of lung recipients can be very laborintensive. These patients require meticulous ventilator management, in order to maintain Fio2 at a minimum and to keep Pao2 at 70 mmHg. Most patients are extubated within the first 24 to 48 hours. Recipients can require multiple bronchoscopies for both airway management and surveillance biopsies. Diuretics are used generously to counteract any positive fluid balance from the operation and to help with pulmonary recovery. Early complications include technical complications, graft dysfunction, infections, and rejection. Technical complications often involve stenosis of one or more anastomoses leading to graft dysfunction. Bronchoscopy, V-Q scanning, echocardiography, and radiologic imaging are useful in identifying the causes of graft dysfunction. In up to 20% of recipients, primary early graft dysfunction can occur with no obvious cause. Such dysfunction may be due to some pathology from the donor, perhaps an unknown aspiration, infection, or contusion; or it could result from poor graft preservation at the time of organ procurement. In the intensive care unit, aggressive ventilator and pharmacologic management can help, but recipients can nonetheless progress to the need for mechanical support in the form of ECMO. Infections are treated with appropriate antibiotics, which can be challenging in patients with cystic fibrosis and a history of multidrug-resistant organisms. Rejection is monitored by biopsies and treated as needed. Late complications include airway complications, such as strictures and, rarely, dehiscence, bronchiolitis obliterans, and malignancies. Strictures are treated with bronchoscopic dilation and intervention. Bronchiolitis obliterans often is a sequela of chronic rejection, but can be due to aspiration, chronic infections, or various other causes. In recipients with a progressive fall in their forced expiratory volume in 1 second (FEV1), bronchiolitis obliterans is suspected. All recipients should be taught to perform microspirometry at home as a screening VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 11 Transplantation Figure 11-28. Bronchial anastomosis. 358 PART I tool posttransplant. Biopsies are performed to confirm the diagnosis of any complication and, if possible, the cause. Despite aggressive screening and treatment, more than 50% of recipients will develop graft dysfunction. Most if not all of the sequelae of chronic immunosuppression that occur in lung transplant recipients are similar to those occurring in other groups of solid organ transplants. Heart-Lung Transplants BASIC CONSIDERATIONS Every year in the United States, 30 to 50 patients are added to the list of patients waiting to receive a simultaneous heart-lung transplant. The most common diagnosis is idiopathic pulmonary fibrosis, followed by primary pulmonary hypertension. Heart-lung candidates are often younger than their single-organ counterparts. The patient survival rates at 1, 3, and 5 years are 66%, 48%, and 39%, respectively. Often, lung complications ultimately lead to graft failure. The immunosuppression is the same as that for single thoracic organ recipients, with emphasis on weaning the patient off corticosteroids as early as possible. Xenotransplants Xenotransplants (i.e., cross-species transplants of organs, tissues, or cells) have immense, yet untapped, potential to solve the critical shortage of available grafts. A primary hurdle is the formidable immunologic barrier between species, especially with vascularized whole organs.1661-170 Other problems include the potential risk of transmitting infections (known as zoonoses or xenoses) and the ethical problems of using animals for widespread human transplants, even though great progress has been made in the past few years in efforts to overcome these problems.166-172 Pigs are generally accepted as the most likely donor species for xenotransplants into human beings.173 Pigs would also be easier to raise on a large-scale basis. Guidelines for raising pigs in specialized facilities designated as pathogen-free have been established; in anticipation of clinical trials, such facilities have already been created and populated.171,172 The immunologic barrier in pig-to-human xenotransplants is highly complex, but generally involves four subtypes of rejection.166 The first is hyperacute rejection (HAR), which is mediated by the presence of natural (preformed) xenoantibodies in humans. These antibodies bind to antigens found mainly on the vascular endothelial cells of porcine donor organs, leading to complement activation, intravascular coagulation, and rapid graft ischemia soon after the transplant. The second subtype is acute humoral xenograft rejection (AHXR), a delayed form of antibody-mediated rejection seen in pig-to-nonhuman-primate transplants after steps to prevent HAR—steps such as depletion of anti-pig antibodies or complement from nonhuman primates’ serum. Alternative names for AHXR include acute vascular rejection or delayed xenograft rejection. The third subtype is an acute cellular rejection process (similar to the classic T-cell–mediated acute rejection seen in allograft recipients). The fourth subtype is chronic rejection in grafts that survive for more than a few weeks (similar to the chronic rejection seen in long-surviving allograft recipients, with features of chronic vasculopathy). Many different options are being tested to overcome this immunologic barrier, including the genetic engineering of pigs, the use of agents to inhibit platelet aggregation and complement activation, and the administration of powerful immunosuppressive drugs.166-173 During the first decade of the twenty-first century, the field of whole-organ xenotransplantation progressed significantly, thanks to the increasing availability of genetically engineered pigs and new immunosuppressive protocols. At a recent symposium organized by the International Xenotransplantation Association, data presented demonstrated extended survival time of porcine solid organs in nonhuman primates: from about 30 days to an average of 60 days and even up to 250 days (depending on the model).166,169,174,175 However, clinical application is still limited by thrombotic microangiopathy and consumptive coagulopathy; novel methods to prevent those complications will be required for further progress. Cellular xenotransplants have made great strides and are currently in the early stages of clinical trials. Porcine islet xenotransplants are the most advanced form; five independent groups have now demonstrated survival and function of porcine islets in nonhuman primates for more than 100 days.166,175-181 For the clinical trials, cost-benefit models have been developed, and the regulatory framework has been established.170-172,178 One trial of particular interest involves transplanting encapsulated porcine islets without immunosuppression.179 Early results are encouraging. But the efficacy of that approach may be limited until further genetic engineering enables proper oxygenation and nourishment of islet grafts, thereby supporting their viability and function. The future of xenotransplantation is exciting. Continued active research will focus on further genetic engineering of pigs, newer immunosuppressive drugs, and tissue engineering approaches that will minimize or eliminate the need for immunosuppression. 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Fryer JP, Granger DK, Leventhal JR, et al. Steroid-related complications in the cyclosporine era. Clin Transplant. 1994; 8:224. 20. Humar A, Crotteau S, Gruessner A, et al. Steroid minimization in liver transplant recipients: impact on hepatitis C recurrence and posttransplant diabetes. Clin Transplant. 2007;21:526. 21. Matas AJ, Kandaswamy R, Gillingham KJ, et al. Prednisonefree maintenance immunosuppression—a 5-year experience. Am J Transplant. 2005;5:2473. 22. Elion GB. The George Hitchings and Gertrude Elion Lecture. The pharmacology of azathioprine. Ann N Y Acad Sci. 1993;685:400-407. 23. Remuzzi G, Lesti M, Gotti E, et al. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomized trial. Lancet. 2004;364:503. 24. Bolin P, Tanriover B, Zibari GB, et al. Improvement in 3-month patient-reported gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients. Transplantation. 2007;84(11):1443-1451. 25. Kaplan B, Schold J, Srinivas T, et al. Effect of sirolimus withdrawal in patients with deteriorating renal function. Am J Transpl. 2004;4(10):1709-1712. 26. Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant. 2006;6:514. 27. Burke JF, Pirsch JD, Ramos EL, et al. Long-term efficacy and safety of cyclosporine in renal transplant recipients. N Engl J Med. 1994;331:358. 28. Calne RY, Rolles K, White DJG, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs. Lancet. 1979;2:1033. 29. Sweny P, Farrington K, Younis F, et al. Sixteen months experience with cyclosporin A in human kidney transplantation. Transplant Proc. 1981;13:365. 30. Mihatsch MJ, Kyo M, Morozumi K, et al. The side-effects of ciclosporine-A and tacrolimus. Clin Nephrol. 1998;49(6): 356-363. 360 51. PART I 52. 53. BASIC CONSIDERATIONS 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. is suitable for pancreas and small-bowel transplantation. Surgery. 2004;135(6):629-641. Cho YW, Terasaki PI, Cecka JM. High kidney graft survival rates using non-heart-beating trauma donors. Transplant Proc. 1998;30(7):3795-3796. Kootstra G, Daemen JHC, Oomen APA. Categories of non-heart-beating donors. Transplant Proc. 1995;27(5): 2893-2894. Jay CL, Lyuksemburg V, Ladner DP, et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation a meta-analysis. Ann Surg. 2011;253(2): 259-264. Casavilla A, Ramirez C, Shapiro R, et al. Liver and kidney transplantation from non-heart beating donors: the Pittsburgh experience. Transplant Proc. 1995;27(1):710-712. Reese PP, Caplan AL, Kesselheim AS, et al. Creating a medical, ethical, and legal framework for complex living kidney donors. Clin J Am Soc Nephrol. 2006;1(6):1148-1153. Barr ML, Belghiti J, Villamil FG, et al. A report of the Vancouver forum on the care of the live organ donor: lung, liver, pancreas, and intestine data and medical guidelines. Transplantation. 2006;81(10):1373-1385. Jeon H, Lee SG. Living donor liver transplantation. Curr Opin Organ Transplant. 2010;15(3):283-287. St. Peter SD, Imber CJ, Friend PJ. Liver and kidney preservation by perfusion. Lancet. 2002;359(9306):604-613. Van der Werf WJ, D’Alessandro AM, Hoffmann RM, et al. Procurement, preservation, and transport of cadaver kidneys. Surg Clin North Am. 1998;78(1):41. Dalessandro AM, Southard JH, Love RB, et al. Organ preservation. Surg Clin North Am. 1994;74(5):1083. Feng L, Zhao N, Yao X, et al. Histidine-tryptophanketoglutarate solution vs. University of Wisconsin solution for liver transplantation: a systematic review. Liver Transplant. 2007;13(8):1125-1136. Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant. 2011;11(11): 2279-2296. Sterling WA, Pierce JC, Lee HM, et al. Comparison of methods of preservation of cadaver kidneys. Transplant Proc. 1972;4(4):621-623. Leeser DB, Bingaman AW, Poliakova L, et al. Pulsatile pump perfusion of pancreata before human islet cell isolation. Transplant Proc. 2004;36(4):1050-1051. van der Plaats A, Maathuis MHJ, Hart NAT, et al. The Groningen hypothermic liver perfusion pump: functional evaluation of a new machine perfusion system. Ann Biomed Engineer. 2006;34(12):1924-1934. Ullman E. Tissue and organ transplantation. Ann Surg. 1914; 60:195-219. Murray JE, Hills W. The first successful organ transplants in man. J Am Coll Surg. 2005;200(1):5-9. Murray JE. The 50th anniversary of the first successful human organ transplant. Revista De Investigacion Clinica. 2005;57(2):118-119. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341(23):1725-1730. Wyld M, Morton RL, Hayen A, et al. A systematic review and meta-analysis of utility-based quality of life in chronic kidney disease treatments. PLoS Med. 2012;9(9):e1001307. Scientific Registry of Transplant Recipients. http://srtr. transplant.hrsa.gov/annual_reports/2010/chapter_index.htm. Ojo AO, Hanson JA, Wolfe RA, et al. Long-term survival in renal transplant recipients with graft function. Kidney Int. 2000;57(1):307-313. 73. Kahwaji J, Bunnapradist S, Hsu JW, et al. Cause of death with graft function among renal transplant recipients in an integrated healthcare system. Transplantation. 2011;91(2):225-230. 74. Lentine KL, Costa SP, Weir MR, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. Circulation. 2012;126(5):617-663. 75. Penn I. Evaluation of transplant candidates with pre-existing malignancies. Ann Transplant. 1997;2(4):14-17. 76. Trends in tuberculosis–United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61(11):181-185. 77. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol. 1995;13:29-60. 78. Harbell J, Fung J, Nissen N, et al. Surgical complications in 275 HIV-infected liver and/or kidney transplantation recipients. Surgery. 2012;152(3):376-381. 79. Fine RN. Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children. Pediatr Nephrol. 2007;22(4):496-502. 80. Araya CE, Dharnidharka VR. The factors that may predict response to rituximab therapy in recurrent focal segmental glomerulosclerosis: a systematic review. J Transplant. 2011;2011:374213. 81. Pham PT, Pham PA, Pham PC, et al. Evaluation of adult kidney transplant candidates. Semin Dial. 2010;23(6):595-605. 82. Taylor CJ, Kosmoliaptsis V, Summers DM, et al. Back to the future: application of contemporary technology to long-standing questions about the clinical relevance of human leukocyte antigen-specific alloantibodies in renal transplantation. Hum Immunol. 2009;70(8):563-568. 83. Hume DM, Merrill JP, Miller BF, et al. Experiences with renal homotransplantation in the human: report of 9 cases. J Clin Invest. 1955;34(2):327-382. 84. Murray JE, Merrill JP, Harrison JH. Kidney transplantation between 7 pairs of identical twins. Ann Surg. 1958;148(3): 343-359. 85. Starzl TE, Marchioro TL, Dickinson TC, et al. Technique of renal homotransplantation: experience with 42 cases. Arch Surg. 1964;89(1):87-104. 86. Ghazanfar A, Tavakoli A, Zaki MR, et al. The outcome of living donor renal transplants with multiple renal arteries; a large cohort study with a mean follow-up period of 10 years. Transplant Proc. 2010;42:1654. 87. Laurence JM, Sandroussi C, Lam VWT, et al. Utilization of small pediatric donor kidneys: a decision analysis. Transplantation. 2011;91(10):1110-1113. 88. Lau KK, Berg GM, Schjoneman YG, et al. Pediatric en bloc kidney transplantation into pediatric recipients. Pediatr Transplant. 2010;14(1):100-104. 89. Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011;11(3):450-462. 90. Rizzari MD, Suszynski TM, Gillingham KJ, et al. Ten-year outcome after rapid discontinuation of prednisone in adult primary kidney transplantation. Clin J Am Soc Nephrol. 2012;7(3):494-503. 91. Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallelgroup study in adult kidney transplant recipients. Am J Transplant. 2012;12(1):210-217. 92. Massy ZA, Guijarro C, Wiederkehr MR, et al. Chronic renal allograft rejection: immunologic and nonimmunologic risk factors. Kidney Int. 1996;49(2):518-524. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 113. Shapiro AM, Ricordi C, Hering Bj, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318-1330. 114. Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005;54(7):2060-2069. 115. McCall M, James Shapiro AM. Update on islet transplantation. Cold Spring Harb Perspect Med. 2012;2(7):1-16. 116. Markmann JF, Deng S, Huang X, et al. Insulin independence following isolated islet transplantation and single islet infusions. Ann Surg. 2003;237(6):741-749. 117. Hering BJ, Kandaswamy R, Ansite JD, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA. 2005;293(7):830-835. 118. Shapiro AM. Strategies toward single-donor islets of Langerhans transplantation. Curr Opin Organ Transplant. 2011; 16(6):627-631. 119. Bellin MD, Kandaswamy R, Parkey J, et al. Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am J Transplant. 2008;8(11):2463-2470. 120. Bellin MD, Barton FB, Heitman A, et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant. 2012;12(6):1576-1583. 121. Rickels MR. Recovery of endocrine function after islet and pancreas transplantation. Curr Diabet Rep. 2012;12: 587-596. 122. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35(7):1436-1445. 123. Busuttil RW, De Carlis LG, Mihaylov PV, Gridelli B, Fassati LR, Starzl TE. The first report of orthotopic liver transplantation in the Western world. Am J Transplant. 2012;12(6): 1385-1387. 124. Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology. 1993;17(6):1127-1152. 125. Cohen C, Benjamin M. Alcoholics and liver transplantation. The Ethics and Social Impact Committee of the Transplant and Health Policy Center. JAMA. 1991;265(10):1299-1301. 126. Lucey MR. Liver transplantation in patients with alcoholic liver disease. Liver Transplant. 2011;17(7):751-759. 127. Longworth L, Young T, Buxton MJ, et al. Midterm costeffectiveness of the liver transplantation program of England and Wales for three disease groups. Liver Transplant. 2003; 9(12):1295-1307. 128. Charlton M, Ruppert K, Belle SH, et al. Long-term results and modeling to predict outcomes in recipients with HCV infection: results of the NIDDK liver transplantation database. Liver Transplant. 2004;10(9):1120-1130. 129. Garcia-Retortillo M, Forns X, Feliu A, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology. 2002;35(3):680-687. 130. Berenguer M, Prieto M, Rayon JM, et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology. 2000;32(4 Pt 1): 852-858. 131. Lake JR, Shorr JS, Steffen BJ, Chu AH, Gordon RD, Wiesner RH. Differential effects of donor age in liver transplant recipients infected with hepatitis B, hepatitis C, and without viral hepatitis. Am J Transplant. 2005;5(3):549-557. 132. Neff GW, Montalbano M, O’Brien CB, et al. Treatment of established recurrent hepatitis C in liver-transplant recipients with pegylated interferon-alfa-2b and ribavirin therapy. Transplantation. 2004;78(9):1303-1307. 133. Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007;5(11):1313-1315. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 361 CHAPTER 11 Transplantation 93. Traynor C, Jenkinson A, Williams Y, et al. Twenty-year survivors of kidney transplantation. Am J Transplant. 2012; 12:3289. 94. Sutherland ER, Gruessner RWG. History of pancreas transplantation (Chapter 4). In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: SpringerVerlag; 2004:39-68. 95. Gruessner AC. 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud. 2011;8:6-16. 96. Effects of pancreas transplantation on secondary complications of diabetes (Chapter 16). In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer-Verlag; 2004:455-508. 97. Gruessner RW, Sutherland DE, Drangstveit MB, Kandaswamy R, Gruessner AC. Pancreas allotransplants in patients with a previous total pancreatectomy for chronic pancreatitis. J Am Coll Surg. 2008;206:458-465. 98. Surgical aspects of pancreas transplantation (Chapter 8). In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer-Verlag; 2004:111-178. 99. Sutherland DER, Zamir GA, Brayman KL. Transplantation of the pancreas. In: Cameron JL, Cameron AM, eds. Current Surgical Therapy. 10th ed. New York: Elsevier Saunders; 2011:460-471. 100. Postoperative management (Chapter 9). In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer-Verlag; 2004:179-266. 101. Pancreas transplantation (Section II). In: Gruessner RWG, Benedetti E, eds. Living Donor Organ Transplantation. New York: McGraw-Hill; 2008:369-437. 102. Gruessner AC, Sutherland DER, Gruessner RWG. Long-term outcome after pancreas transplantation. Curr Opin Transplant. 2012;17:100-105. 103. Shapiro AM, Ricordi C, Hering BJ. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355:1318-3130. 104. Maffi P, Scavini M, Socci C, et al. Risks and benefits of transplantation in the cure of type 1 diabetes; whole pancreas versus islet transplantation. A single center study. Rev Diabet Stud. 2011;8:44-50. 105. Williams PW. Notes on diabetes treated with extract and by grafts of sheep’s pancreas. Br Med J. 1894;1303-1304. 106. Kelly WD, Lillehei RC, Merkel FK, et al. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery. 1967;61(6):827-837. 107. Ballinger WF, Lacy PE. Transplantation of intact pancreatic islets in rats. Surgery. 1972;72:175-186. 108. Najarian JS, Sutherland DE, Baumgartner D, et al. Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis. Ann Surg. 1980;192(4): 526-542. 109. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343(4):230-238. 110. Ryan EA, Lakey JR, Paty BW, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes. 2002;51(7):2148-2157. 111. Ryan EA, Lakey JR, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes. 2001;50(4):710-719. 112. Shapiro AM, Ricordi C, Hering B. Edmonton’s islet success has indeed been replicated elsewhere. Lancet. 2003; 362(9391):1242. 362 PART I BASIC CONSIDERATIONS 134. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuberger J. Transplantation for primary biliary cirrhosis: retrospective analysis of 400 patients in a single center. Hepatology. 2001;33(1):22-27. 135. Campsen J, Zimmerman MA, Trotter JF, et al. Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course. Liver Transplant. 2008;14(2): 181-185. 136. Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson’s disease: indications and outcome. Hepatology. 1994;19(3):583-587. 137. Medici V, Mirante VG, Fassati LR, et al. Liver transplantation for Wilson’s disease: the burden of neurological and psychiatric disorders. Liver Transplant. 2005;11(9):1056-1063. 138. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11): 693-699. 139. Heimbach JK, Haddock MG, Alberts SR, et al. Transplantation for hilar cholangiocarcinoma. Liver Transplant. 2004;10 (10 Suppl 2):S65-S68. 140. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-445. 141. Boyer TD, Haskal ZJ. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology. 2010;51(1):306. 142. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-470. 143. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124(1):91-96. 144. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, Wolfe RA. The survival benefit of liver transplantation. Am J Transplant. 2005;5(2):307-313. 145. Safdar K, Neff GW, Montalbano M, et al. Liver transplant for the septuagenarians: importance of patient selection. Transplant Proc. 2004;36(5):1445-1448. 146. Bellamy CO, DiMartini AM, Ruppert K, et al. Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence. Transplantation. 2001;72(4):619-626. 147. Vagefi PA, Parekh J, Ascher NL, Roberts JP, Freise CE. Outcomes with split liver transplantation in 106 recipients: the University of California, San Francisco, experience from 1993 to 2010. Arch Surg. 2011;146(9):1052-1059. 148. Brown RS Jr., Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med. 2003;348(9):818-825. 149. Bilzer M, Gerbes AL. Preservation injury of the liver: mechanisms and novel therapeutic strategies. J Hepatol. 2000; 32(3):508-515. 150. Jaeschke H. Preservation injury: mechanisms, prevention, and consequences. J Hepatol. 1996;25(5):774-780. 151. Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemiareperfusion injury. Am J Surg. 2001;181(2):160-166. 152. Drazan K, Shaked A, Olthoff KM, et al. Etiology and management of symptomatic adult hepatic artery thrombosis after orthotopic liver transplantation (OLT). Am Surg. 1996;62(3):237-240. 153. Tzakis AG, Gordon RD, Shaw BW Jr., Iwatsuki S, Starzl TE. Clinical presentation of hepatic artery thrombosis after liver transplantation in the cyclosporine era. Transplantation. 1985;40(6):667-671. 154. Grant D, Abu-Elmagd K, Reyes J, et al. 2003 report of the intestine transplant registry: a new era has dawned. Ann Surg. 2005;241(4):607-613. 155. Abu-Elmagd K, Mazariegos G, Bond G, et al. Intestinal transplantation: current status and future considerations. Am J Gastroenterol. 2006;101(9):S145-S146. 156. Yersiz H, Renz JF, Hisatake GM, et al. Multivisceral and isolated intestinal procurement techniques. Liver Transplant. 2003;9(8):881-886. 157. Bueno J, Abu-Elmagd K, Mazariegos G, Madariaga J, Fung J, Reyes J. Composite liver–small bowel allografts with preservation of donor duodenum and hepatic biliary system in children. J Pediatr Surg. 2000;35(2):291-295; discussion 95-96. 158. Farmer DG, McDiarmid SV, Edelstein S, et al. Improved outcome after intestinal transplantation at a single institution over 12 years. Transplant Proc. 2004;36(2):303-304. 159. Tzakis AG, Kato T, Levi DM, et al. 100 multivisceral transplants at a single center. Ann Surg. 2005;242(4):480-490; discussion 91-93. 160. Gruessner RWG, Sharp HL. Living related intestinal transplantation: first report of a standardized surgical technique. Transplant. 1997;64:1605-1607. 161. Kouchoukos NT, Blackstone EH, Doty DB. Heart failure. In: Kouchoukos NT, Blackstone EH, Doty DB, et al, eds. Cardiac Surgery. 3rd ed. New York: Kirklin/Barratt-Boyes; 2003:1725. 162. First human heart transplant. The History Channel website. Retrieved October 15, 2012, from http://www.history.com/ this-day-in-history/first-human-heart-transplant. 163. Meyers BF, Patterson GA, Haverich A, Harringer W. Lung transplantation, heart-lung transplantation. In: Pearson FG, Cooper JD, Deslauriers J, et al, eds. Thoracic Surgery. 2nd ed. New York: Churchill-Livingston; 2002:1085-1131. 164. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914-956. 165. National Transplant Data. UNOS/HRSA website. Retrieved October 12, 2012, from http://www.optn.transplant.hrsa.gov/ latestData. 166. Esker B, Cooper DKC. Overcoming the barriers to xenotransplantation: prospects for the future. Exp Rev Clin Immunol. 2010;6(2):219-230. 167. Schuurman HJ. Xenotransplantation: from the lab to the clinic: Sunrise Symposium at the XXIII International Congress of the Transplantation Society, Vancouver, Canada, August 2010. Clin Transplant. 2011;25(4):E415-E421. 168. Dooldeniya MD, Warrens AN. Xenotransplantation: where are we today? J R Soc Med. 2003;96:111. 169. Thompson P, Badell IR, Lowe M, et al. Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival. Am J Transplant. 2012;12(7):1765-1775. 170. Hering BJ, Cooper DKC, Cozzi E, et al. The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type I diabetes: executive summary. Xenotransplantation. 2009;16:196-202. 171. Schuurman HJ. Regulatory aspects of pig-to-human islet transplantation. Xenotransplantation. 2008;15(2):116-120. 172. Schuurman HJ. The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—chapter 2: Source pigs. Xenotransplantation. 2009;16(4):215-222. 173. Dorling A. Clinical xenotransplantation: pigs might fly? Am J Transplant. 2002;2:695. 174. Greenstein JL, Schuurman H-J. Solid organ xenotransplantation: progress, promise, and regulatory issues. J Comm Biotech. 2001;8:15-29. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 179. Elliot RB, Living Cell Technologies, Ltd. Towards xenotransplantation of pig islets in the clinic. Curr Opin Organ Transplant. 2011;16(2):195-200. 180. Marigliano M, Bertera S, Grupillo M, et al. Pig-to-nonhuman primate pancreatic islet xenotransplantation: an overview. Curr Diab Rep. 2011;11(5):402-412. 181. Dufrane D, Gianello P. Pig islet for xenotransplantation in human: structural and physiological compatibility for human clinical application. Transplant Rev (Orlando). 2012;26: 183-188. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 363 CHAPTER 11 Transplantation 175. Thompson P, Badell IR, Lowe M, et al. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am J Transplant. 2011;11:2593-2602. 176. Rood PPM, Cooper DKC. Islet xenotransplantation: are we really ready for clinical trials? Am J Transplant. 2006; 6(6):1269-1274. 177. Mihalicz D, Rajotte R, Rayat G. Porcine islet xenotransplantation for the treatment of type I diabetes. In: Type I Diabetes: Pathogenesis, Genetics and Immunotherapy. New York: InTech; 2011:479-502. 178. Beckwith J, Nyman JA, Flanagan B, et al. A health-economic analysis of porcine islet xenotransplantation. Xenotransplantation. 2010;17:233-242. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 12 chapter Background The Science of Patient Safety 365 365 High Reliability Organizations / 365 The Institute Of Medicine Report / 366 The Conceptual Model / 366 Creating a Culture of Safety 368 Assessing An Organization’s Safety ­Culture / 368 Teamwork and Communication 368 Measuring Teamwork / 369 Communication Tools 370 Operating Room Briefings / 370 Operating Room Debriefings / 370 Sign Outs / 371 Implementation / 372 Patient Safety Catherine L. Chen, Michol A. Cooper, Mark L. Shapiro, Peter B. Angood, and Martin A. Makary Comprehensive Unit-Based Safety Program 372 Measuring Quality in Surgery 373 Agency For Healthcare Research and Quality Patient Safety Indicators / 373 The Surgical Care Improvement Project Measures / 374 National Surgical Quality Improvement Program / 374 The Leapfrog Group / 375 World Health Organization “Safe Surgery Saves Lives” Initiative / 375 National Quality Forum / 376 “Never Events” in Surgery Retained Surgical Items / 377 BACKGROUND Patient harm due to medical mistakes can be catastrophic, resulting in high-profile consequences for the patient, surgeon, and institution. A single error can even destroy a surgeon’s 1 career. While mistakes are inherent to human nature, it is becoming more recognized that many mistakes are preventable. Patient safety is a science that promotes the use of ­evidence-based medicine and local wisdom to minimize the impact of human error on quality patient care. Wrong-site/ 2 wrong-procedure surgeries, retained sponges, unchecked blood transfusions, mismatched organ transplants, and overlooked allergies are all examples of potentially catastrophic events that can be prevented by implementing safer hospital systems. This chapter provides an overview of the modern-day field of patient safety by reviewing key measures of safety and quality, components of culture, interventions and tools, and risk management strategies in surgery. THE SCIENCE OF PATIENT SAFETY Medicine is considered a high-risk system with a high error rate, but these two characteristics are not always correlated. Other high-risk industries have managed to maintain an impeccably low error rate. For example, one of the highest risk systems in existence today, the U.S. Navy’s nuclear submarine program, has an unmatched safety record. Much of the credit for their safety record is due to the culture of the nuclear submarine program, with its insistence 376 Surgical Counts / 378 Wrong-Site Surgery / 378 The Joint Commission Universal Protocol To Ensure Correct Surgery / 378 Transparency in Healthcare Risk Management 379 380 The Importance Of Communication in Managing Risk / 380 Complications 380 Complications in Minor Procedures / 380 Organ System Complications / 383 Wounds, Drains, And Infection / 389 Nutritional And Metabolic Support ­Complications / 391 Problems With Thermoregulation / 393 on individual ownership, responsibility, attention to detail, professionalism, moral integrity, and mutual respect. These characteristics have created the cultural context necessary for high-quality communications under high-risk, high-stress ­conditions. Each reactor operator is aware of what is going on at all times and is responsible for understanding the implications and possible consequences of any action. Communication flows freely between crewmen and officers, and information about any mistakes that occur are dispersed rapidly through the entire system so that other workers can learn how to prevent similar mistakes in the future.1 High Reliability Organizations The nuclear submarine program is an example of an organization that has achieved the distinction of being considered a “high reliability organization.” High reliability organization theory recognizes that there are certain high-risk industries and organizations that have achieved very low accident and error rates compared to what would be expected given the inherent risks involved in their daily operations. Other high reliability industries and organizations include aircraft carrier flight decks, nuclear power plants, and the Federal Aviation Administration’s air traffic control system. In fact, one reason why nuclear power plants have such an excellent reliability record may be that their operators are often former naval submarine officers whose ­previous experience and training within one highly reliable organization are easily transferable to other organizations.1 One of the assumptions underlying the science of high reliability organizations is that humans who operate and m ­ anage VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 Patient harm due to medical mistakes can be catastrophic and, in some cases, result in high-profile consequences not only for the patient, but also for the surgeon and institution. Patient safety is a science that promotes the use of evidencebased medicine and common sense improvements in an attempt to minimize the impact of human error on the routine delivery of services. The structure-process-outcome framework within the context of an organization’s culture helps to clarify how risks and ­hazards embedded within the organization’s structure may potentially lead to error and injure or harm patients. complex systems are themselves not sufficiently complex to sense and anticipate the problems generated by the system.2 This introduces another important idea undergirding the science of patient safety: the concept of normal accident theory. Instead of attributing accidents to individual error, this theory states that accidents are intrinsic to high-volume activities and even inevitable in some settings. Accidents should not be used merely to identify and punish the person at fault, but should be seen as a systems problem and addressed at a broader level. As Reason states, even the “best people can make the worst errors as a result of latent conditions.”2 High-risk systems, as defined by Perrow in 19841: • H  ave the potential to create a catastrophe, loosely defined as an event leading to loss of human or animal life, despoiling of the environment, or some other situation that gives rise to the sense of “dread.” • Are complex, in that they have large numbers of highly interdependent subsystems with many possible combinations that are nonlinear and poorly understood. • Are tightly coupled, so that any perturbation in the ­system is transmitted rapidly between subsystems with little ­attenuation. However, high reliability organization theory suggests that proper oversight of people, processes, and technology can handle complex and hazardous activities and keep error rates acceptably low.2 Studies of multiple high reliability organizations show that they share the following common characteristics2: • People are supportive of one another. • People trust one another. • People have friendly, open relationships emphasizing credibility and attentiveness. • The work environment is resilient and emphasizes creativity and goal achievement, providing strong feelings of credibility and personal trust. 366 Developing these characteristics is an important step toward achieving a low error rate in any organization. For this reason, safety culture is a measure used by hospitals nationwide to improve outcomes and is increasingly recognized as a metric of hospital quality. 4 5 6 7 Poor communication contributes to approximately 60% of the sentinel events reported to The Joint Commission. Operating room briefings are team discussions of critical issues and potential hazards that can improve the safety of the operation and have been shown to improve operating room culture and decrease operating room delays. National Quality Forum surgical “never events” include retained surgical items, wrong-site surgery, and death on the day of surgery of a normal healthy patient (American Society of Anesthesiologists Class 1). Patient rapport is the most important determinant of ­malpractice claims against a surgeon. The Institute of Medicine Report Although healthcare as a whole can be considered a high-risk system, it is far from a high reliability organization. This fact was brought to light in the Institute of Medicine’s report “To Err Is Human: Building a Safer Health System,” which was published in 2000.3 A landmark document in raising awareness of the magnitude of the problem of medical mistakes, the report is the most frequently cited document in the medical literature in recent years.4 The Institute of Medicine (IOM) report shocked the healthcare community by concluding that between 44,000 and 98,000 deaths and over 1 million injuries occurred each year in American hospitals due to medical error. In fact, the number of deaths attributed to medical error is the aviation equivalent of one jumbo jet crash per day. As this report was disseminated, awareness about medical errors increased, and physicians and other health providers began speaking openly about mistakes and the difficulties they face when dealing with them. The IOM report brought much-needed attention to the field of patient safety. In addition, it standardized the language used to describe errors in medicine, defining important terms for future research and quality improvement (Table 12-1). Following its publication, interest in patient safety research and programs increased exponentially. In an effort to improve patient safety, health services researchers began to collaborate with scientists from other disciplines, such as human factors engineering, psychology, and informatics to develop innovative solutions to longstanding safety problems. The discussion around patient safety also became more personalized by highlighting the stories of individual patients who had died from medical errors. Most importantly, the report transformed the conversation about patient safety from blaming individuals for errors to improving the systems that allow them to take place (Case 12-1).5 The Conceptual Model The Donabedian model of measuring quality identifies three main types of improvements: changes to structure, process, and outcome (Fig. 12-1).6 Structure refers to the physical and 3 organizational tools, equipment, and policies that improve safety. Structural measures ask, “Do the right tools, equipment, and policies exist?” Process is the application of these tools, equipment, and policies/procedures to patients (good practices VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 367 Table 12-1 Types of medical error Source: From Woreta et al,50 with permission. Case 12-1 Systems change resulting from medical error Libby Zion was an 18-year-old woman who died after being admitted to the New York Hospital with fever and agitation on the evening of October 4, 1984. Her father, Sidney Zion, a lawyer and columnist for the N.Y. Daily News, was convinced that his daughter’s death was due to inadequate staffing and overworked physicians at the hospital and was determined to bring about changes to prevent other patients from suffering as a result of the teaching hospital system. Due to his efforts to publicize the circumstances surrounding his daughter’s death, Manhattan District Attorney Robert Morgenthau agreed to let a grand jury consider murder charges. Although the hospital was not indicted, in May 1986, a grand jury issued a report strongly criticizing “the supervision of interns and junior residents at a hospital in NY County.” As a result, New York State Health Commissioner David Axelrod convened a panel of experts headed by Bertrand M. Bell, a primary care physician at Albert Einstein College of Medicine who had long been critical of the lack of supervision of physicians-in-training, to evaluate the training and supervision of doctors in New York State. The Bell Commission recommended that residents work no more than 80 hours per week and no more than 24 consecutive hours per shift, and that a senior physician needed to be physically present in the hospital at all times. These recommendations were adopted by New York State in 1989. In 2003, the Accreditation Council on Graduate Medical Education followed by mandating that all residency training programs adhere to the reduced work hour schedule. Structure Process Outcome Context: Are we improving the safety culture? Figure 12-1. Donebedian model for measuring quality. (From Makary et al,6 with permission.) and evidence-based medicine). Process measures ask, “Are the right tools, policies, and equipment being used?” Outcome is the result on patients. Outcome measures ask, “How often are patients harmed?” In this model, structure (how care is organized) plus process (what we do) influences patient outcomes (the results achieved).7 The structure, process, and outcome components of quality measurement all occur within the context of an organization’s overall culture. The local culture impacts all aspects of the delivery of care because it affects how front-line personnel understand and deliver safe patient care. In fact, culture (collective attitudes and beliefs of caregivers) is increasingly being recognized to be the fourth measurable component to the structure-process-outcome model. This recognition is based on growing evidence that local culture is linked to a variety of important clinical outcomes.7 For any new patient safety initiative to be deemed successful, any change in structure or process must lead to a corresponding positive change in patient outcomes.8 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 12 Patient Safety Adverse event • Injury caused by medical management rather than the underlying condition of the patient • Prolongs hospitalization, produces a disability at discharge, or both • Classified as preventable or unpreventable Negligence • Care that falls below a recognized standard of care • Standard of care is considered to be care a reasonable physician of similar knowledge, training, and experience would use in similar circumstances Near miss • An error that does not result in patient harm • Analysis of near misses provides the opportunity to identify and remedy system failures before the occurrence of harm Sentinel event • An unexpected occurrence involving death or serious physical or psychological injury • The injury involves loss of limb or function • This type of event requires immediate investigation and response • Other examples • Hemolytic transfusion reaction involving administration of blood or blood products having major blood group incompatibilities • Wrong-site, wrong-procedure, or wrong-patient surgery • A medication error or other treatment-related error resulting in death • Unintentional retention of a foreign body in a patient after surgery 368 CREATING A CULTURE OF SAFETY PART I Culture is to an organization what personality is to the ­individual—a hidden, yet unifying theme that provides meaning, direction, and mobilization.2 Organizations with effective safety cultures share a constant commitment to safety as a ­top-level priority that permeates the entire organization. These organizations frequently share the following characteristics9: Case 12-2 High-profile sentinel event BASIC CONSIDERATIONS • A  n acknowledgment of the high-risk, error-prone nature of an organization’s activities • A nonpunitive environment where individuals are able to report errors or close calls without fear of punishment or retaliation • An expectation of collaboration across ranks to seek solutions to vulnerabilities • A willingness on the part of the organization to direct resources to address safety concerns Traditional surgical culture stands almost in direct o­ pposition to the values upheld by organizations with effective safety cultures for several reasons. Surgeons are less likely to acknowledge their propensity to make mistakes or to admit these mistakes to others.10 Surgeons tend to minimize the effect of stress on their ability to make decisions.11 The surgical culture, especially in the operating room (OR), is traditionally rife with hierarchy. Intimidation of other OR personnel by surgeons was historically accepted as the norm. This can prevent nurses and other OR staff from pointing out potential errors or mistakes. Moreover, this culture is not limited to the OR. In the intensive care unit (ICU), when compared to physicians, nurses reported more difficulty speaking up, disagreements were not appropriately resolved, and decisions were made without adequate input.12 In addition, the field of medicine strongly values professional autonomy, which frequently promotes individualism over cooperation, often to the detriment of patient care.13 Finally, patient safety, although often viewed as important, is seldom promoted from an organizational priority to an organizational value. Organizations often do not feel the need to devote resources to overhauling their patient safety systems as long as they perceive their existing processes to be adequate. It often takes a high-profile sentinel event to motivate leaders to commit the necessary time and resources to improving patient safety within their organization, as exemplified by the Dana-Farber Institute in the aftermath of Betsy Lehman’s death (Case 12-2). Assessing an Organization’s Safety Culture Efforts to foster cultural change within an organization with regard to patient safety have been limited in the past by the inability to measure the impact of any given intervention. However, studies have shown that employee attitudes about culture are associated with error reduction behaviors in aviation and with patient outcomes in ICUs. The Safety Attitudes Questionnaire (SAQ) is a validated survey instrument that can be used to measure culture in a healthcare setting.6 Adapted from two safety tools used in aviation, the Flight Management Attitudes Questionnaire and its predecessor, the Cockpit Management Attitudes Questionnaire, the SAQ consists of a series of questions measuring six domains: teamwork climate, safety climate, job satisfaction, perception of management, stress recognition, and working conditions. The safety climate scale portion of the questionnaire ­consists of the following seven items: On December 3, 1994, Betsy Lehman, a Boston Globe health columnist, died as a result of receiving four times the intended dose of chemotherapy for breast cancer. Remarkably, 2 days later, Maureen Bateman, a teacher being treated for cancer, also received a chemotherapy overdose and suffered irreversible heart damage. After investigating the medication errors, the prescribing doctor, three druggists, and 15 nurses were disciplined by state regulators. The hospital was sued by the two women’s families and by one of the doctors disciplined. As a result of this widely publicized event, the DanaFarber Cancer Institute invested more than $11 million to overhaul their safety programs, including providing new training for their employees and giving doctors more time to meet with patients. The hospital adopted a full disclosure policy so that patients would be informed anytime a mistake had affected their care. Dana-Farber also started a patient committee providing advice and feedback on ways to improve care at the hospital. • I am encouraged by my colleagues to report any patient safety concerns I may have. • The culture in this clinical area makes it easy to learn from the mistakes of others. • Medical errors are handled appropriately in this clinical area. • I know the proper channels to direct questions regarding patient safety in this clinical area. • I receive appropriate feedback about my performance. • I would feel safe being treated here as a patient. • In this clinical area, it is difficult to discuss mistakes. Although perceptions of teamwork climate can differ as a function of one’s role in the OR, perceptions of safety ­climate are relatively consistent across OR providers in a given hospital. Validated in over 500 hospitals, the SAQ is used to establish benchmark safety culture scores by healthcare worker type, department, and hospital. Using this survey, hospitals can compare culture between different types of healthcare workers within a department as well as culture between departments throughout the institution. Scores can be compared to those of other participating institutions to compare safety climates. This allows hospitals to participate with one another to implement programs to improve safety culture. In addition, scores are used to evaluate the effectiveness of safety interventions by comparing the SAQ safety climate scores after implementation to baseline scores. Strong teamwork is at the core of any effective organization and is a key element to ensuring patient safety in the OR. Teamwork is dependent on the underlying culture and patterns of communication. The ability for all team members, to “speak up” about patient safety concerns is one of the most important elements of creating a culture of patient safety. TEAMWORK AND COMMUNICATION According to The Joint Commission, communication breakdown is one of the top three root causes of sentinel events such as wrong-site surgery (Fig. 12-2). Poor communication ­contributed to over 60% of sentinel events reported to The Joint VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 369 0 20 40 60 80 Percent of Events (%) Measuring Teamwork Research in commercial aviation has demonstrated a strong correlation between better teamwork and improved safety performance. Cockpit crew members’ reluctance to question a ­captain’s judgment has been identified as a root cause of aviation accidents. Good attitudes about teamwork are associated with error-reduction behaviors in aviation, improved patient outcomes in ICUs, and decreased nurse turnover in the OR. It is also associated with higher job satisfaction ratings and less sick time taken from work. The SAQ can be used to measure teamwork and provide benchmarks for departments or hospitals seeking to measure and improve their teamwork climate.17 The SAQ teamwork scores are responsive to interventions that aim to improve teamwork among operating teams, such as the implementation of ICU checklists, executive walk rounds, and preoperative briefing team discussions. The communication and collaboration sections of the SAQ reflect OR caregiver views on teamwork and can be used to distinguish meaningful interventions from impractical and ineffective programs. In a survey of OR personnel across 60 hospitals, the SAQ identified substantial differences in the perception of teamwork in the OR depending on one’s role. Physicians frequently rated the teamwork of others as good, while nurses at the same institutions perceived teamwork as poor (Fig. 12-3). Similar discrepancies have been found in ICUs. These discrepancies can be attributed to differences in the communication skills that are valued by surgeons and nurses. For example, nurses describe good collaboration as having their input respected, while physicians describe good collaboration as having nurses who can anticipate their needs and follow instructions. Efforts to improve the communication that takes place between physicians and nurses can directly improve the perception of teamwork and collaboration by the OR team (Table 12-2). Empowering well-respected surgeons to promote principles of teamwork and communication can go a long way toward transforming attitudinal and behavioral changes in fellow physicians as well as other members of the surgical team. Surgeons are increasingly encouraging the respectful and timely voicing of concerns of OR personnel. Percent rating quality of collaboration and communication as high or very high Commission in 2011.14 Good communication is an essential component of teamwork and is especially is important in the OR, one of the most complex work environments in healthcare. Within the realm of patient care, there are enormous amounts of information being exchanged between healthcare providers on a daily basis. Much of this information, if prioritized correctly, has the potential to prevent unintended medical errors and serious harm to patients. The importance of good communication in preventing medical errors is undeniable; however, it is difficult to achieve. The traditional surgical hierarchy can prevent OR personnel from sharing important patient data and expressing safety concerns. One perioperative field study showed a 30% rate of communication failure in the OR, with 36% of these breakdowns having a substantial impact on patient safety.15 In addition to overcoming the cultural barrier to ­better teamwork and communication, The prospective study by C ­ hristian and associates of patient safety in the OR demonstrated that the standard workflow of the OR itself presents many opportunities for the loss or degradation of critical information.16 Hand-offs of patient care from the OR to other locations or providers are particularly prone to information loss, which has been demonstrated in other clinical settings. ­Hand-offs and auxiliary tasks, such as the surgical count, frequently take place during critical portions of the case and place competing demands on provider attention from primary patient-centered activities. Communication between the surgeon and pathologist also is vulnerable, because the communication often occurs through secondary messengers such as nurses or technicians. This information loss can lead to delays, overuse of staff and resources, uncertainty in clinical decision making and planning, and oversights in patient preparation. 4 Figure 12-2. Root causes of sentinel events 2004 to 2012. (From Makary et al,17 with permission from Elsevier. ©2006 by the American College of Surgeons.) 100% 90% 87% 80% 70% 60% 48% 50% 40% 30% 20% 10% 0% Surgeon rates OR nurse OR nurse rates surgeon Figure 12-3. Differences in teamwork perceptions between surgeons and operating room (OR) nurses. (From Makary et al,17 with permission. Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 12 Patient Safety Human Factors Leadership Communication Assessment Physical Environment Information Management Operative Care Care Planning Continuum of Care Medication Use 370 Table 12-2 Percentage of operating room caregivers reporting a high or very high level of collaboration with other members of the operating room team PART I Caregiver Position Performing Rating Caregiver Position Being Rated Surgeon Anesthesiologist Nurse CRNA BASIC CONSIDERATIONS Surgeon 85 84 88 87 Anesthesiologist 70 96 89 92 Nurse 48 63 81 68 CRNA 58 75 76 93 The best teamwork scores were recorded by anesthesiologists when they rated their teamwork with other anesthesiologists (“high” or “very high” 96% of the time). The lowest teamwork ratings were recorded by nurses when they rated their teamwork with surgeons (“high” or “very high” 48% of the time). CRNA = certified registered nurse anesthetist. Source: From Makary et al,17 with permission from Elsevier. ©2006 by the American College of Surgeons. COMMUNICATION TOOLS High reliability organizations such as aviation frequently use tools such as prompts, checks, standard operating protocols, and communication interventions such as team briefings and debriefings. These tools identify and mitigate hazards and allow an organization to complete tasks more efficiently. They also foster a culture of open communication and speaking up if a team member senses a safety concern. Safety checks and 5 standardized team discussions serve as prompts to help “engineer out” human error, providing quality assurance and improving information flow. They also can prevent errors related to omissions, which are more likely to occur when there is information overload, multiple steps in a process, repetitions in steps, and planned departures from routine processes, and when there are other interruptions and distractions present while the process is being executed. These same interventions have been shown to improve patient safety in ORs and ICUs.18,19 Operating Room Briefings Preoperative briefings and checklists, when used appropriately, help to facilitate transfer of information between team members (Table 12-3). A briefing, or checklist, is any preprocedure discussion of requirements, needs, and special issues of the procedure. Briefings often are locally adapted to the specific needs of the specialty. They have been associated with an improved safety culture, including increased awareness of wrong-site/ wrong-procedure errors, early reporting of equipment problems, reduced operational costs and fewer unexpected delays. In one Table 12-3 Five-point operating room briefing What are the names and roles of the team members? Is the correct patient/procedure confirmed? (The Joint Commission Universal Protocol [TIME-OUT]) Have antibiotics been given? (if appropriate) What are the critical steps of the procedure? What are the potential problems for the case? Source: From Makary et al,19 with permission from Elsevier. ©2007 by the American College of Surgeons. study, 30.9% of OR personnel reported a delay before the institution of OR briefings, and only 23.3% reported delays after briefings were instituted.20 OR briefings are increasingly being used to ensure evidence-based measures, such as the appropriate administration of preoperative antibiotics and deep vein thrombosis (DVT) prophylaxis, are used. Briefings allow personnel to discuss potential problems, before they become a “near miss” or cause actual harm. The World Health Organization (WHO) has recently developed a comprehensive perioperative checklist as a primary intervention of the “Safe Surgery Saves Lives” program—an effort to reduce surgical deaths across the globe (Fig. 12-4).21 The WHO checklist includes prompts to ensure that infection prevention measures are followed, potential airway complications are precluded (e.g., anesthesia has necessary equipment and assistance for a patient with a difficult airway), and the groundwork for effective surgical teamwork is established (e.g., proper introductions of all OR personnel). Aspects of The Joint Commission’s preprocedure “Universal Protocol” (or “timeout”) also are included in the checklist (e.g., checks to ensure operation performed on correct patient and correct site). Operating Room Debriefings Postprocedural debriefings improve patient safety by allowing for discussion and reflection on causes for errors and critical incidents that occurred during the case. Errors or critical incidents are regarded as learning opportunities rather than cause for punishment. During the debriefing, the team also can discuss what went well during the case and designate a point person to follow up on any proposed actions that result from the discussion. In addition, most debriefings include a verification of the sponge, needle, and instrument counts and confirmation of the correct labeling of the surgical specimen. Errors in surgical specimen labeling have not received as much attention as incorrect sponge or instrument counts as an indicator of the quality of communication in the OR. However, an error in communication or during the hand-off process increases the risk of mislabeling a surgical specimen before its arrival in a pathology laboratory. In one study, this type of identification error occurred in 4.3 per 1000 surgical specimens, which implies an annualized rate of occurrence of 182 mislabeled VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 371 Surgical Safety Checklist Before skin incision Before patient leaves operating room (with at least nurse and anaesthetist) (with nurse, anaesthetist and surgeon) (with nurse, anaesthetist and surgeon) Has the patient confirmed his/her identity, site, procedure, and consent? Yes Confirm all team members have introduced themselves by name and role. Confirm the patient’s name, procedure, and where the incision will be made. Is the site marked? Yes Not applicable Is the anaesthesia machine and medication check complete? Yes Is the pulse oximeter on the patient and functioning? Yes Has antibiotic prophylaxis been given within the last 60 minutes? Yes Not applicable Anticipated Critical Events To Surgeon: What are the critical or non-routine steps? How long will the case take? What is the anticipated blood loss? Does the patient have a: Known allergy? No Yes Nurse Verbally Confirms: The name of the procedure Completion of instrument, sponge and needle counts Specimen labelling (read specimen labels aloud, including patient name) Whether there are any equipment problems to be addressed To Surgeon, Anaesthetist and Nurse: What are the key concerns for recovery and management of this patient? To Anaesthetist: Are there any patient-specific concerns? To Nursing Team: Has sterility (including indicator results) been confirmed? Are there equipment issues or any concerns? Difficult airway or aspiration risk? No Yes, and equipment/assistance available Risk of >500ml blood loss (7ml/kg in children)? No Yes, and two IVs/central access and fluids planned Is essential imaging displayed? Yes Not applicable This checklist is not intended to be comprehensive. Additions and modifications to fit local practice are encouraged. Revised 1 / 2009 © WHO, 2009 Figure 12-4. World Health Organization surgical safety checklist. (Reproduced with permission from World Health Organization Safe Surgery Saves Lives. Available at: http://www.who.int/patientsafety/safesurgery/en/. Accessed November 8, 2012.) specimens per year (Fig. 12-5).22 Errors involving specimen identification can result in delays in care, the need for an additional biopsy or therapy, failure to use appropriate therapy, or therapy administered to the wrong body site, side, or patient. These system failures can lead to significant harm to the patient, costs to the institution, and distrust by a community. Given the frequency of occurrence and the feasibility and validity of measuring them, mislabeled surgical specimens may serve as a useful indicator of patient safety, and should be included in any postprocedural debriefing checklist. Sign Outs In healthcare, information frequently passes to covering providers without prioritizing potential concerns. This makes sign outs a very vulnerable process of care, which can lead to catastrophic events. The term sign out can refer to either the verbal or written communication of patient information to familiarize oncoming physicians about patients who will be under their care. Sign outs should occur whenever a patient’s care setting or provider is changing. When performed well, sign outs help to ensure the Incidence (per 1000 specimens) 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Specimen Empty not labeled container Incorrect laterality Incorrect tissue site Incorrect patient name No patient name No tissue site Error type VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 12-5. Incidence of identification errors observed per 1000 specimens (n = 21,351). (From Makary et al,22 with permission. Copyright Elsevier.) CHAPTER 12 Patient Safety Before induction of anaesthesia Case 12-3 Inadequate sign out leading to medical error PART I BASIC CONSIDERATIONS Josie King was an 18-month-old child who was admitted to Johns Hopkins Hospital in January of 2001 for first- and seconddegree burns. She spent 10 days in the pediatric intensive care unit and was well on her way to recovery. She was transferred to an intermediate care floor with the expectation that she would be sent home in a few days. The following week, her central line was removed, but nurses would not allow Josie to drink anything by mouth. Around 1 p.m. the next day, a nurse came to Josie’s bedside with a syringe of methadone. Although Josie’s mother told the nurse that there was no order for narcotics, the nurse insisted that the orders had been changed and administered the drug. Josie’s heart stopped, and her eyes became fixed. She was moved to the pediatric intensive care unit and placed on life support. Two days later, on February 22, 2001, she died from severe dehydration. After her death, Josie’s parents, Sorrel and Jay King, were motivated to work with leaders at Johns Hopkins to ensure that no other family would have to endure the death of a child due to medical error. They later funded the Josie King Patient Safety Program and an academic scholarship in the field of safety. transfer of pertinent information. However, previous studies have shown the hand-off process to be variable, unstructured, and prone to error. Common categories of communication failure during sign outs include content omissions, such as failure to mention active medical problems, and failures in the actual communication process, such as leaving illegible or unclear notes (Case 12-3).23 These failures lead to confusion and uncertainty by the covering physician during patient care decisions, resulting in the delivery of inefficient and suboptimal care. The use of more structured verbal communication such as the Situational Debriefing Model, otherwise known as SBAR (situation, background, assessment, and recommendation), used by the U.S. Navy, can be applied to healthcare to improve the communication of critical information in a timely and orderly fashion.23 In addition, all sign outs should begin with the statement, “In this patient, I am most concerned about . . .” to signal to the healthcare provider on the receiving end the most important safety concerns regarding that specific patient. Implementation Tools such as checklists, sign outs, briefings, and debriefings improve communication between healthcare providers and create a safer patient environment (Fig. 12-6). Although their use in healthcare is still highly variable, specialties that have ­incorporated them, such as intensive care and anesthesia, have made impressive strides in patient safety. Currently, communication breakdowns, information loss, hand off, multiple competing tasks, and high workload are considered “annoying but accepted features” of the perioperative environment.17 As physician attitudes toward errors, stress, and teamwork in medicine become more favorable toward the common goals of reducing error and improving teamwork and communication, medicine will likely achieve many of the milestones in safety that high-reliability industries such as aviation have already accomplished. COMPREHENSIVE UNIT-BASED SAFETY PROGRAM As medical care and hospitals continue to expand, the care that is provided to patients is becoming more fragmented. This f­ragmentation makes communication more difficult and opportunities for medical errors more common. These problems require common sense solutions, often necessitating a change in the way that care is delivered on the local level. Unit-based meetings to discuss processes that are potentially dangerous for patients can quickly bring danger areas out into the open. 100 Percent of respondents who agreed 372 90 80 Prebriefing Postbriefing 70 60 50 40 30 20 10 0 A preoperative The surgical site Decision making Surgery and of the operation utilized input anesthesia discussion increased my was clear to me from relevant worked together before the personnel. as a wellawareness of the incision. coordinated surgical site and team. side being operated on. Figure 12-6. Impact of operating room briefings on teamwork and communication. (From Makary et al,19 with permission from Elsevier. ©2007 by the American College of Surgeons.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ MEASURING QUALITY IN SURGERY Despite the newfound focus on patient safety in surgery and the number of initiatives being undertaken by many organizations to improve their safety culture, there are few tools to actually measure whether these efforts actually are effective in reducing the number of errors. Several agencies and private groups have developed criteria to evaluate quality and safety within hospitals. Table 12-4 Agency for Healthcare Research and Quality patient safety indicators Provider-level patient safety indicators • Complications of anesthesia • Death in low mortality diagnosis-related groups • Decubitus ulcer • Failure to rescue • Foreign body left in during procedure • Iatrogenic pneumothorax • Selected infections due to medical care • Postoperative hip fracture • Postoperative hemorrhage or hematoma • Postoperative physiologic and metabolic derangements • Postoperative respiratory failure • Postoperative pulmonary embolism or deep vein thrombosis • Postoperative sepsis • Postoperative wound dehiscence in abdominopelvic surgical patients • Accidental puncture and laceration • Transfusion reaction • Birth trauma—injury to neonate • Obstetric trauma—vaginal delivery with instrument • Obstetric trauma—vaginal delivery without instrument • Obstetric trauma—cesarean delivery Area-level patient safety indicators • Foreign body left in during procedure • Iatrogenic pneumothorax • Selected infections due to medical care • Postoperative wound dehiscence in abdominopelvic surgical patients • Accidental puncture and laceration • Transfusion reaction • Postoperative hemorrhage or hematoma Source: From Agency for Healthcare Research and Quality27 Agency for Healthcare Research and Quality Patient Safety Indicators The Agency for Healthcare Research and Quality (AHRQ) was created in 1989 as a Public Health Service agency in the Department of Health and Human Services. Its mission is to improve the quality, safety, efficiency, and effectiveness of healthcare for all Americans. Nearly 80% of the AHRQ’s budget is awarded as grants and contracts to researchers at universities and other research institutions across the country. The AHRQ sponsors and conducts research that provides evidence-based information on healthcare outcomes, quality, cost, use, and access. It has advocated the use of readily available hospital inpatient administrative data to measure healthcare quality. The information helps healthcare decision makers make more informed decisions and improve the quality of healthcare services.26 One of the major contributions of the AHRQ is a set of Patient Safety Indicators (PSIs), initially released in 2003 and revised in 2010. PSIs are a tool to help health system leaders identify potential adverse events occurring during hospitalization. Developed after a comprehensive literature review, ­analysis of International Classification of Diseases, Ninth ­Revision, Clinical Modification (ICD-9-CM) codes, review by a clinician panel, implementation of risk adjustment, and empirical analyses, these 27 indicators provide information on potential in-hospital complications and adverse events following surgeries, procedures, and childbirth (Table 12-4). Provider-level indicators provide a measure of the potentially preventable complications for patients who received their initial care and the complication of care within the same ­hospitalization. They include only those cases where a secondary diagnosis code flags a potentially preventable complication. Area-level indicators capture all cases of the potentially ­preventable complications that occur in a given area (e.g., ­ metropolitan area or county), either during their initial hospitalization or resulting in subsequent hospitalization.27 Currently, PSIs are considered indicators, not definitive measures, of patient safety concerns. They can identify potential safety problems that merit further investigation. They also can be used to better prioritize and evaluate local and national initiatives, and even as benchmarks for tracking progress in patient safety. In the future, further growth in electronic health data will make administrative data based tools like the PSIs more useful.28 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 373 CHAPTER 12 Patient Safety These meetings should be held on a regular basis and bring together a multidisciplinary team of physicians, nurses, technicians, social workers, and other staff who can each voice their concerns about safety hazards in their area. This enables all aspects of patient care to be addressed and improved continuously, thereby streamlining and improving patient care.24 The implementation of the Comprehensive Unit-Based Safety Program (CUSP) involves measurement of a unit’s safety culture prior to starting the program and inclusion of hospital management from the start. Having management involved allows for more efficient allocation of resources and allows them to better understand the problems faced by front-line providers. Once CUSP is in place, changes can be made using local wisdom to advance patient care.24 The impact of changes made using CUSP can be measured using both patient outcomes and safety culture data. Implementation of CUSP has been associated with improved patient outcomes including decreased surgical site infections. In a 2-year study of colorectal patients, where the first year was pre-CUSP implementation and the second year was post-CUSP implementation, there was a 33% decrease in the surgical site infection rate after CUSP.25 In this study, the CUSP group met monthly and came up with a list of interventions based on their experience with these cases, including ­standardization of skin preparation and warming of patients in the preanesthesia area. This study showed that CUSP can be highly effective in ameliorating patient harm and improving patient care. 374 The Surgical Care Improvement Project Measures PART I BASIC CONSIDERATIONS The Surgical Care Improvement Project (SCIP) was established in 2003 by a national partnership of organizations committed to improving surgical care by reducing surgical complications. The steering committee is comprised of groups such as the ­Centers for Medicare and Medicaid Services, the American Hospital Association, Centers for Disease Control and Prevention (CDC), Institute for Healthcare Improvement, The Joint Commission, and others. The incidence of postoperative complications ranges from 6% for patients undergoing noncardiac surgery to more than 30% for patients undergoing high-risk surgery. Common postoperative complications include surgical site infections (SSIs), myocardial infarction, postoperative pneumonia, and thromboembolic complications. Patients who experience postoperative complications have increased hospital length of stay (3–11 days longer than those without complications), increased hospital costs (ranging from $1398 for an infectious complication to $18,310 for a thromboembolic event), and increased mortality (median patient survival decreases by up to 69%).29 Despite well-established evidence that many of these adverse events are preventable, failure to comply with standards of care known to prevent them results in unnecessary harm to a large number of patients. SCIP has identified three broad areas within surgery where potential complications have a high incidence and cost and there is a significant opportunity for prevention: SSIs, venous thromboembolism, and adverse cardiac events. The SCIP measures aim to reduce the incidence of these events during the perioperative period by advocating the use of proven process and outcome measures. These process and outcome measures are detailed in Table 12-5. SSIs account for 14% to 16% of all hospital-acquired infections and are a common complication of care, occurring in 2% to 5% of patients after clean extra-abdominal operations and up to 20% of patients undergoing intra-abdominal procedures. By implementing steps to reduce SSIs, hospitals could recognize a savings of $3152 and reduction in extended length of stay by 7 days on each patient developing an infection.30 Adverse cardiac events occur in 2% to 5% of patients undergoing noncardiac surgery and as many as 34% of patients undergoing vascular surgery. Certain perioperative cardiac events, such as myocardial infarction, are associated with a mortality rate of 40% to 70% per event, prolonged hospitalization, and higher costs. Appropriately administered β-blockers reduce perioperative ischemia, especially in at-risk patients. It has been found that nearly half of the fatal cardiac events could be preventable with β-blocker therapy.30 DVT occurs after approximately 25% of all major surgical procedures performed without prophylaxis, and pulmonary embolism (PE) occurs after 7%. Despite the well-established efficacy and safety of preventive measures, studies show that prophylaxis often is underused or used inappropriately. Both low-dose unfractionated heparin and low molecular weight heparin have similar efficacy in DVT and PE prevention. ­Prophylaxis using low-dose unfractionated heparin has been shown to reduce the incidence of fatal PEs by 50%.30 The SCIP effort provides an infrastructure and guidelines for data collection and quality improvement on a national scale. By achieving high levels of compliance with evidence-based practices to reduce SSIs, venous thromboembolism events, and perioperative cardiac complications, the potential number of Table 12-5 The Surgical Care Improvement Project measures Process of care performance measures Infection • Prophylactic antibiotic received within 1 h before surgical incision • Prophylactic antibiotic selection for surgical patients • Prophylactic antibiotics discontinued within 24 h after surgery end time (48 h for cardiac patients) • Cardiac surgery patients with controlled 6 a.m. postoperative serum glucose • Surgery patients with appropriate hair removal • Colorectal surgery patients with immediate postoperative normothermia Venous thromboembolism • Surgery patients with recommended venous thromboembolism prophylaxis ordered • Surgery patients who received appropriate venous thromboembolism prophylaxis within 24 h before surgery to 24 h after surgery Cardiac events • Surgery patients on a β-blocker prior to arrival who received a β-blocker during the perioperative period Proposed outcome measures Infection • Postoperative wound infection diagnosed during index hospitalization Venous thromboembolism • Intra- or postoperative pulmonary embolism diagnosed during index hospitalization and within 30 d of surgery • Intra- or postoperative deep vein thrombosis diagnosed during index hospitalization and within 30 d of surgery Cardiac events • Intra- or postoperative acute myocardial infarction diagnosed during index hospitalization and within 30 d of surgery Global measures • Mortality within 30 d of surgery • Readmission within 30 d of surgery Source: From Surgical Care Improvement Project,30 with permission. lives saved in the Medicare patient population alone exceeds 13,000 annually.29 National Surgical Quality Improvement Program The National Surgical Quality Improvement Program (NSQIP) is a measurement program that allows hospitals to sample their rates of postoperative events and compare them to similar hospitals. Created by the Veterans Health Administration (VA) in 1991, NSQIP has been credited with measuring and improving morbidity and mortality outcomes at the VA, reducing 30-day mortality rate after major surgery by 31%, and 30-day postoperative morbidity by 45% in its first decade.31 Beta testing at 18 non-VA sites from 2001 to 2004 demonstrated the feasibility and utility of the program in the private sector. The program was subsequently expanded to the private sector in 2004 when the American College of Surgeons endorsed the program and encouraged hospital participation to measure and evaluate outcomes on VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ The Leapfrog Group One of the largest efforts to standardize evidence-based medicine in the United States is led by The Leapfrog Group, an alliance of large public and private healthcare purchasers representing more than 37 million individuals across the United States. This healthcare consortium was founded in 2000 with the aim to exert their combined leverage toward improving nationwide standards of healthcare quality, optimizing patient outcomes, and ultimately lowering healthcare costs. The Leapfrog Group’s strategy to achieve these goals is through providing patient referral, financial incentives, and public recognition for hospitals that practice or implement evidence-based healthcare standards. The healthcare quality and safety practices (leaps) that Leapfrog initially identified to measure healthcare standards were hospital use of computerized physician order entry systems, 24-hour ICU physician staffing, and evidence-based hospital referral (EBHR) standards for five high-risk operations.33 In 2010, after the National Quality Forum (NQF) released its updated Safe Practices for Better Healthcare, Leapfrog added a safe practices leap, which includes eight practices from the NQF report.34 Leapfrog collects data on these practices through administration of an ongoing, voluntary, web-based hospital quality and safety survey. This survey is conducted in 41 regions that cover over half of the U.S. population and 62% of all hospital beds in the country. In 2011, more than 1200 urban, suburban, 375 Table 12-6 Recommended annual volumes: hospitals and surgeons 1. Coronary artery bypass graft ≥450/100 2. Percutaneous coronary intervention ≥400/75 3. Abdominal aortic aneurysm repair ≥50/22 4. Aortic valve replacement ≥120/22 5. Pancreatic resection ≥11/2 6. Esophagectomy ≥13/2 7. Bariatric surgery >100/20 Source: From The Leapfrog Group, with permission. 34 and rural hospitals participated in the survey. Leapfrog asks for information on eight high-risk conditions or procedures, including coronary artery bypass graft, percutaneous coronary intervention, abdominal aortic aneurysm (AAA) repair, pancreatic resection, and esophagectomy. These procedures were chosen because evidence exists that adherence to certain process measures can dramatically improve the outcomes of these procedures. In addition, more than 100 studies also have demonstrated that better results are obtained at high-volume hospitals when undergoing cardiovascular surgery, major cancer resections, and other high-risk procedures. Hospitals fulfilling the EBHR Safety Standard are expected to meet the hospital and surgeon volume criteria shown in Table 12-6. Hospitals that do not meet these criteria but adhere to the Leapfrog-endorsed process measures for coronary artery bypass graft surgery, percutaneous coronary intervention, AAA repair, and care for highrisk neonates, receive partial credit toward fulfilling the EBHR Safety Standard. ­Leapfrog purchasers work to recognize and reward hospitals that provide care for their enrollees who meet EBHR standards.32 In a recent study, Brooke and associates analyzed whether achieving Leapfrog’s established evidence-based standards for AAA repair, including meeting targets for case volume and perioperative β-blocker usage, correlated with improved patient outcomes over time.33 After controlling for differences in hospital and patient characteristics, hospitals that implemented a policy for perioperative β-blocker usage had an estimated 51% reduction in mortality following open AAA repair cases. Among 111 California hospitals in which endovascular AAA repair was performed, in-hospital mortality was reduced by an estimated 61% over time among hospitals meeting Leapfrog case volume standards, although this result was not statistically significant. These results suggest that hospital compliance with Leapfrog standards for elective AAA repair is an effective means to help improve in-hospital mortality outcomes over time and support further efforts aimed at standardizing patient referral to hospitals that comply with evidence-based medicine standards for other surgical procedures. The newest effort of the Leapfrog group is to promote transparency of hospital outcomes using a safety scorecard. This information can be viewed at hospitalsafetyscore.org. World Health Organization “Safe Surgery Saves Lives” Initiative In October 2004, the WHO launched a global initiative to strengthen healthcare safety and monitoring systems by creating the World Alliance for Patient Safety. As part of the group’s efforts to improve patient safety, the alliance implemented a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 12 Patient Safety a large scale. A study of 118 hospitals participating in NSQIP between 2005 to 2007 showed that 82% of hospitals decreased their complication rates, and there was a decrease in morbidity of 11% and mortality of 17% annually per hospital.32 Currently, over 400 private-sector U.S. hospitals participate in the program. NSQIP uses a risk-adjusted ratio of the observed to expected outcome (focusing primarily on 30-day morbidity and mortality) to compare the performance of participating hospitals with their peers. The data the program has compiled also can be used to conduct observational studies using prospectively collected information on more than 1.5 million patients and operations. The expansion of NSQIP to the private sector has helped shift the focus from merely preventing the provider errors and sentinel events highlighted by the IOM publication “To Err Is Human” to the larger goal of preventing all adverse postoperative outcomes. Several insights about patient safety have arisen as a result of NSQIP. First, safety is indistinguishable from overall quality of surgical care and should not be addressed separately. Defining quality in terms of keeping a patient safe from adverse outcomes allows the NSQIP data to be used to assess and improve quality of care by making improvements in patient safety. In other words, prevention of errors is synonymous with the reduction of adverse outcomes and can be used as a reliable quality measure. Second, during an episode of surgical care, adverse outcomes, and hence, patient safety, are primarily determined by the quality of the systems of care. Errors in hospitals with higher than expected observed to expected outcomes ratios are more likely to be from system errors than from provider incompetence. This underscores the importance of adequate communication, coordination, and teamwork in achieving quality surgical care. Finally, reliable comparative outcomes data are imperative for the identification of system problems. Risk-adjusted rates of adverse outcomes must be compared with those at peer institutions to appreciate more subtle system errors that lead to adverse outcomes to prompt changes in the quality of an institution’s processes and structures. 376 PART I BASIC CONSIDERATIONS series of safety campaigns that brought together experts in specific problem areas through individual Global Patient Safety Challenges. The second Global Patient Safety Challenge focuses on improving the safety of surgical care. The main goal of the campaign, called Safe Surgery Saves Lives, is to reduce surgical deaths and complications through the universal adaptation of a comprehensive perioperative surgical safety checklist in ORs worldwide. In addition to the checklist, the WHO defined a set of uniform measures for national and international surveillance of surgical care to better assess the quantity and quality of surgical care being delivered worldwide.21 At the population level, metrics include the number of surgeon, anesthesia, and nurse providers per capita, the number of ORs per capita, and overall surgical case volumes and mortality rates. At the hospital level, metrics include safety improvement structures and a surgical “Apgar score,” a validated method of prognosticating patient outcomes based on intraoperative events (i.e., hypotension, tachycardia, blood loss).35 National Quality Forum The National Quality Forum (NQF) is a coalition of healthcare organizations that has worked to develop and implement a national strategy for healthcare quality measurement and reporting. Their mission is to improve the quality of American healthcare by setting national priorities and goals for performance improvement, endorsing national consensus standards for measuring and publicly reporting on performance, and promoting the attainment of national goals through education and outreach programs. One of the major contributions of the NQF is the development of a list of Serious Reportable Events, which are frequently referred to as “never events.”36 According to the NQF, “never events” are errors in medical care that are clearly identifiable, preventable, and serious in their consequences for patients and that indicate a real problem in the safety and credibility of a healthcare facility. Examples of “never events” include surgery performed on the wrong body part; a foreign body left in a patient after surgery; a mismatched blood transfusion; a major medication error; a severe “pressure ulcer” acquired in the hospital; and preventable postoperative deaths 6 (Table 12-7). Criteria for inclusion as a “never event” are listed below. The event must be: • U  nambiguous (i.e., the event must be clearly identifiable and measurable, and thus feasible to include in a reporting ­system); • Usually preventable, with the recognition that some events are not always avoidable, given the complexity of healthcare; Table 12-7 Surgical “never events” • Surgery performed on the wrong body part • Surgery performed on the wrong patient • Wrong surgical procedure performed on a patient • Unintended retention of a foreign object in a patient after surgery or other procedure • Intraoperative or immediately postoperative death in an ASA Class 1 patient ASA = American Society of Anesthesiologists. Source: From National Quality Forum,36 with permission. Case 12-4 Surgical “never event” In 2002, Mike Hurewitz, a reporter for The Times Union of Albany, suddenly began vomiting blood 3 days after donating part of his liver to his brother while recovering on a hospital floor in which 34 patients were being cared for by one first-year resident. He aspirated and died immediately with no other physician available to assist the overworked first-year resident. Recognized for its advances in the field of liver transplantation, at the time, Mount Sinai Hospital was performing more adult-to-adult live-donor operations than any other hospital in the country. But the program was shut down by this event. Mount Sinai was held accountable for inadequate care and was banned from performing any livedonor adult liver transplants for more than 1 year. Of the 92 complaints investigated by the state, 75 were filed against the liver transplant unit, with 62 involving patient deaths. The state concluded that most of the 33 serious violations exhibited by the hospital occurred within the liver transplant unit. As a result of the investigation, Mount Sinai revamped many of the procedures within its transplant unit. Among the changes, first-year residents no longer staffed the transplant service, two healthcare practitioners physically present in the hospital oversaw the transplant unit at all times, and any page coming from the transplant unit had to be answered within 5 minutes of the initial call. In addition, nurses monitored patients’ vital signs more closely after surgery, transplant surgeons were required to make postoperative visits to both organ donor and recipient, and each registered nurse was assigned to four patients, rather than six or seven. The death also led New York to become the first state to develop guidelines for treating live organ donors. Finally, Mike Hurewitz’s widow became a patient safety advocate, urging stricter controls on live donor programs. • S  erious, resulting in death or loss of a body part, disability, or more than transient loss of a body function; and • Any one of the following: • Adverse, and/or • Indicative of a problem in a healthcare facility’s safety ­systems, and/or • Important for public credibility or public accountability. These events are not a reasonable medical risk of undergoing surgery that the patient must accept but medical errors that should never happen (Case 12-4). The occurrence of any of these events signals that an organization’s patient safety culture or processes have defects that need to be evaluated and corrected (Table 12-8). “NEVER EVENTS” IN SURGERY Never events are errors in medical care that are clearly identifiable, preventable, and serious in their consequences for patients and that indicate a real problem in the safety and credibility of a healthcare facility.36 Despite widespread agreement that surgical never events are preventable and despite several national and local programs being launched to decrease them, never events are still a significant problem. A study from Mehtsun VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 377 Table 12-8 Four patient events that advanced the modern field of patient safety Institution Year Event Root Cause Outcome Libby Zion New York Hospital, New York, NY 1984 Missed allergy to Demerol Physician fatigue Bell Commission shortened resident work hours Betsy Lehman Dana-Farber Cancer Institute, Boston, MA 1994 Chemotherapy overdose Lack of medication checks and triggers Fired doctor, three pharmacists, 15 nurses; overhauled safety program Josie King Johns Hopkins Hospital, 2001 Baltimore, MD Severe dehydration Poor communication Increased safety research funding Mike Hurewitz Mt. Sinai Hospital, New York, NY Inadequate postoperative care Inadequate supervision Transplant program shut down until better patient safety safeguards implemented 2002 and colleagues showed that from October 1990 to October 2010, nationwide there were 9744 paid malpractice claims for never events. Of these, mortality was reported in 6.6%, permanent injury in 33%, and temporary injury in 59%. The cost of the never events totaled $1.3 billion. Also, of physicians who were named in a surgical never event claim, 12.4% were named in a future never events claim.37 Another study in 2010 by The Joint Commission found that wrong-site surgery occurs 40 times per week nationwide.38 Future directions for decreasing these problems include public reporting of never events by hospitals to increase hospital accountability, more formal training in teamwork, and CUSP programs in hospitals that have higher rates of never events to help elucidate the root cause. Retained Surgical Items A retained surgical item refers to any surgical item found to be inside a patient after he or she has left the OR, thus requiring a second operation to remove the item.39 Estimates of retained foreign bodies in surgical procedures range from one case per 8000 to 18,000 operations, corresponding to one case or more each year for a typical large hospital or approximately 1500 cases per year in the United States.40 This estimate is based on an analysis of malpractice claims and is likely to underestimate the true incidence. The risk of having a retained surgical item increases during emergency surgery, when there are unplanned changes in procedure (due to new diagnoses encountered in the OR), and in patients with higher body mass index (Table 12-9).40 The most common retained surgical item is a ­surgical sponge, but other items, such as surgical instruments and needles, can also be inadvertently left inside a patient after Table 12-9 Risk factors for retained surgical sponges • Emergency surgery • Unplanned changes in procedure • Patient with higher body mass index • Multiple surgeons involved in same operation • Multiple procedures performed on same patient • Involvement of multiple operating room nurses/staff members • Case duration covers multiple nursing “shifts” an operation. Retained surgical sponges are commonly discovered as an incidental finding on a routine postoperative radiograph, but also have been discovered in patients presenting with a mass or abdominal pain. Patients with sponges that were originally left in an intracavitary position (such as inside the chest or abdomen) also can present with complications such as abscess, erosion through the skin, fistula formation, bowel obstruction, hematuria, or the development of a new, tumor-like lesion. Retained surgical needles usually are discovered incidentally, and reports of retained needles are uncommon. Retained surgical needles have not been reported to cause injury in the same way that nonsurgical needles (e.g., sewing needles, hypodermic needles) have been reported to perforate bowel or lodge in vessels and migrate. However, there have been reports of chronic pelvic pain and ocular irritation caused by retained surgical needles. A study of plain abdominal radiographs in pigs has demonstrated that medium- to large-size needles can easily be detected. The decision to remove these retained needles depends on symptoms and patient preference. Needles smaller than 13 mm have been found to be undetectable on plain radiograph in several studies, have not been shown to cause injury to vessels or visceral organs, and can probably be left alone. Although the actual incidence of retained surgical instruments is unknown, they are retained with far less frequency than surgical sponges. The initial presentation of a retained surgical instrument is most commonly pain in the surgical site or the sensation of a mass of fullness after a surgical procedure that leads to the discovery of a metallic object on a radiographic study. Commonly retained instruments include the malleable and “FISH” instrument that are used to protect the viscera when closing abdominal surgery. A retained surgical foreign body should be included in the differential diagnosis of any postoperative patient who presents with pain, infection, a palpable mass, or a radiopaque structure on imaging. The diagnosis can usually be made using a computed tomographic (CT) scan, and this is often the only test needed. If a retained surgical item is identified in the setting of an acute clinical presentation, the treatment usually is removal of the item. However, if the attempt to remove the retained ­surgical item can potentially cause more harm than the item itself, as in the case of a needle or a small part of a surgical item, then removal is occasionally not recommended. Retained surgical sponges should always be removed. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 12 Patient Safety Patient 378 PART I BASIC CONSIDERATIONS The American College of Surgeons and the Association of Perioperative Registered Nurses, in addition to The Joint ­Commission, have issued guidelines to try to prevent the occurrence of retained surgical items. Current recommendations include the use of standard counting procedures, performing a thorough wound exploration before closing a surgical site, and using only x-ray–detectable items in the surgical wound. These organizations also strongly endorse the completion of a postoperative debriefing after every operation. An x-ray at the completion of an operation is encouraged if there is any concern for a foreign body based on confusion regarding the counts by even a single member of the OR team or in the presence of a risk factor. Surgical Counts The benefit of performing surgical counts to prevent the occurrence of retained surgical items is controversial. The increased risk of a retained surgical item during emergency surgery in the study by Gawande and colleagues appeared to be related to bypassing the surgical count in many of these cases.40 However, in another study, the “falsely correct count,” in which a count is performed and declared correct when it is actually incorrect, occurred in 21% to 100% of cases in which a retained surgical item was found.39 This type of count was the most common circumstance encountered in all retained surgical item cases, which suggests that performing a surgical count in and of itself does not prevent this error from taking place. The counting protocol also imposes significant demands on the nursing staff and distracts them from focusing on other primarily patient-centered tasks, often during critical portions of the case.16 A retained surgical item can occur even in the presence of a known incorrect count. This event is usually a result of poor communication in which a surgeon will dismiss the incorrect count and/or fail to obtain a radiograph before the patient leaves the OR. Having stronger institutional policies in place in case of an incorrect count (such as requiring a mandatory radiograph while the patient is still in the OR) can avoid conflict among caregivers and mitigate the likelihood of a retained surgical item occurring as a result of a known incorrect count. Although there is no single tool to prevent all errors, the development of multiple lines of defense to prevent retained surgical items and universally standardizing and adhering to OR safety protocols by all members of the surgical team will help reduce the incidence of this never event.41 Surgeons should take the lead in the prevention of retained surgical items by avoiding the use of small or nonradiologically detectable sponges in large cavities, performing a thorough wound inspection before closing any surgical incision, and having a vested interest in the counting procedure performed by nursing staff. The value of routine radiography to prevent a retained surgical item in emergency cases or when major procedures involving multiple surgical teams are being performed is becoming more apparent. The widely accepted legal doctrine when a foreign body is erroneously left in a patient is that the mere presence of the item in the plaintiff’s body indicates that the patient did not receive proper surgical care. The characteristics of the surgeon and their style, bedside manner, honesty, and confidence demonstrated in the management of the case can go a long way in averting a lawsuit or mitigating damages. Wrong-Site Surgery Wrong-site surgery is any surgical procedure performed on the wrong patient, wrong body part, wrong side of the body, or wrong level of a correctly identified anatomic site. It is difficult to determine the true incidence of wrong-site surgery for several reasons. First, there is no standard definition for what constitutes wrong-site surgery among various healthcare organizations. Another factor is that wrong-site surgery is underreported by healthcare providers. Finally, the total number of potential opportunities for each type of wrong-site error is unknown. However, various studies show incidences ranging from one in 112,994 cases to one in 15,500 cases.42 The Washington University School of Medicine suggests a rate of one in 17,000 operations, which adds up to approximately 4000 wrong-site surgeries in the United States each year. If these numbers are correct, wrong-site surgery is the third most frequent life-threatening medical error in the United States.43 Several states now require mandatory reporting of all wrong-site surgery events, including near misses. These data provide some insight into the number of actual errors compared to the number of potential opportunities to perform wrong-site surgery. Of the 427 reports of wrong-site surgery submitted from June 2004 through December 2006 to the Pennsylvania Patient Safety Reporting System, more than 40% of the errors actually reached the patient, and nearly 20% involved completion of a wrong-site procedure.42 The risk of performing wrong-site surgery increases when there are multiple surgeons involved in the same operation or multiple procedures are performed on the same patient, especially if the procedures are scheduled or performed on different areas of the body.43 Time pressure, emergency surgery, abnormal patient anatomy, and morbid obesity are also thought to be risk factors.43 Communication errors are the root cause in more than 70% of the wrong-site surgeries reported to The Joint Commission.42 Other risk factors include receiving an incomplete preoperative assessment; having inadequate procedures in place to verify the correct surgical site; or having an organizational culture that lacks teamwork or reveres the surgeon as someone whose judgment should never be questioned.42 There is a one in four chance that surgeons who work on symmetric anatomic structures will be involved in a wrong-site error sometime during their careers.43 The specialties most commonly involved in reporting wrong-site surgeries according to The Joint Commission are orthopedic/podiatric surgery (41%), general surgery (20%), neurosurgery (14%), urology (11%), and maxillofacial, cardiovascular, otolaryngology, and ophthalmology (14%).42 Most errors involved symmetric anatomic structures: lower extremities (30%), head/neck (24%), and genital/ urinary/pelvic/groin (21%).38 Although orthopedic surgery is the most frequently involved, this may be due to the higher volume of cases performed as well as the increased opportunity for lateralization errors inherent in the specialty. In addition, because the American Academy of Orthopaedic Surgeons has historically tried as a professional organization to reduce wrong-site operations, orthopedic surgeons may be more likely to report these events when they do occur.43 The Joint Commission Universal Protocol to Ensure Correct Surgery The movement to eliminate wrong-site surgery began among professional orthopedic societies in the mid-1990s, when both the Canadian Orthopaedic Association and the ­American ­Academy of Orthopaedic Surgeons issued position statements and embarked on educational campaigns to prevent the occurrence of wrong-site surgery within their specialty.43 Other ­organizations that issued position statements advocating for the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ • Verifying the patient’s identity • Marking the surgical site • Using a preoperative site verification process such as a ­checklist • Confirming the availability of appropriate documents and studies before the start of a procedure • Taking a brief time-out immediately before skin incision, in which all members of the surgical team actively communicate and provide oral verification of the patient’s identity, surgical site, surgical procedure, administration of preoperative medications, and presence of appropriate medical records, imaging studies, and equipment • Monitoring compliance with protocol recommendations Focusing on individual process components of the universal protocol, such as surgical site marking or the time-out, is not enough to prevent wrong-site surgery. Over a 30-month period in Pennsylvania, 21 wrong-side errors occurred despite the proper use of time-out procedures, with 12 of these errors resulting in complete wrong-side procedures. During the same period, correct site markings failed to prevent another 16 wrongsite surgeries, of which six were not recognized until after the procedure had been completed.43 Site verification begins with the initial patient encounter by the surgeon, continues throughout the preoperative verification process and during multiple critical points in the OR, and requires the active participation of the entire operating team, especially the surgeon and anesthesia provider. Based on a recent review of malpractice claims, two thirds of wrong-site operations could have been prevented by a site-verification ­protocol.44 Despite the proliferation of wrong-site protocols in the last decade, their effectiveness is difficult to measure as the incidence of wrong-site surgery is too rare to measure as a rate. Interestingly, the number of sentinel events reported to The Joint Commission has not changed significantly since the widespread implementation of the Universal Protocol in 2004.43 This could be due to an increase in reporting rather than an actual increase in the incidence of wrong-site surgery. The legal treatment of wrong-site surgery is similar to that of surgical items erroneously left in a patient: the mere fact that it occurred indicates that the patient did not receive proper surgical care. A malpractice claim may lead to a settlement or award on verdict in the six- or seven-figure range in 2011 U.S. dollars.37 Ultimately, the occurrence of retained surgical items or wrong-site surgery is a reflection of the quality of professional communication between caregivers and the degree of Table 12-10 379 Best practices for operating room safety • Conduct The Joint Commission Universal Protocol (“timeout”) to prevent wrong-site surgery. • Perform an operating room briefing (checklist) to identify and mitigate hazards early. • Promote a culture of speaking up about safety concerns. • Use a screening x-ray to detect foreign bodies in high-risk cases. • Begin patient sign-outs with the most likely immediate safety hazard. Source: Reproduced with permission from Michaels RK, et al. Achieving the National Quality Forum’s “Never Events”: Prevention of wrong site, wrong procedure, and wrong patient operations. Ann Surg 245:526, 2007. t­eamwork among the members of the operating team. In addition to s­ tandardizing procedures like the surgical count, instituting mandatory postoperative radiographs in the presence of a known miscount, and reforming the processes of patient identification and site verification, organizations should also strive to create a culture of safety, create independent and redundant checks for key processes, and create a system in which caregivers can learn from their mistakes (Table 12-10).45 TRANSPARENCY IN HEALTHCARE Despite a large increase in data being collected about patient safety and harm, much of it is not available to the public or other hospitals. This lack of transparency allows some hospitals to continue to practice outdated medicine and, in some cases, puts patients at a higher risk of serious complications. In a study by Mark Chassin, the health commissioner of New York State, having hospitals publicly disclose their mortality rates for coronary artery bypass graft (CABG) procedures resulted in a 41% decline in mortality from CABGs statewide.46 In this study, when CABG mortality data were initially made public, there was a wide range in cardiac surgery-related mortality from 1% to 18%, depending on the hospital; the standard of care is 2%. The reasons for higher mortality in the poorly performing hospitals ranged from poor communication between care teams to one rogue surgeon operating when the surgeon should not have been. The consequence of making this data transparent was that the hospitals held multidisciplinary, CUSP-like meetings, where as a team they decided on the measures to implement for improvement. Through this, over the next year, most hospitals decreased their mortality rate to below 2%. Even the hospital that had an 18% mortality rate decreased it to 7% within 3 years and 1.7% over the next several years. Transparency in healthcare is becoming central to the healthcare quality discussion. A new SCIP core measure is publishing practitioner performance, and all Leapfrog survey results are published online where other hospitals and the public can see them. Additionally, different large medical societies, including the Society for Thoracic Surgery (STS), are encouraging and rewarding practitioners and hospitals that are transparent with their outcomes. Making hospital outcomes transparent makes hospitals accountable to the public for their outcomes and, in the case of New York, caused a radical improvement in the quality of care provided to patients. It also empowers patients by making them better informed about which hospital they choose for their care, which will further incentivize hospitals to improve. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 12 Patient Safety elimination of wrong-site surgery include the North American Spine Society, the American Academy of Ophthalmology, the Association of Perioperative Registered Nurses, and the ­American College of Surgeons. After issuing a review of wrong-site ­surgery in their Sentinel Event Alert in 1998, The Joint Commission made the elimination of wrong-site surgery one of their first National Patient Safety Goals in 2003 and adopted a universal protocol for preventing wrong-site, wrong-procedure, and wrongperson surgery in 2004. The protocol has been endorsed by more than 50 professional associations and organizations. A preoperative “time-out” or “pause for the cause” to confirm the patient, procedure, and site to be operated on before incision was recommended by The Joint Commission and is now mandatory for all ORs in the United States. Elements of the protocol include the following: 380 RISK MANAGEMENT PART I BASIC CONSIDERATIONS Between one half and two thirds of hospital-wide adverse events are attributable to surgical care. Most surgical errors occur in the OR and are technical in nature. Surgical complications and adverse outcomes have previously been linked to lack of surgeon specialization, low hospital volume, communication breakdowns, fatigue, surgical residents and trainees, and numerous other factors.47 However, poor surgical outcomes are not necessarily correlated with a surgeon’s level of experience in performing a certain procedure. In one study, three fourths of the technical errors that occurred in a review of malpractice claims data involved fully trained and experienced surgeons operating within their area of expertise, and 84% occurred in routine operations that do not require advanced training. Rather than surgeon expertise, these errors likely occurred due to situations complicated by patient comorbidity, complex anatomy, repeat surgery, or equipment problems (Table 12-11). Because these errors occurred during routine operations, previous suggestions to limit the performance of high-complexity operations using selective referral, regionalization, or limitation of privileging may not actually be effective in reducing the incidence of technical error among surgical patients.47 In any event, although there has been much emphasis on reducing the prevalence of surgical technical errors as a way of improving surgical care, a technical error in the OR may not be the most important indicator of whether a surgeon will be sued by a patient. Recent studies point to the importance of a surgeon’s communication skills in averting malpractice litigation. In the American College of Surgeons’ Closed Claims Study, although intraoperative organ injuries occurred in 40% of patients, a surgical technical misadventure was the most deficient component of care in only 12% of patients. In fact, communication and practice pattern violations were the most common deficiency in care for one third of patients in the Closed Claims Study who received the expected standard of surgical care.48 The Importance of Communication in Managing Risk The manner and tone in which a physician communicates is potentially more important to avoiding a malpractice claim than the actual content of the dialogue. For example, a physician relating to a patient in a “negative” manner may trigger litigious feelings when there is a bad result, whereas a physician relating in a “positive” manner may not. Expressions of dominance, in which the voice tone is deep, loud, moderately fast, unaccented, and clearly articulated, may communicate a lack of empathy and understanding for the patient, whereas concern or anxiety in the surgeon’s voice is often positively related to expressing concern Table 12-11 Common causes of lawsuits in surgery • • • • • • • • Positional nerve injury Common bile duct injury Failure to diagnose or delayed diagnosis Failure to treat, delayed treatment, or wrong treatment Inadequate documentation Inappropriate surgical indication Failure to call a specialist Cases resulting in amputation/limb loss and empathy. General and orthopedic surgeons whose tone of voice was judged to be more dominant were more likely to have been sued than those who sounded less dominant.49 When significant medical errors do occur, physicians have an ethical and professional responsibility to immediately disclose them to patients. Failure to disclose errors to patients undermines public confidence in medicine and can create legal liability related to fraud. Physicians’ fear of litigation represents a major barrier to error disclosure. However, when handled appropriately, immediate disclosure of errors frequently leads to improved patient rapport, improved satisfaction, and fewer malpractice claims.50 In fact, rapport is the most important 7 factor in determining whether a lawsuit is filed against a ­physician. In 1987, the Department of Veterans Affairs Hospital in Lexington, Kentucky, implemented the nation’s first formal apology and medical error full disclosure program, which called for the hospital and its doctors to work with patients and their families to settle a case. As a result, the hospital improved from having one of the highest malpractice claims totals in the VA system to being ranked among the lowest quartile of a comparative group of similar hospitals for settlement and litigation costs over a 7-year period. Its average payout in 2005 was $16,000 per settlement, vs. the national VA average of $98,000 per settlement, and only two lawsuits went to trial during a 10-year period. As a result of the success of this program, the D ­ epartment of Veteran Affairs expanded the program to all VA hospitals nationwide in October 2005. This model also was replicated at the University of Michigan Health System with similar results. Its full-disclosure program cut the number of pending lawsuits by one half and reduced litigation costs per case from $65,000 to $35,000, saving the hospital approximately $2 million in defense litigation bills each year. In addition, University of Michigan doctors, patients, and lawyers are happier with this system. The cultural shift toward honesty and openness also has led to the improvement of systems and processes to reduce medical errors, especially repeat medical errors.51 With regard to risk management, the importance of good communication by surgeons and other care providers cannot be overemphasized. Whether alerting other members of the care team about a patient’s needs, openly discussing concerns the patient and/or family might have, or disclosing the cause of a medical error, open communication with all parties involved can reduce anger and mistrust of the medical system; the frequency, morbidity, and mortality of preventable adverse events; and the likelihood of litigation. COMPLICATIONS Despite the increased focus on improving patient safety and minimizing medical errors, it is impossible to eliminate human error entirely. Individual errors can cause minor or major complications during or after a surgical procedure. Although these types of errors may not be publicized as much as wrong-site surgery or a retained surgical item, they can still lead to surgical complications that prolong the course of illness, lengthen hospital stay, and increase morbidity and mortality rates. Complications in Minor Procedures Central Venous Access Catheters. Complications of central venous access catheters are common. Improvements in ultrasound technology and mass education surrounding the use and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ • Ensure that central venous access is indicated. • Experienced personnel should insert the catheter or should supervise the insertion. • Use proper positioning and sterile technique. • Ultrasound is recommended for internal jugular vein ­insertion. • All central venous catheters should be assessed on a daily basis and should be exchanged only for specific indications (not as a matter of routine). • All central catheters should be removed as soon as possible. Common complications of central venous access include the following. Pneumothorax Occurrence rates from both subclavian and internal jugular vein approaches are 1% to 6%. Prevention requires proper positioning of the patient and correct insertion technique. A postprocedure chest x-ray is mandatory to confirm the presence or absence of a pneumothorax, regardless of whether a pneumothorax is suspected. Pneumothorax rates are higher among the inexperienced but occur with experienced operators as well. If the patient is stable, and the pneumothorax is small (<15%), close expectant observation may be adequate. If the patient is symptomatic, a thoracostomy tube should be placed. Occasionally, pneumothorax will occur as late as 48 to 72 hours after central venous access attempts. This usually creates sufficient compromise that a tube thoracostomy is required. Arrhythmias Arrhythmias result from myocardial irritability secondary to guidewire placement and usually resolve when the catheter or guidewire is withdrawn from the right heart. Prevention requires electrocardiogram (ECG) monitoring whenever possible during catheter insertion and rapid recognition when a new arrhythmia begins. Arterial Puncture Inadvertent puncture or laceration of an adjacent artery with bleeding can occur, but the majority will resolve with direct pressure on or near the arterial injury site. Rarely will angiography, stent placement, or surgery be required to repair the puncture site, but close observation and a chest x-ray are indicated. Ultrasound guided insertion has not mitigated this complication, but may decrease the incidence of arterial puncture. Ultrasound has also been shown to decrease the number of attempts and the time it takes to complete insertion. Lost Guidewire A guidewire or catheter that inadvertently migrates further into the vascular space away from the insertion site can be readily retrieved with interventional angiography techniques. A prompt chest x-ray and close monitoring of the patient until retrieval are indicated. Air Embolus Although estimated to occur in only 0.2% to 1% of patients, an air embolism can be dramatic and fatal. If an embolus is suspected, the patient should immediately be placed into a left lateral decubitus Trendelenburg position, so the entrapped air can be stabilized within the right ventricle. Auscultation over the precordium may reveal a “crunching” noise, but a portable chest x-ray will help confirm the diagnosis. Aspiration via a central venous line accessing the heart may decrease the volume of gas in the right side of the heart and minimize the amount traversing into the pulmonary circulation. Subsequent recovery of intracardiac and intrapulmonary air may require open surgical or angiographic techniques. Treatment may prove futile if the air bolus is larger than 50 mL, however. Pulmonary Artery Rupture Flow-directed, pulmonary artery (“Swan-Ganz”) catheters can cause pulmonary artery rupture due to excessive advancement of the catheter into the pulmonary circulation. There usually is a sentinel bleed with coughing noted when a pulmonary artery catheter balloon is inflated, followed by uncontrolled hemoptysis. Reinflation of the catheter balloon is the initial step in management, followed by immediate airway intubation with mechanical ventilation, an urgent portable chest x-ray, and notification of the OR that an emergent thoracotomy may be required. If there is no further bleeding after the balloon is reinflated, the x-ray shows no significant consolidation of lung fields from ongoing bleeding, and the patient is easily ventilated, then a conservative nonoperative approach may be considered. However, more typically a pulmonary angiogram with angioembolization or vascular stenting is required. Hemodynamically unstable patients rarely survive because of the time needed to initiate and perform interventional procedures or a thoracotomy and to identify the ruptured branch of the pulmonary artery. Central Venous Line Infection The CDC reports mortality rates of 12% to 25% when a central venous line infection becomes systemic, with a cost of approximately $25,000 per episode.52-54 The CDC does not recommend routine central line changes, but when the clinical suspicion is high, the site of venous access must be changed. Nearly 15% of hospitalized patients will acquire central venous line sepsis. In many instances, once an infection is recognized as central line sepsis, removing the line is adequate. Staphylococcus aureus infections, however, present a unique problem because of the potential for metastatic seeding of bacterial emboli. The required treatment is 4 to 6 weeks of tailored antibiotic therapy. Using a checklist when inserting central venous catheters has been shown to significantly decrease rates of line infections.55 Following a checklist strategy and close monitoring of catheters has resulted in significant reductions in infection rates for numerous institutions and many are now reporting zero annual infection rates. Arterial Lines. Arterial lines are placed to facilitate arterial blood gas sampling and hemodynamic monitoring. The use of ultrasound to assist in placement of these catheters has become commonplace and markedly reduces the number of attempts and time for insertion completion. Arterial access requires a sterile Seldinger technique, and a variety of arteries are used, including the radial, femoral, ­brachial, axillary, dorsalis pedis, or superficial temporal arteries. Although complications occur less than 1% of the time, they can be catastrophic. Complications include thrombosis, bleeding, hematoma, arterial spasm (nonthrombotic pulselessness), and infection. Thrombosis or embolization of an extremity arterial catheter can result in the loss of a digit, hand, or foot, and the risk is nearly the same for both femoral and radial cannulation. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 381 CHAPTER 12 Patient Safety techniques in ultrasonography have led to increased employment and enthusiasm for its use in central venous catheter placement. Numerous institutions have recently begun to mandate use of ultrasound for placement of all central venous lines. Anecdotally, many subclavian catheters have been alternatively placed at the internal jugular position due to a perceived benefit of decreasing complications. Literature exists that there is some merit to this; however, one should proceed with caution as the decrease in pneumothoraces may not be balanced by the increase in line infections as the neck is difficult to keep the site clean and the dressing intact. Steps to decrease complications include the following: 382 Thrombosis with distal tissue ischemia is treated with ­anticoagulation, but occasionally surgical intervention is required. Pseudoaneurysms and arteriovenous fistulae can also occur. Endoscopy and Bronchoscopy. The principal risk of gas- PART I BASIC CONSIDERATIONS trointestinal (GI) endoscopy is perforation. Perforations occur in 1:10,000 patients with endoscopy alone, but have a higher incidence rate when biopsies are performed (up to 10%). This increased risk is due to complications of intubating a GI diverticulum (either esophageal or colonic), or from the presence of weakened or inflamed tissue in the intestinal wall (e.g., diverticulitis, glucocorticoid use, or inflammatory bowel disease). Patients will usually complain of diffuse abdominal pain shortly after the procedure, and then progress with worsening abdominal discomfort and peritonitis on examination. In obtunded or elderly patients, a change in clinical status may take 24 to 48 hours. Radiologic studies to look for free intraperitoneal air, retroperitoneal air, or a pneumothorax are diagnostic. Open or laparoscopic exploration locates the perforation and allows repair and local decontamination of the surrounding tissues. The occasional patient who may be a candidate for nonoperative management is one in whom perforation arises during an elective, bowel-prepped endoscopy and who does not have significant pain or clinical signs of infection. These patients must be closely observed in a monitored setting, on strict dietary restriction and broad-spectrum antibiotics. Complications of bronchoscopy include bronchial plugging, hypoxemia, pneumothorax, lobar collapse, and bleeding. When diagnosed in a timely fashion, they are rarely life threatening. Bleeding usually resolves spontaneously and rarely requires surgery, but may require repeat endoscopy for thermocoagulation or fibrin glue application. The presence of a pneumothorax necessitates placement of a thoracostomy tube when significant deoxygenation occurs or the pulmonary mechanics are compromised. Lobar collapse or mucous plugging usually responds to aggressive pulmonary toilet, but occasionally requires repeat bronchoscopy. If biopsies have been performed, the risk for these complications increases. Tracheostomy. Tracheostomy facilitates weaning from a ventilator, may decrease length of ICU or hospital stay, and improves pulmonary toilet. Tracheostomies are performed open, percutaneously, with or without bronchoscopy, and with or without Doppler guidance. Arguments for percutaneous tracheostomy largely side with efficiency and cost containment over open tracheostomy. A recent literature review examining early (<3–7 days) vs. late (>14 days) tracheostomy demonstrates little difference in outcomes but does demonstrate greater patient comfort in those patients with tracheostomy than those with an endotracheal tube. Complications and outcomes between the two different methods remain largely equivalent. Recent studies do not support obtaining a routine chest x-ray after percutaneous or open tracheostomy.56,57 However, significant lobar collapse can occur from copious tracheal secretions or mechanical obstruction. The most dramatic complication of tracheostomy is tracheoinnominate artery fistula (TIAF) (Fig. 12-7).58,59 This occurs rarely (~0.3%) but carries a 50% to 80% mortality rate. TIAFs can occur as early as 2 days or as late as 2 months after tracheostomy. A sentinel bleed occurs in 50% of TIAF cases, followed by a large-volume bleed. Should a TIAF be suspected, the patient should be transported immediately to the OR for fiberoptic evaluation. If needed, remove the tracheostomy and place a finger through the tracheostomy site to apply direct pressure anteriorly for compression of Figure 12-7. This illustration depicts improper positioning of the percutaneous needle. It is possible to access the innominate artery via the trachea, thus placing the patient at risk for early tracheoinnominate artery fistula. the innominate artery while preparation for a more definitive approach is organized. Percutaneous Endogastrostomy. A misplaced percutaneous endogastrostomy (PEG) tube may lead to intra-abdominal sepsis with peritonitis and/or an abdominal wall abscess with necrotizing fasciitis. As in other minor procedures, the initial placement technique must be fastidious to avoid complications. Transillumination of the abdomen may decrease the risk for error, but this is unsubstantiated in the literature. Inadvertent colotomies, intraperitoneal placement of the tube and subsequent leakage of tube feeds with peritonitis, and abdominal wall abscesses require surgery to correct the complications and to replace the PEG with an alternate feeding tube, usually a jejunostomy. A dislodged or prematurely removed PEG tube should be replaced as early as possible after dislodgment because the gastrostomy site closes rapidly. A contrast x-ray (sinogram) should be performed to confirm the tube’s intragastric position before feeding. If there is uncertainty of the tube location, conversion to an open tube placement procedure is required. Tube Thoracostomy. Chest tube insertion is performed for pneumothorax, hemothorax, pleural effusions, or empyema. In most patients, a chest tube can be easily placed with a combination of local analgesia and light conscious sedation. Common complications include inadequate analgesia or sedation, incomplete penetration of the pleura with formation of a subcutaneous track for the tube, lacerations to the lung or diaphragm, intraperitoneal placement of the tube through the diaphragm, and bleeding related to these various lacerations or injury to pleural adhesions. Additional problems include slippage of the tube out of position or mechanical problems related to the drainage system. In patients with bullous disease, there can be significant intrapleural scarring and it can be easy to mistakenly place the chest tube into a bullae. All of these complications can be avoided with proper initial insertion techniques, plus a daily review of the drainage system and follow-up radiographs. Tube removal can create a residual pneumothorax if the patient does not maintain positive intrapleural pressure by Valsalva’s maneuver during tube removal and dressing application. Complications of Angiography. Intramural dissection of a cannulated artery can lead to complications such as ischemic stroke from a carotid artery dissection or occlusion, mesenteric ischemia from dissection of the superior mesenteric artery, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Complications of Biopsies. Lymph node biopsies have direct and indirect complications that include bleeding, infection, lymph leakage, and seromas. Measures to prevent direct complications include proper surgical hemostasis, proper skin preparation, and a single preoperative dose of antibiotic to cover skin flora 30 to 60 minutes before incision. Bleeding at a biopsy site usually can be controlled with direct pressure. Infection at a biopsy site will appear 5 to 10 days postoperatively and may require opening of the wound to drain the infection. Seromas or lymphatic leaks resolve with aspiration of seromas and the application of pressure dressings, but may require repeated treatments or even placement of a vacuum drain. Organ System Complications Neurologic System. Neurologic complications that occur after surgery include motor or sensory deficits and mental status changes. Peripheral motor and sensory deficits are often due to neurapraxia secondary to improper positioning and/or padding during operations. Treatment is largely clinical observation, and the majority of deficits resolve spontaneously within 1 to 3 months. Direct injury to nerves during a surgical intervention is a well-known complication of several specific operations, including superficial parotidectomy (facial nerve), carotid endarterectomy (hypoglossal nerve), thyroidectomy (recurrent laryngeal nerve), prostatectomy (nervi erigentes), inguinal herniorrhaphy (ilioinguinal nerve), and mastectomy (long thoracic and thoracodorsal nerves). The nerve injury may be a stretch injury or an unintentionally severed nerve. In addition to loss of function, severed nerves can result in a painful neuroma that may require subsequent surgery. Mental status changes in the postoperative patient can have numerous causes (Table 12-12). Mental status changes must be continually assessed. A noncontrast CT scan should be used early to detect new or evolving intracranial causes. Atherosclerotic disease increases the risk for intraoperative and postoperative stroke (cerebrovascular accident). Postoperatively, hypotension and hypoxemia are the most likely causes of a cerebrovascular accident. ­Neurologic consultation should be obtained immediately to confirm the diagnosis. Management is largely supportive and includes adequate intravascular volume replacement plus optimal oxygen delivery. Advents in interventional radiology by radiologists and vascular and neurologic surgeons have proven successful alternatives in patients requiring diagnostic and therapeutic care in the immediate and acute postoperative period. Catheter-directed therapy with anticoagulants such as the kinases and tissue plasminogen activator (tPA) has potential benefit in postoperative thrombosis where reoperation carries significant risk. In addition, endoluminal stents with drug-eluting stents (DESs) or non-DESs have been used with some degree of success. DESs do require systemic antiplatelet therapy due to the alternative coagulation pathway. Duration of antiplatelet therapy of 1 year is routine. Eyes, Ears, and Nose. Corneal abrasions are unusual, but are due to inadequate protection of the eyes during anesthesia. Overlooked contact lenses in patients occasionally may cause conjunctivitis. Table 12-12 Common causes of mental status changes Electrolyte Imbalance Toxins Trauma Metabolic Medications Sodium Ethanol Closed head injury Thyrotoxicosis Aspirin Magnesium Methanol Pain Adrenal insufficiency β-Blockers Calcium Venoms and poisons Shock Hypoxemia Narcotics Inflammation Ethylene glycol Psychiatric Acidosis Antiemetics Sepsis Carbon monoxide Dementia Severe anemia MAOIs AIDS Depression Hyperammonemia TCAs Cerebral abscess ICU psychosis Poor glycemic control Amphetamines Meningitis Schizophrenia Hypothermia Antiarrhythmics Hyperthermia Corticosteroids, anabolic steroids Fever/hyperpyrexia AIDS = acquired immunodeficiency syndrome; ICU = intensive care unit; MAOI = monoamine oxidase inhibitor; TCA = tricyclic antidepressant. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 383 CHAPTER 12 Patient Safety or a more innocuous finding of “blue toe syndrome” from a dissected artery in a peripheral limb. Invasive or noninvasive imaging studies confirm the suspected problem. The severity of ischemia and extent of dissection determine if anticoagulation therapy or urgent surgical exploration is indicated. Bleeding from a vascular access site usually is obvious, but may not be visible when the blood loss is tracking into the retroperitoneal tissue planes after femoral artery cannulation. These patients can present with hemorrhagic shock; an abdominopelvic CT scan delineates the extent of bleeding along the retroperitoneum. Initial management is direct compression at the access site and resuscitation as indicated. Urgent surgical exploration may be required to control the bleeding site and evacuate larger hematomas. Renal complications of angiography occur in 1% to 2% of patients. Contrast nephropathy is a temporary and preventable complication of radiologic studies such as CT, angiography, and/or venography. Intravenous (IV) hydration before and after the procedure is the most efficient method for preventing contrast nephropathy. Nonionic contrast also may be of benefit in higher-risk patients. Close communication between providers is often required to resolve the priorities in care as well as to balance the risks versus benefits of renal protection when managing patients in need of angiographic procedures. 384 PART I BASIC CONSIDERATIONS Persistent epistaxis can occur after nasogastric tube placement or removal, and nasal packing is the best treatment option if prolonged persistent direct pressure on the external nares fails. Anterior and posterior nasal gauze packing with balloon tamponade, angioembolization, and fibrin glue placement may be required in refractory cases. The use of antibiotics for posterior packing is controversial. External otitis and otitis media occasionally occur postoperatively. Patients complain of ear pain or decreased hearing, and treatment includes topical antibiotics and nasal decongestion for symptomatic improvement. Ototoxicity due to aminoglycoside administration occurs in up to 10% of patients, and is often irreversible. Vancomycinrelated ototoxicity occurs about 3% of the time when used alone, and as often as 6% when used with other ototoxic agents.60,61 Vascular Problems of the Neck. Complications of carotid endarterectomy include central or regional neurologic deficits or bleeding with an expanding neck hematoma. An acute change in mental status or the presence of localized neurologic deficit requires an immediate return to the OR. An expanding hematoma may warrant emergent airway intubation and subsequent transfer to the OR for control of hemorrhage. Intraoperative anticoagulation with heparin during carotid surgery makes bleeding a postoperative risk. Other complications include arteriovenous fistulae, pseudoaneurysms, and infection, all of which are treated surgically. Intraoperative hypotension during manipulation of the carotid bifurcation can occur and is related to increased tone from baroreceptors that reflexly cause bradycardia. Should hypotension occur when manipulating the carotid bifurcation, an injection of 1% lidocaine solution around this structure should attenuate this reflexive response. The most common delayed complication following carotid endarterectomy remains myocardial infarction. The possibility of a postoperative myocardial infarction should be considered as a cause of labile blood pressure and arrhythmias in high-risk patients. Thyroid and Parathyroid Glands. Surgery of the thyroid and parathyroid glands can result in hypocalcemia in the immediate postoperative period. Manifestations include ECG changes (shortened P-R interval), muscle spasm (tetany, Chvostek’s sign, and Trousseau’s sign), paresthesias, and laryngospasm. Treatment includes calcium gluconate infusion and, if tetany ensues, chemical paralysis with intubation. Maintenance treatment is thyroid hormone replacement (after thyroidectomy) in addition to calcium carbonate and vitamin D. Recurrent laryngeal nerve (RLN) injury occurs in less than 5% of patients. Of those with injury, approximately 10% are permanent. Dissection near the inferior thyroid artery is a common area for RLN injury. At the conclusion of the operation, if there is suspicion of an RLN injury, direct laryngoscopy is diagnostic. The cord on the affected side will be in the paramedian position. With bilateral RLN injury, the chance of a successful extubation is poor. If paralysis of the cords is not permanent, function may return 1 to 2 months after injury. Permanent RLN injury can be treated by various techniques to stent the cords in a position of function. Superior laryngeal nerve injury is less debilitating, as the common symptom is loss of projection of the voice. The glottic aperture is asymmetrical on direct laryngoscopy, and management is limited to clinical observation. Respiratory System. Surgical complications that put the respiratory system in jeopardy are not confined to technical errors. Malnutrition, inadequate pain control, inadequate mechanical ventilation, inadequate pulmonary toilet, and aspiration can cause serious pulmonary problems. Pneumothorax can occur from central line insertion during anesthesia or from a diaphragmatic injury during an abdominal procedure. Hypotension, hypoxemia, and tracheal deviation away from the affected side may be present. A tension pneumothorax can cause complete cardiovascular collapse. Treatment is by needle thoracostomy, followed by tube thoracostomy. The chest tube is inserted at the fifth intercostal space in the anterior axillary line. The anterior chest wall is up to 1 cm thicker than the lateral chest wall, so needle decompression is more effective in the lateral position. Attempted prehospital needle decompression in the traditional anterior position results in only 50% needle entry into the thoracic cavity. Hemothoraces should be evacuated completely. Delay in evacuation of a hemothorax leaves the patient at risk for empyema and entrapped lung. If evacuation is incomplete with tube thoracostomy, video-assisted thoracoscopy or open evacuation and pleurodesis may be required. Pulmonary atelectasis results in a loss of functional residual capacity (FRC) of the lung and can predispose to pneumonia. Poor pain control in the postoperative period contributes to poor inspiratory effort and collapse of the lower lobes in ­particular. The prevention of atelectasis is facilitated by sitting the patient up as much as possible, early ambulation, and a­dequate pain control. An increase in FRC by 700 mL or more can be accomplished by sitting patients up to greater than 45°. For mechanically ventilated patients, simply placing the head of the bed at 30 to 45° elevation and delivering adequate tidal volumes (8–10 mL/kg) improves pulmonary outcomes. Patients with inadequate pulmonary toilet are at increased risk for bronchial plugging and lobar collapse. Patients with copious and tenacious secretions develop these plugs most often, but foreign bodies in the bronchus can be the cause of lobar collapse as well. The diagnosis of bronchial plugging is based on chest x-ray and clinical suspicion with acute pulmonary decompensation with increased work of breathing and hypoxemia. Fiberoptic bronchoscopy can be useful to clear mucous plugs and secretions. Aspiration complications include pneumonitis and pneumonia. The treatment of pneumonitis is similar to that for acute respiratory distress syndrome (see later in this section) and includes oxygenation with general supportive care. Antibiotics are not indicated. Hospitalized patients who develop aspiration pneumonitis have a mortality rate as high as 70% to 80%. Early, aggressive, and repeated bronchoscopy for suctioning of aspirated material from the tracheobronchial tree will help minimize the inflammatory reaction of pneumonitis and facilitate improved pulmonary toilet. Forced diuresis to overcome anasarca and over-resuscitation remains controversial and unsubstantiated. Complications of forced diuresis include electrolyte disturbances, replacement of those electrolytes, metabolic alkalosis, hypotension, and acute kidney injury. Pneumonia is the second most common nosocomial infection and is the most common infection in ventilated patients. Ventilator-associated pneumonia (VAP) occurs in 15% to 40% of ventilated ICU patients, with a probability rate of 5% per day, up to 70% at 30 days. The 30-day mortality rate of nosocomial pneumonia can be as high as 40% and depends on the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 12-13 Inclusion criteria for the acute respiratory distress ­syndrome Acute onset Predisposing condition Pao2:Fio2 <200 (regardless of positive end-expiratory pressure) Bilateral infiltrates Pulmonary artery occlusion pressure <18 mmHg No clinical evidence of right heart failure Fio2 = fraction of inspired oxygen; Pao2 = partial pressure of arterial oxygen Protocol-driven ventilator weaning strategies are successful and have become part of the standard of care. The use of a weaning protocol for patients on mechanical ventilation greater than 48 hours reduces the incidence of VAP and the overall length of time on mechanical ventilation. Unfortunately, there is still no reliable way of predicting which patient will be successfully extubated after a weaning program, and the decision for extubation is based on a combination of clinical parameters and measured pulmonary mechanics.71 The Tobin Index (frequency [breaths per minute]/tidal volume [L]), also known as the rapid shallow breathing index, is perhaps the best negative predictive instrument.72 If the result equals less than 105, then there is nearly a 70% chance the patient will pass extubation. If the score is greater than 105, the patient has an approximately 80% chance of failing extubation. Other parameters such as the negative inspiratory force, minute ventilation, and respiratory rate are used, but individually have no better predictive value than the rapid shallow breathing index.73 Malnutrition and poor nutritional support may adversely affect the respiratory system. The respiratory quotient (RQ), or respiratory exchange ratio, is the ratio of the rate of ­carbon dioxide . (CO2) produced to the rate of oxygen uptake (RQ = Vco2/Vo2). Lipids, carbohydrates, and protein have differing effects on CO2 production. Patients consuming a diet of mostly carbohydrates have an RQ of 1 or greater. The RQ for a diet of mostly lipids is closer to 0.7, and that for a diet of mostly protein is closer to 0.8. Ideally, an RQ of 0.75 to 0.85 suggests adequate balance and composition of nutrient intake. An excess of carbohydrate may negatively affect ventilator weaning because of the abnormal RQ due to higher CO2 production and altered pulmonary gas exchange. Although not without risk, tracheostomy decreases the pulmonary dead space and provides for improved pulmonary toilet. When performed before the tenth day of ventilatory support, tracheostomy may decrease the incidence of VAP, the overall length of ventilator time, and the number of ICU patient days. The occurrence of PE is probably underdiagnosed. Its ­etiology is thought to stem from DVT. This concept, however, has recently been questioned from Spaniolas et al.74 The diagnosis of PE is made when a high degree of clinical suspicion for PE leads to imaging techniques such as ventilation:perfusion nuclear scans or CT pulmonary angiogram. Clinical findings include elevated central venous pressure, hypoxemia, shortness of breath, hypocarbia secondary to tachypnea, and right heart strain on ECG. Ventilation:perfusion nuclear scans are often VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 385 CHAPTER 12 Patient Safety microorganisms involved and the timeliness of initiating appropriate antimicrobials Protocol-driven approaches for prevention and treatment of VAP are recognized as beneficial in managing these difficult infectious complications. Once the diagnosis of pneumonia is suspected (an abnormal chest x-ray, fever, productive cough with purulent sputum, and no other obvious fever sources), it is invariably necessary to initially begin treatment with broad-spectrum antibiotics until proper identification, colony count (≥100,000 colonyforming units [CFU]), and sensitivity of the microorganisms are determined.62 The spectrum of antibiotic coverage should be narrowed as soon as the culture sensitivities are determined. Double-coverage antibiotic strategy for the two pathogens, Pseudomonas and Acinetobacter spp., may be appropriate if the local prevalence of these particularly virulent organisms is high. One of the most helpful tools in treating pneumonia and other infections is the tracking of a medical center’s antibiogram every 6 to 12 months.63 Epidural analgesia decreases the risk of perioperative pneumonia. This method of pain control improves p­ ulmonary toilet and the early return of bowel function; both have a ­significant impact on the potential for aspiration and for acquiring pneumonia. The routine use of epidural analgesia results in a lower incidence of pneumonia than patient-controlled ­analgesia.64 Acute lung injury (ALI) was a diagnosis applied to patients with similar findings to those with acute respiratory distress syndrome (ARDS). The Berlin definition of ARDS developed by the American-European Consensus Conference of 2012 effectively not only simplifies the definition of ARDS, but eliminates the term ALI from critical care vernacular. ARDS is now classified by partial pressure of oxygen in arterial blood (Pao2)/fraction of inspired oxygen (Fio2) ratios as mild (300–201 mmHg), moderate (200–101 mmHg), and severe (<100 mmHg). Elements of modification of the definition include the following: less than 7 days of onset; removal of pulmonary artery occlusion pressure; and clinical judgment for characterizing hydrostatic pulmonary edema is acceptable, unless risk factors for ARDS have been eliminated, in which case objective analysis is necessary.65-68 The definition of ARDS traditionally included five criteria (Table 12-13). The multicenter ARDS Research Network (ARDSnet) research trial demonstrated improved clinical outcomes for ARDS patients ventilated at tidal volumes of only 5 to 7 mL/kg.69 This strategy is no longer prescribed solely for patients with ARDS, but is also recommended for patients with normal pulmonary physiology as well who are intubated for reasons other than acute respiratory failure. The beneficial effects of positive end-expiratory pressure (PEEP) for ARDS were confirmed in this study as well. The maintenance of PEEP during ventilatory support is determined based on blood gas analysis, pulmonary mechanics, and requirements for supplemental oxygen. As gas exchange improves with resolving ARDS, the initial step in decreasing ventilatory support should be to decrease the levels of supplemental oxygen first, and then to slowly bring the PEEP levels back down to minimal levels.70 This is done to minimize the potential for recurrent alveolar collapse and a worsening gas exchange. Not all patients can be weaned easily from mechanical ventilation. When the respiratory muscle energy demands are not balanced or there is an ongoing active disease state external to the lungs, patients may require prolonged ventilatory ­support. 386 PART I BASIC CONSIDERATIONS indeterminate in patients who have an abnormal chest x-ray and are less sensitive than a CT angiogram or pulmonary angiogram for diagnosing PE. The pulmonary angiogram remains the gold standard for diagnosing PE, but spiral CT angiogram has become an alternative method because of its relative ease of use and reasonable rates of diagnostic accuracy. For cases without clinical contraindications to therapeutic anticoagulation, patients should be empirically started on heparin infusion until the imaging studies are completed if the suspicion of a PE is high. Sequential compression devices on the lower extremities and low-dose subcutaneous heparin or low molecular weight heparinoid administration are routinely used to prevent DVT and, by inference, the risk of PE. Neurosurgical and orthopedic patients have higher rates of PE, as do obese patients and those at prolonged bed rest. When anticoagulation is contraindicated, or when a known clot exists in the inferior vena cava (IVC), decreasing risk for PE includes insertion of an IVC filter. The Greenfield filter has been most widely studied, and it has a failure rate of less than 4%. Newer devices include those with nitinol wire that expands with body temperature and retrievable filters. Retrievable filters, however, must be considered as permanent. In most studies, the actual retrievable rate only reached about 20%. Some studies recognize the benefit of automated reminders and diligence of outlying patient follow-up, where higher retrieval rates have been achieved.75 Patients with spinal cord injury and multiple long-bone or pelvic fractures frequently receive IVC filters, and there appears to be a low, but not insignificant, long-term complication rate with their use. However, IVC filters do not prevent PEs that originate from DVTs of the upper extremities. Cardiac System. Arrhythmias are often seen preoperatively in elderly patients but may occur postoperatively in any age group. Atrial fibrillation is the most common arrhythmia76 and occurs between postoperative days 3 to 5 in high-risk patients. This is typically when patients begin to mobilize their interstitial fluid into the vascular fluid space. Contemporary evidence suggests that rate control is more important than rhythm control for atrial fibrillation.77,78 The first-line treatment includes β-blockade and/or calcium channel blockade. β-Blockade must be used judiciously, because hypotension, as well as withdrawal from β-blockade with rebound hypertension, is possible. Calcium channel blockers are an option if β-blockers are not tolerated by the patient, but caution must be exercised in those with a history of congestive heart failure. Although digoxin is still a standby medication, it has limitations due to the need for optimal dosing levels. Cardioversion may be required if patients become hemodynamically unstable and the rhythm cannot be controlled. Ventricular arrhythmias and other tachyarrhythmias may occur in surgical patients as well. Similar to atrial rhythm problems, these are best controlled with β-blockade, but the use of other antiarrhythmics or cardioversion may be required if patients become hemodynamically unstable. Cardiac ischemia is a cause of postoperative mortality. Acute myocardial infarction (AMI) can present insidiously, or it can be more dramatic with the classic presentation of shortness of breath, severe angina, and sudden cardiogenic shock. The workup to rule out an AMI includes an ECG and cardiac enzyme measurements. The patient should be transferred to a monitored (telemetry) floor. Morphine, supplemental oxygen, nitroglycerine, and aspirin (MONA) are the initial therapeutic maneuvers for those being investigated for AMI. Gastrointestinal System. Surgery of the esophagus is potentially complicated because of its anatomic location and blood supply. Nutritional support strategies should be considered for esophageal resection patients to maximize the potential for survival. The two primary types of esophageal resection performed are the transhiatal resection and the transthoracic (Ivor-Lewis) resection.79 The transhiatal resection has the advantage that a formal thoracotomy incision is avoided. However, dissection of the esophagus is blind, and anastomotic leaks occur more than with other resections. However, when a leak does occur, simple opening of the cervical incision and draining the leak is all that is usually required. The transthoracic Ivor-Lewis resection includes an esophageal anastomosis performed in the chest near the level of the azygos vein. These have lower leak rates, but leaks result in mediastinitis and can be difficult to control. The reported mortality is about 50% with an anastomotic leak, and the overall mortality is about 5%, which is similar to transhiatal resection. Postoperative ileus is related to dysfunction of the neural reflex axis of the intestine. Excessive narcotic use may delay return of bowel function. Epidural anesthesia results in better pain control, and there is an earlier return of bowel function and a shorter length of hospital stay. The limited use of nasogastric tubes and the initiation of early postoperative feeding are associated with an earlier return of bowel function.80 The use of chewing gum and other oral stimulants to minimize ileus remains controversial. Pharmacologic agents commonly used to stimulate bowel function include metoclopramide and erythromycin. Metoclopramide’s action is limited to the stomach and duodenum, and it may help primarily with gastroparesis. Erythromycin is a motilin agonist that works throughout the stomach and bowel. Several studies demonstrate significant benefit from the administration of erythromycin in those suffering from an ileus.81 Alvimopan, a newer agent and a mu-opioid receptor antagonist, has shown some promise in many studies for earlier return of gut function and subsequent reduction in length of stay.82,83 Neostigmine has been used in refractory pan-ileus patients (Ogilvie’s syndrome) with some degree of success. It is recommended for patients receiving this type of therapy to be in a monitored unit.84 0 Small bowel obstruction occurs in less than 1% of early postoperative patients. When it does occur, adhesions are usually the cause. Internal and external hernias, technical errors, and infections or abscesses are also causative. Hyaluronidase is a mucolytic enzyme that degrades connective tissue, and the use of a methylcellulose form of hyaluronidase, Seprafilm, has been shown to result in a 50% decrease in adhesion formation in some patients.85,86 This should translate into a lower occurrence of postoperative bowel obstruction, but this has yet to be proven. Fistulae are the abnormal communication of one structure to an adjacent structure or compartment and are associated with extensive morbidity and mortality. Common causes for fistula formation are summarized in the mnemonic FRIENDS (Foreign body, Radiation, Ischemia/Inflammation/Infection, Epithelialization of a tract, Neoplasia, Distal obstruction, and Steroid use). Postoperatively, they are most often caused by infection or obstruction leading to an anastomotic leak. The cause of the fistula must be recognized early, and treatment may include nonoperative management with observation and nutritional support, or a delayed operative management strategy that also includes nutritional support and wound care. GI bleeding can occur perioperatively (Table 12-14). Technical errors such as a poorly tied suture, a nonhemostatic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 12-14 Upper GI Bleed Lower GI Bleed Erosive esophagitis Angiodysplasia Gastric varices Radiation proctitis Esophageal varices Hemangioma Dieulafoy’s lesion Diverticulosis Aortoduodenal fistula Neoplastic diseases Mallory-Weiss tear Trauma Peptic ulcer disease Vasculitis Trauma Hemorrhoids Neoplastic disease Aortoenteric fistula Intussusception Ischemic colitis Inflammatory bowel disease Postprocedure bleeding staple line, or a missed injury can all lead to postoperative intestinal bleeding.87,88 The source of bleeding is in the upper GI tract about 85% of the time and is usually detected and treated endoscopically. Surgical control of intestinal bleeding is required in up to 40% of patients.89 When patients in the ICU have a major bleed from stress gastritis, the mortality risk is as high as 50%. It is important to keep the gastric pH greater than 4 to decrease the overall risk for stress gastritis in patients mechanically ventilated for 48 hours or greater and patients who are coagulopathic.90 Proton pump inhibitors, H2-receptor antagonists, and intragastric antacid installation are all effective measures. However, patients who are not mechanically ventilated or who do not have a history of gastritis or peptic ulcer disease should not be placed on gastritis prophylaxis postoperatively because it carries a higher risk of causing pneumonia. Hepatobiliary-Pancreatic System. Complications involving the hepatobiliary system are usually due to technical errors. Laparoscopic cholecystectomy has become the standard of care for cholecystectomy, but common bile duct injury remains a nemesis of this approach. Intraoperative cholangiography has not been shown to decrease the incidence of common bile duct injuries because the injury to the bile duct usually occurs before the cholangiogram.91,92 Early recognition and immediate repair of an injury are important, because delayed bile duct leaks often require a more complex repair. Ischemic injury due to devascularization of the common bile duct has a delayed presentation days to weeks after an operation. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrates a stenotic, smooth common bile duct, and liver function studies are elevated. The recommended treatment is a Roux-en-Y hepaticojejunostomy. A bile leak due to an unrecognized injury to the ducts may present after cholecystectomy as a biloma. These patients may present with abdominal pain and hyperbilirubinemia. The diagnosis of a biliary leak can be confirmed by CT scan, ERCP, or radionuclide scan. Once a leak is confirmed, a retrograde biliary stent and external drainage are the treatment of choice. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 387 CHAPTER 12 Patient Safety Common causes of upper and lower gastrointestinal (GI) hemorrhage Hyperbilirubinemia in the surgical patient can be a c­ omplex problem. Cholestasis makes up the majority of causes for hyperbilirubinemia, but other mechanisms of hyperbilirubinemia include reabsorption of blood (e.g., hematoma from trauma), decreased bile excretion (e.g., sepsis), increased unconjugated bilirubin due to hemolysis, hyperthyroidism, and impaired excretion due to congenital abnormalities or acquired disease. Errors in surgery that cause hyperbilirubinemia largely involve missed or iatrogenic injuries. The presence of cirrhosis predisposes to postoperative complications. Abdominal or hepatobiliary surgery is problematic in the cirrhotic patient. Ascites leak in the postoperative period can be an issue when any abdominal operation has been performed. Maintaining proper intravascular oncotic pressure in the immediate postoperative period can be difficult, and resuscitation should be maintained with crystalloid solutions. Prevention of renal failure and the management of the hepatorenal syndrome can be difficult, as the demands of fluid resuscitation and altered glomerular filtration become competitive. Spironolactone with other diuretic agents may be helpful in the postoperative care. These patients often have a labile course, and bleeding complications due to coagulopathy are common. The operative mortality in cirrhotic patients is 10% for Child class A, 30% for Child class B, and 82% for Child class C patients.93 Pyogenic liver abscess occurs in less than 0.5% of adult admissions, due to retained necrotic liver tissue, occult intestinal perforations, benign or malignant hepatobiliary obstruction, sepsis, and hepatic arterial occlusion. The treatment is long-term antibiotics with percutaneous drainage of large abscesses. Pancreatitis can occur following injection of contrast during cholangiography and ERCP. These episodes range from a mild elevation in amylase and lipase with abdominal pain, to a fulminant course of pancreatitis with necrosis requiring surgical débridement. Traumatic injuries to the pancreas can occur during surgical procedures on the kidneys, GI tract, and spleen most commonly. Treatment involves serial CT scans and percutaneous drainage to manage infected fluid and abscess collections; sterile collections should not be drained because drain placement can introduce infection. A pancreatic fistula may respond to antisecretory therapy with a somatostatin analogue. Management of these fistulae initially includes ERCP with or without pancreatic stenting, percutaneous drainage of any fistula fluid collections, total parenteral nutrition (TPN) with bowel rest, and repeated CT scans. The majority of pancreatic fistulae will eventually heal spontaneously. Renal System. Renal failure can be classified as prerenal failure, intrinsic renal failure, and postrenal failure. Postrenal failure, or obstructive renal failure, should always be considered when low urine output (oliguria) or anuria occurs. The most common cause is a misplaced or clogged urinary catheter. Other, less common causes to consider are unintentional ligation or transection of ureters during a difficult surgical dissection (e.g., colon resection for diverticular disease) or a large retroperitoneal hematoma (e.g., ruptured aortic aneurysm). Oliguria is initially evaluated by flushing the urinary catheter using sterile technique. Urine electrolytes should also be measured (Table 12-15). A hemoglobin and hematocrit level should be checked immediately. Patients in compensated shock from acute blood loss may manifest anemia and end-organ malperfusion as oliguria. Acute tubular necrosis (ATN) carries a mortality risk of 25% to 50% due to the many complications that can cause, or result from, this insult. When ATN is due to poor inflow 388 Table 12-15 Urinary electrolytes associated with acute renal failure and their possible etiologies PART I BASIC CONSIDERATIONS FENa Osmolarity URNa Etiology Prerenal <1 >500 <20 CHF, cirrhosis Intrinsic failure >1 <350 >40 Sepsis, shock CHF = congestive heart failure; FENa = fractional excretion of sodium; URNa = urinary excretion of sodium. (­ prerenal failure), the remedy begins with IV administration of crystalloid or colloid fluids as needed. If cardiac insufficiency is the problem, the optimization of vascular volume is achieved first, followed by inotropic agents, as needed. Intrinsic renal failure and subsequent ATN are often the result of direct renal toxins. Aminoglycosides, vancomycin, and furosemide, among other commonly used agents, contribute directly to nephrotoxicity. Contrast-induced nephropathy usually leads to a subtle or transient rise in creatinine. In patients who are volume depleted or have poor cardiac function, contrast nephropathy may permanently impair renal function.94-97 The treatment of renal failure due to myoglobinuria has shifted away from the use of sodium bicarbonate for alkalinizing the urine, to merely maintaining brisk urine output of 100 mL/h with crystalloid fluid infusion. Mannitol and furosemide are not recommended. Patients who do not respond to resuscitation are at risk for needing renal replacement therapy. Fortunately, most of these patients eventually recover from their renal dysfunction. Musculoskeletal System. A compartment syndrome can develop in any compartment of the body. Compartment syndrome of the extremities generally occurs after a closed fracture. The injury alone may predispose the patient to compartment syndrome, but aggressive fluid resuscitation can exacerbate the problem. Pain with passive motion is the hallmark of compartment syndrome, and the anterior compartment of the leg is usually the first compartment to be involved. Confirmation of the diagnosis is obtained by direct pressure measurement of the individual compartments. If the pressures are greater than 20 to 25 mmHg in any of the compartments, then a four-compartment fasciotomy is considered. Compartment syndrome can be due to ischemia-reperfusion injury, after an ischemic time of 4 to 6 hours. Renal failure (due to myoglobinuria), tissue loss, and a permanent loss of function are possible results of untreated compartment syndrome. Decubitus ulcers are preventable complications of ­prolonged bed rest due to traumatic paralysis, dementia, chemical paralysis, or coma. Unfortunately, they are still occurring despite extensive research and clinical initiatives that demonstrate successful prevention strategies. Ischemic changes in the microcirculation of the skin can be significant after 2 hours of sustained pressure. Routine skin care and turning of the patient help ensure a reduction in skin ulceration. This can be labor intensive, and special mattresses and beds are available to help. The treatment of a decubitus ulcer in the noncoagulopathic patient is surgical débridement. Once the wound bed has a viable granulation base without an excess of fibrinous debris, a vacuum-assisted closure dressing can be applied. Wet to moist dressings with frequent dressing changes is the alternative and is labor intensive. Expensive topical enzyme preparations are also available. If the wounds fail to respond to these measures, soft tissue coverage by flap is considered. Contractures are the result of muscle disuse. Whether from trauma, amputation, or vascular insufficiency, contractures can be prevented by physical therapy and splinting. If not attended to early, contractures will prolong rehabilitation and may lead to further wounds and wound healing issues. Depending on the functional status of the patient, contracture releases may be required for long-term care. Hematologic System. The transfusion guideline of maintaining the hematocrit level in all patients at greater than 30% is no longer valid. Only patients with symptomatic anemia, who have significant cardiac disease, or who are critically ill and require increased oxygen-carrying capacity to adequately perfuse end organs require higher levels of hemoglobin. Other than these select patients, the decision to transfuse should generally not occur until the hemoglobin level reaches 7 mg/dL or the hematocrit reaches 21%. Transfusion reactions are common complications of blood transfusion. These can be attenuated with a leukocyte filter, but not completely prevented. The manifestations of a transfusion reaction include simple fever, pruritus, chills, muscle rigidity, and renal failure due to myoglobinuria secondary to hemolysis. Discontinuing the transfusion and returning the blood products to the blood bank is an important first step, but administration of antihistamine and possibly steroids may be required to control the reaction symptoms. Severe transfusion reactions are rare but can be fatal. Infectious complications in blood transfusion range from cytomegalovirus transmission, which is benign in the nontransplant patient, to human immunodeficiency virus (HIV) infection, to passage of the hepatitis viruses (Table 12-16). Patients on warfarin (Coumadin) who require surgery can have anticoagulation reversal by administration of freshfrozen plasma. Each unit of fresh frozen plasma contains 200 to 250 mL of plasma and includes one unit of coagulation factor per milliliter of plasma. Thrombocytopenia may require platelet transfusion for a platelet count less than 20,000/mL when invasive procedures are performed, or when platelet counts are low and ongoing bleeding from raw surface areas persists. One unit of platelets will increase the platelet count by 5000 to 7500 per mL in adults. It is important to delineate the cause of the low platelet count. Table 12-16 Rate of viral transmission in blood product transfusionsa HIV 1:1.9 million HBV 1:137,000 HCV 1:1 million b Post-nucleic acid amplification technology (1999). Earlier rates were erroneously reported higher due to lack of contemporary technology. b HBV is reported with pre-nucleic acid amplification technology. Statistical information is unavailable with post-nucleic acid amplification technology at this writing. Note that bacterial transmission is 50 to 250 times higher than viral transmission per transfusion. HBV = hepatitis B virus; HCV = hepatitis C virus. a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Patients with intra-abdominal hypertension should be monitored closely with repeated examinations and measurements of bladder pressure, so that any further deterioration is detected and operative management can be initiated. Left untreated, ACS may lead to multiple system end-organ dysfunction or failure and has a high mortality. Abdominal wall closure should be attempted every 48 to 72 hours until the fascia can be reapproximated. If the abdomen cannot be closed within 5 to 7 days following release of the abdominal fascia, a large incisional hernia is the net result. A variety of surgical options have evolved for prevention and closure of the resultant hernias, but no standard approach has yet evolved. Wounds, Drains, and Infection Wound (Surgical Site) Infection. No prospective, randomized, double-blind, controlled studies exist that demonstrate antibiotics used beyond 24 hours in the perioperative period prevent infections. Prophylactic use of antibiotics should simply not be continued beyond this time. Irrigation of the operative field and the surgical wound with saline solution has shown benefit in controlling wound inoculum.107 Irrigation with an antibiotic-based solution has not demonstrated significant benefit in controlling postoperative infection. Antibacterial-impregnated polyvinyl placed over the operative wound area for the duration of the surgical procedure has not been shown to decrease the rate of wound infection.108-112 Although skin preparation with 70% isopropyl alcohol has the best bactericidal effect, it is flammable and could be hazardous when electrocautery is used. The contemporary formulas of chlorhexidine gluconate with isopropyl alcohol remain more advantageous.113-115 There is a difference between wound colonization and infection. Overtreating colonization is just as injurious as u­ ndertreating infection. The strict definition of wound (soft t­issue) infection is more than 105 CFU per gram of tissue. This warrants expeditious and proper antibiotic/antifungal treatment.63,116 Often, however, clinical signs raise enough suspicion that the patient is treated before a confirmatory culture is undertaken. The clinical signs of wound infection include rubor, tumor, calor, and dolor (redness, swelling, heat, and pain). Once the diagnosis of wound infection has been established, the most definitive treatment remains open drainage of the wound. The use of antibiotics for wound infection treatment should be limited.117-120 One type of wound dressing/drainage system that is gaining popularity is the vacuum-assisted closure dressing. The principle of the system is to decrease local wound edema and to promote healing through the application of a sterile dressing that is then covered and placed under controlled suction for a period of 2 to 4 days at a time. Although costly, the benefits are frequently dramatic and may offset the costs of nursing care, frequent dressing changes, and operative wound débridement. Drain Management. The four indications for applying a surgical drain are: • T  o collapse surgical dead space in areas of redundant tissue (e.g., neck and axilla) • To provide focused drainage of an abscess or grossly infected surgical site • To provide early warning notice of a surgical leak (either bowel contents, secretions, urine, air, or blood)—the s­ o-called sentinel drain • To control an established fistula leak VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 389 CHAPTER 12 Patient Safety Usually there is a self-limiting or reversible condition such as sepsis. Rarely, it is due to heparin-induced thrombocytopenia I and II. Complications of heparin-induced thrombocytopenia II can be serious because of the diffuse thrombogenic nature of the disorder. Simple precautions to limit this hypercoagulable state include saline solution flushes instead of heparin solutions and limiting the use of heparin-coated catheters. The treatment is anticoagulation with synthetic agents such as argatroban. For patients with uncontrollable bleeding due to disseminated intravascular coagulopathy (DIC), a potentially useful drug is factor VIIa, but its use should be judicious.98-100 ­Originally used in hepatic trauma and obstetric emergencies, this agent was lifesaving in some circumstances. The ­CONTROL Trial,101 however, has largely decreased overuse of this agent because investigators demonstrated no benefit over simple factor replacement in severely coagulopathic patients. Factor VIIa use may also be limited due to its potential thrombotic complications. For some situations, the combination of ongoing, nonsurgical bleeding and renal failure can occasionally be successfully treated with desmopressin. In addition to classic hemophilia, other inherited coagulation factor deficiencies can be difficult to manage in surgery. When required, transfusion of appropriate replacement products is coordinated with the regional blood bank center before ­surgery. Other blood dyscrasias seen by surgeons include hypercoagulopathic patients. Those who carry congenital anomalies such as the most common factor V Leiden deficiency, as well as protein C and S deficiencies, are likely to form thromboses if inadequately anticoagulated, and these patients should be managed in conjunction with a hematologist. Abdominal Compartment Syndrome. Multisystem trauma, thermal burns, retroperitoneal injuries, and surgery related to the retroperitoneum are the major initial causative factors that may lead to abdominal compartment syndrome (ACS). Ruptured AAA, major pancreatic injury and resection, or multiple intestinal injuries are also examples of clinical s­ ituations in which a large volume of IV fluid resuscitation puts these patients at risk for intra-abdominal hypertension. Manifestations of ACS typically include progressive abdominal distention followed by increased peak airway ventilator pressures, oliguria followed by anuria, and an insidious development of intracranial hypertension.102 These findings are related to elevation of the diaphragm and inadequate venous return from the vena cava or renal veins secondary to the transmitted pressure on the venous system. Measurement of abdominal pressures is easily accomplished by transducing bladder pressures from the urinary catheter after instilling 100 mL of sterile saline into the urinary bladder.103 A pressure greater than 20 mmHg constitutes intraabdominal hypertension, but the diagnosis of ACS requires intra-abdominal pressure greater than 25 to 30 mmHg, with at least one of the following: compromised respiratory mechanics and ventilation, oliguria or anuria, or increasing intracranial pressures.104-106 The treatment of ACS is to open any recent abdominal incision to release the abdominal fascia or to open the fascia directly if no abdominal incision is present. Immediate improvement in mechanical ventilation pressures, intracranial pressures, and urine output is usually noted. When expectant management for ACS is considered in the OR, the abdominal fascia should be left open and covered under sterile conditions (e.g., a vacuum-assisted open abdominal wound closure system) with plans made for a second-look operation and delayed fascial closure. 390 PART I BASIC CONSIDERATIONS Open drains are often used for large contaminated wounds such as perirectal or perianal fistulas and subcutaneous abscess cavities. They prevent premature closure of an abscess cavity in a contaminated wound. More commonly, surgical sites are drained by closed suction drainage systems, but data do not support closed suction drainage to “protect an anastomosis” or to “control a leak” when placed at the time of surgery. Closed suction devices can exert a negative pressure of 70 to 170 mmHg at the level of the drain; therefore, the presence of this excess suction may call into question whether an anastomosis breaks down on its own or whether the drain creates a suction injury that promotes leakage (Fig. 12-8).121 On the other hand, CT- or ultrasound-guided placement of percutaneous drains is now the standard of care for abscesses, loculated infections, and other isolated fluid collections such as pancreatic leaks. The risk of surgery is far greater than the placement of an image-guided drain. The use of antibiotics when drains are in place is often unnecessary as the drain provides direct source control. Twentyfour to 48 hours of antibiotic use after drain placement is prophylactic, and after this period, only specific treatment of positive cultures should be performed, to avoid increased drug resistance and superinfection. Urinary Catheters. Several complications of urinary catheters can occur that lead to an increased length of hospital stay and morbidity. In general, use of urinary catheters should be minimized and every opportunity to expeditiously remove them should be encouraged. If needed, it is recommended that the catheter be inserted its full length up to the hub and that urine flow is established before the balloon is inflated, because misplacement of the catheter in the urethra with ­premature inflation of the balloon can lead to tears and disruption of the urethra. Enlarged prostatic tissue can make catheter insertion difficult, and a catheter coudé may be required. If this attempt is also unsuccessful, then a urologic consultation for endoscopic placement of the catheter may be required to prevent harm to the urethra. For patients with urethral strictures, filiform-tipped catheters and followers may be used, but these can potentially cause bladder injury. If endoscopic attempts fail, the patient may require a percutaneously placed suprapubic catheter to obtain decompression of the bladder. Follow-up investigations of these patients are recommended so definitive care of the urethral abnormalities can be pursued. The most frequent nosocomial infection is urinary tract infection (UTI). These infections are classified into complicated and uncomplicated forms. The uncomplicated type is a UTI that can be treated with outpatient antibiotic therapy. The complicated UTI usually involves a hospitalized patient with an indwelling catheter whose UTI is diagnosed as part of a fever workup. The interpretation of urine culture results of less than 100,000 CFU/mL is controversial. Before treating such a patient, one should change the catheter and then repeat the culture to see if the catheter was simply colonized with organisms. Cultures with more than 100,000 CFU/mL should be treated with the appropriate antibiotics and the catheter changed or removed as soon as possible. Undertreatment or misdiagnosis of a UTI can lead to urosepsis and septic shock. Recommendations are mixed on the proper way to treat Candida albicans fungal bladder infections. Continuous bladder washings with fungicidal solution for 72 hours have been recommended, but this is not always effective. Replacement of the urinary catheter and a course of fluconazole are appropriate A B Figure 12-8. This illustration demonstrates typical intraoperative placement of closed suction devices in pancreatic or small bowel surgery, where there may be an anastomosis. At negative pressures of 70 to 170 mmHg, these devices may actually encourage anastomotic leaks and not prevent them or become clogged by them. treatments, but some infectious disease specialists claim that C. albicans in the urine may serve as an indication of ­fungal infection elsewhere in the body. If this is the case, then screening cultures for other sources of fungal infection should be performed whenever a fungal UTI is found. Empyema. One of the most debilitating infections is an empyema, or infection of the pleural space. Frequently, an VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Abdominal Abscesses. Postsurgical intra-abdominal abscesses can present with vague complaints of intermittent abdominal pain, fever, leukocytosis, and a change in bowel habits. Depending on the type and timing of the original procedure, the clinical assessment of these complaints is sometimes difficult, and a CT scan is usually required. When a fluid collection within the peritoneal cavity is found on CT scan, antibiotics and percutaneous drainage of the collection is the treatment of choice. Initial antibiotic treatment is usually with broad-spectrum antibiotics such as piperacillin-tazobactam or imipenem. Should the patient exhibit signs of peritonitis and/or have free air on x-ray or CT scan, then re-exploration should be considered. For patients who present primarily (i.e., not postoperatively) with the clinical and radiologic findings of an abscess but are clinically stable, the etiology of the abscess must be determined. A plan for drainage of the abscess and decisions about further diagnostic studies with consideration of the timing of any definitive surgery all need to be balanced. This can be a complex set of decisions, depending on the etiology (e.g., appendicitis or diverticulitis), but if the patient exhibits signs of peritonitis, urgent surgical exploration should be performed. Necrotizing Fasciitis. Postoperative infections that progress to the fulminant soft tissue infection known as necrotizing fasciitis are uncommon. Group A streptococcal (M types 1, 3, 12, and 28) soft tissue infections, as well as infections with Clostridium perfringens and C. septicum, carry a mortality of 30% to 70%. Septic shock can be present, and patients can become hypotensive less than 6 hours following inoculation. Manifestations of a group A Streptococcus pyogenes infection in its most severe form include hypotension, renal insufficiency, coagulopathy, hepatic insufficiency, ARDS, tissue necrosis, and ­erythematous rash. These findings constitute a surgical emergency, and the mainstay of treatment remains wide débridement of the necrotic tissue to the level of bleeding, viable tissue. A gray serous fluid at the level of the necrotic tissue is usually noted, and as the infection spreads, thrombosed blood vessels are noted along the tissue planes involved with the infection. Typically, the patient requires serial trips to the OR for wide débridement until the infection is under control. Antibiotics are an important adjunct to surgical débridement, and broad-spectrum coverage should be used because these infections may be polymicrobial (i.e., socalled mixed-synergistic infections). S. pyogenes is eradicated with penicillin, and it should still be used as the initial drug of choice. 391 Table 12-17 Mortality associated with patients exhibiting two or more criteria for systemic inflammatory response ­syndrome (SIRS) Prognosis Mortality (%) 2 SIRS criteria 5 3 SIRS criteria 10 4 SIRS criteria 15–20 Systemic Inflammatory Response Syndrome, Sepsis, and Multiple-Organ Dysfunction Syndrome. The systemic inflammatory response syndrome (SIRS) and the multipleorgan dysfunction syndrome (MODS) carry significant mortality risks (Table 12-17). Specific criteria have been established for the diagnosis of SIRS (Table 12-18), but two criteria are not required for the diagnosis of SIRS: lowered blood pressure and blood cultures positive for infection. SIRS is the result of proinflammatory cytokines related to tissue malperfusion or injury. The dominant cytokines implicated in this process include interleukin (IL)-1, IL-6, and tissue necrosis factor (TNF). Other mediators include nitric oxide, inducible macrophage-type nitric oxide synthase, and prostaglandin I2. Sepsis is categorized as sepsis, severe sepsis, and septic shock. Sepsis is SIRS plus infection. Severe sepsis is sepsis plus signs of cellular hypoperfusion or end-organ dysfunction. Septic shock is sepsis plus hypotension after adequate fluid resuscitation. MODS is the culmination of septic shock and multiple end-organ failure.122 Usually there is an inciting event (e.g., perforated sigmoid diverticulitis), and as the patient undergoes resuscitation, he or she develops cardiac hypokinesis and oliguric or anuric renal failure, followed by the development of ARDS and eventually septic shock with death. The international Surviving Sepsis Campaign (http:// www.sccm.org/Documents/SSC-Guidelines.pdf) continues to demonstrate the importance of early recognition and initiation of specific treatment guidelines for optimal management of sepsis. Management of SIRS/MODS includes aggressive global resuscitation and support of end-organ perfusion, correction of the inciting etiology, control of infectious complications, and management of iatrogenic complications.123-125 Drotrecogin-α, or recombinant activated protein C, appears to specifically counteract the cytokine cascade of SIRS/MODS, but its use is still limited.126,127 Other adjuncts for supportive therapy include Table 12-18 Inclusion criteria for the systemic inflammatory response syndrome Temperature >38°C or <36°C (>100.4°F or <96.8°F) Heart rate >90 beats/min Respiratory rate >20 breaths/min or Paco2 <32 mmHg White blood cell count <4000 or >12,000 cells/mm3 or >10% immature forms Paco2 = partial pressure of arterial carbon dioxide. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 12 Patient Safety overwhelming pneumonia is the source of an empyema, but a retained hemothorax, systemic sepsis, esophageal perforation from any cause, and infections with a predilection for the lung (e.g., tuberculosis) are potential etiologies as well. The diagnosis is confirmed by chest x-ray or CT scan, ­followed by aspiration of pleural fluid for bacteriologic analysis. Gram’s stain, lactate dehydrogenase, protein, pH, and cell count are obtained, and broad-spectrum antibiotics are initiated while the laboratory studies are performed. Once the specific organisms are confirmed, anti-infective agents are tailored appropriately. Placement of a thoracostomy tube is needed to evacuate and drain the infected pleural fluid, but depending on the specific nidus of infection, video-assisted thoracoscopy may also be helpful for irrigation and drainage of the infection. Refractory empyemas require specialized surgical approaches. 392 tight glucose control, low tidal volumes in ARDS, vasopressin in septic shock, and steroid replacement therapy. PART I Nutritional and Metabolic Support Complications BASIC CONSIDERATIONS Nutrition-Related Complications. A basic principle is to use enteral feeding whenever possible, but complications can intervene such as aspiration, ileus, and to a lesser extent, sinusitis. There is no difference in aspiration rates when a small-caliber feeding tube is placed post-pyloric or if it remains in the stomach. Patients who are fed via nasogastric tubes are at risk for aspiration pneumonia, because these relatively large-bore tubes stent open the gastroesophageal junction, creating the possibility of gastric reflux. The use of enteric and gastric feeding tubes obviates complications of TPN, such as pneumothorax, line sepsis, upper extremity DVT, and the related expense. There is growing evidence to support the initiation of enteral feeding in the early postoperative period, before the return of bowel function, where it is usually well tolerated. In patients who have had any type of nasal intubation who are having high, unexplained fevers, sinusitis must be entertained as a diagnosis. CT scan of the sinuses is warranted, ­followed by aspiration of sinus contents so the organism(s) are appropriately treated. Patients who have not been enterally fed for prolonged periods secondary to multiple operations, those who have had enteral feeds interrupted for any other reason, or those with poor enteral access are at risk for the refeeding syndrome, which is characterized by severe hypophosphatemia and respiratory failure. Slow progression of the enteral feeding administration rate can avoid this complication. Common TPN problems are mostly related to electrolyte abnormalities that may develop. These electrolyte errors include deficits or excesses in sodium, potassium, calcium, magnesium, and phosphate. Acid-base abnormalities can also occur with the improper administration of acetate or bicarbonate solutions. The most common cause for hypernatremia in hospitalized patients is underresuscitation, and conversely, hyponatremia is most often caused by fluid overload. Treatment for hyponatremia is fluid restriction in mild or moderate cases and the administration of hypertonic saline for severe cases. An overly rapid correction of the sodium abnormality may result in central pontine myelinolysis, which results in a severe neurologic deficit. Treatment for hyponatremic patients includes fluid restriction to correct the free water deficit by 50% in the first 24 hours. An overcorrection of hyponatremia can result in severe cerebral edema, a neurologic deficit, or seizures. Glycemic Control. In 2001, Van den Berghe and colleagues demonstrated that tight glycemic control by insulin infusion is associated with a 50% reduction in mortality in the critical care setting.128 This prospective, randomized, controlled trial of 1500 patients had two study arms: the intensive-control arm, where the serum glucose was maintained between 80 and 110 mg/dL with insulin infusion; and the control arm, where patients received an insulin infusion only if blood glucose was greater than 215 mg/dL, but serum glucose was then maintained at 180 to 200 mg/dL. The tight glycemic control group had an average serum glucose level of 103 mg/dL, and the average glucose level in the control group was 153 mg/dL. Hypoglycemic episodes (glucose <40 mg/dL) occurred in 39 patients in the tightly controlled group, while the control group had episodes in six patients. The overall mortality was reduced from 8% to 4.6%, but the mortality of those patients whose ICU stay lasted longer than 5 days was reduced from 20% to 10%. Secondary findings included an improvement in overall morbidity, a decreased percentage of ventilator days, less renal impairment, and a lower incidence of bloodstream infections. These finding have been corroborated by subsequent similar studies, and the principal benefit appears to be a greatly reduced incidence of nosocomial infections and sepsis. It is not known whether the benefits are due to strict euglycemia, to the anabolic properties of insulin, or both, but the maintenance of strict euglycemia between 140 and 180 mg/dL appears to be a powerful therapeutic strategy.128-130 A number of studies followed this sentinel publication of tight glycemic control. NICE-SUGAR131 and COIITSS132 revisited the Van den Berghe study and found that the glycemic goals found initially to improve outcomes in critically ill patients were now found to be associated with a higher mortality when glucose was kept below 180 mg/dL, due to an increase in incidents of hypoglycemia. When targeted goals of 180 mg/dL are achieved, less occurrences of hypoglycemia have been documented and improved survivorship has been achieved. In addition, some studies find no relationship between glycemic control and improved outcomes. Thus, glycemic control in the critically ill still remains unclear and elusive at best.133,134 Part of the difficulty in achieving “tight glycemic control” is the necessity for frequent (every 1–2 hours) blood glucose determinations. When this is performed, glycemic control is enhanced and hypoglycemia is avoided. Metabolism-Related Complications. “Stress dose steroids” have been advocated for the perioperative treatment of patients on corticosteroid therapy, but recent studies strongly discourage the use of supraphysiologic doses of steroids when patients are on low or maintenance doses (e.g., 5–15 mg) of prednisone daily. Parenteral glucocorticoid treatment need only replicate physiologic replacement steroids in the perioperative period. When patients are on steroid replacement doses equal to or greater than 20 mg per day of prednisone, it may be appropriate to administer additional glucocorticoid doses for no more than 2 perioperative days.135-137 Adrenal insufficiency may be present in patients with a baseline serum cortisol less than 20 μg/dL. A rapid provocative test with synthetic adrenocorticotropic hormone may confirm the diagnosis. After a baseline serum cortisol level is drawn, 250 μg of cosyntropin is administered. At exactly 30 and 60 minutes following the dose of cosyntropin, serum cortisol levels are obtained. There should be an incremental increase in the cortisol level of between 7 and 10 μg/dL for each half hour. If the patient is below these levels, a diagnosis of adrenal insufficiency is made, and glucocorticoid and mineralocorticoid administration is then warranted. Mixed results are common, but the complication of performing major surgery on an adrenally insufficient patient is sudden or profound hypotension that is not responsive to fluid resuscitation.123 Thyroid hormone abnormalities usually consist of previously undiagnosed thyroid abnormalities. Hypothyroidism and the so-called sick-euthyroid syndrome are more commonly recognized in the critical care setting. When surgical patients are not progressing satisfactorily in the perioperative period, screening for thyroid abnormalities should be performed. If the results show mild to moderate hypothyroidism, then thyroid replacement should begin immediately and thyroid function studies should be monitored closely. All patients should VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ be ­reassessed after the acute illness has subsided regarding the need for chronic thyroid replacement therapy. Hypothermia. Hypothermia is defined as a core temperature less than 35°C (95°F) and is divided into subsets of mild (35–32°C [95–89.6°F]), moderate (32–28°C [89.6–82.4°F]), and severe (<28°C [<82.4°F]) hypothermia. Shivering, the body’s attempt to reverse the effects of hypothermia, occurs between 37 and 31°C (98.6 and 87.8°F), but ceases at temperatures below 31°C (87.8°F). Patients who are moderately hypothermic are at higher risk for complications than are those who are more profoundly hypothermic. Hypothermia creates a coagulopathy that is related to platelet and clotting cascade enzyme dysfunction. This triad of metabolic acidosis, coagulopathy, and hypothermia is commonly found in long operative cases and in patients with blood dyscrasias. The enzymes that contribute to the clotting cascade and platelet activity are most efficient at normal body temperatures; therefore all measures must be used to reduce heat loss intraoperatively.138 The most common cardiac abnormality is the development of arrhythmias when body temperature drops below 35°C (95°F). Bradycardia occurs with temperatures below 30°C (86°F). It is well known that hypothermia may induce CO2 retention, resulting in respiratory acidosis. Renal dysfunction of hypothermia manifests itself as a paradoxic polyuria and is related to an increased glomerular filtration rate, as peripheral vascular constriction creates central shunting of blood. This is potentially perplexing in patients who are undergoing resuscitation for hemodynamic instability, because the brisk urine output provides a false sense of an adequate intravascular fluid volume. Induced peripheral hypothermia for hyperpyrexia due to infection (not to include neurologic or cardiac disease) is likely deleterious and does not appear to be beneficial. Placing cooling blankets on or under the patient or ice packs in the axillae or groin may be effective in cooling the skin, and when this occurs, a subsequent feedback loop triggers the hypothalamus to raise the internally regulated set point, thus raising core temperature even higher. This paradoxical reaction may be why outcomes for those who feel the need to treat a fever in the ICU by cooling the skin and arguably the core have worse outcomes. Cooling core temperatures can be achieved reliably with catheter-directed therapy with commercially available devices. Whether this is a worthwhile practice or not may be controversial. Poor data exist in support of treating fevers lower than 42°C in any fashion.133,134,139-142 Adult trauma patients who underwent induced hypothermia had poor outcomes in a recent investigation, and thus, this remains a procedure to be avoided. In a similar vein, pediatric patients who were induced did not show any improvement, and therefore, induced hypothermia is not recommended. Complications with induced hypothermia include, but are not limited to, hypokalemia, diuresis, DVT (due to catheter-related vein injury), arrhythmias, shivering, undiagnosed catheter-related bloodstream infection, and bacteremia.143-146 Neurologic dysfunction is inconsistent in hypothermia, but a deterioration in reasoning and decision-making skills progresses as body temperature falls, and profound coma (and a flat electroencephalogram) occurs as the temperature drops below 30°C (86°F). The diagnosis of hypothermia is important, Common causes of elevated temperature in surgical patients Hyperthermia Hyperpyrexia Environmental Sepsis Malignant hyperthermia Infection Neuroleptic malignant syndrome Drug reaction Thyrotoxicosis Transfusion reaction Pheochromocytoma Collagen disorders Carcinoid syndrome Factitious syndrome Iatrogenic Neoplastic disorders Central/hypothalamic responses Pulmonary embolism Adrenal insufficiency so accurate measurement techniques are required to get a true core temperature. Methods used to warm patients include warm air circulation over the patient and heated IV fluids, and more aggressive measures such as bilateral chest tubes with warm solution lavage, intraperitoneal rewarming lavage, and extracorporeal membrane oxygenation. A rate of temperature rise of 2 to 4°C/h (3.6–7.2°F/h) is considered adequate, but the most common complication for nonbypass rewarming is arrhythmia with ventricular arrest. Hyperthermia. Hyperthermia is a core temperature greater than 38.6°C (101.5°F) and has a host of etiologies (Table 12-19).147 Hyperthermia can be environmentally induced (e.g., summer heat with inability to dissipate heat or control exposure), iatrogenically induced (e.g., heat lamps and medications), endocrine in origin (e.g., thyrotoxicosis), or neurologically induced (i.e., hypothalamic). Malignant hyperthermia occurs after exposure to agents such as succinylcholine and some halothane-based inhalational anesthetics. The presentation is dramatic, with rapid onset of increased temperature, rigors, and myoglobinuria related to myonecrosis. Medications must be discontinued immediately and dantrolene administered (2.5 mg/kg every 5 minutes) until symptoms subside. Aggressive cooling methods are also implemented, such as an alcohol bath, or packing in ice. In cases of severe malignant hyperthermia, the mortality rate is nearly 30%. Thyrotoxicosis can occur after surgery due to undiagnosed Graves’ disease. Hyperthermia (>40°C [104°F]), anxiety, copious diaphoresis, congestive heart failure (present in about one fourth of episodes), tachycardia (most commonly atrial fibrillation), and hypokalemia (up to 50% of patients) are hallmarks of the disease. The treatment of thyrotoxicosis includes glucocorticoids, propylthiouracil, β-blockade, and iodide (Lugol’s solution) delivered in an emergent fashion. As the name suggests, these patients are usually toxic and require supportive measures as well. Acetaminophen, the cooling modalities noted in the previous paragraph, and vasoactive agents often are indicated. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 12 Patient Safety Problems with Thermoregulation 393 Table 12-19 394 REFERENCES Entries highlighted in bright blue are key references. PART I BASIC CONSIDERATIONS 1. Bierly PE III, Spender JC. 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An assessment of the management of acute bleeding varices: a multicenter prospective member-based study. Am J Gastroenterol. 2003;98:2424. Domschke W, Lederer P, Lux G. The value of emergency endoscopy in upper gastrointestinal bleeding: review and analysis of 2014 cases. Endoscopy. 1983;15:126. Cash BD. Evidence-based medicine as it applies to acid suppression in the hospitalized patient. Crit Care Med. 2002;30:S373. Lidwig K, Bernhardt J, Steffen H, et al. Contribution of intraoperative cholangiography to incidence and outcome of ­common bile duct injuries during laparoscopic ­cholecystectomy. Surg Endosc. 2002;16:1098. Flum DR, Dellinger EP, Cheadle A, et al. Intraoperative cholangiography and risk of common bile duct injury during ­cholecystectomy. JAMA. 2003;289:1639. Yoon YH, Hsiao-ye Y, Grant BF, et al. Liver cirrhosis mortality in the United States, 1970-98. Surveillance Report No. 57. Rockville, MD: National Institute on Alcohol Abuse and Alcoholism; December 2001. Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994;331:1416. Stevens MA, McCullough PA, Tobin KJ, et al. A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy: results of the P.R.I.N.C.E. study. Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation. J Am Coll Cardiol. 1999;33:403. Birck R, Krzossok S, Markowetz F, et al. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet. 2003;362:598. Baker CS, Wragg A, Kumar S, et al. A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. J Am Coll Cardiol. 2003;41:2114. Laffan M, O’Connell NM, Perry DJ, et al. Analysis and results of the recombinant factor VIIa extended-use registry. Blood Coagul Fibrinolysis. 2003;14:S35. Hedner U. Dosing with recombinant factor VIIa based on current evidence. Semin Hematol. 2004;41:35. Midathada MV, Mehta P, Waner M, et al. Recombinant factor VIIa in the treatment of bleeding. Am J Clin Pathol. 2004;121:124. Dutton RP, Parr M, Tortella BJ, et al. Recombinant activated factor VII safety in trauma patients: results from the ­CONTROL trial. J Trauma. 2011;71(1):12-19. Bloomfield GL, Dalton JM, Sugerman HJ, et al. Treatment of increasing intracranial pressure secondary to the acute abdominal compartment syndrome in a patient with combined abdominal and head trauma. J Trauma. 1995;39:1168. Kron I, Harman PK, Nolan SP. The measurement of intraabdominal pressure as a criterion for abdominal re-­exploration. Ann Surg. 1984;199:28. Ivatury RR, Porter JM, Simon RJ, et al. Intra-abdominal hypertension after life-threatening penetrating abdominal trauma: prophylaxis, incidence, and clinical relevance to gastric mucosal pH and abdominal compartment syndrome. J Trauma. 1998;44:1016. Ivatury RR, Sugerman HJ, Peitzman AB. Abdominal ­compartment syndrome: recognition and management. Adv Surg. 2001;35:251. Saggi BH, Sugerman HJ, Ivatury RR, et al. Abdominal compartment syndrome. J Trauma. 1998;45:597. 107. Anglen J, Apostoles PS, Christensen G, et al. Removal of surface bacteria by irrigation. J Orthop Res. 1966;14:251. 108. Lewis DA, Leaper DJ, Speller DC. Prevention of bacterial colonization of wounds at operation: comparison of iodineimpregnated (“Ioban”) drapes with conventional methods. J Hosp Infect. 1984;5:431. 109. O’Rourke E, Runyan D, O’Leary J, et al. Contaminated iodophor in the operating room. Am J Infect Control. 2003;31: 255. 110. Ostrander RV, Brage ME, Botte MJ. Bacterial skin contamination after surgical preparation in foot and ankle surgery. Clin Orthop. 2003;406:246. 111. Ghogawala Z, Furtado D. In vitro and in vivo bactericidal activities of 10%, 2.5%, and 1% povidone-iodine solution. Am J Hosp Pharm. 1990;47:1562. 112. Anderson RL, Vess RW, Carr JH. Investigations of intrinsic Pseudomonas cepacia contamination in commercially manufactured povidone-iodine. Infect Control Hosp Epidemiol. 1991;12:297. 113. Birnbach DJ, Meadows W, Stein DJ, et al. Comparison of povidone iodine and DuraPrep, an iodophor-in-isopropyl alcohol solution, for skin disinfection prior to epidural catheter insertion in parturients. Anesthesiology. 2003;98:164. 114. Moen MD, Noone MG, Kirson I. Povidone-iodine spray technique versus traditional scrub-paint technique for preoperative abdominal wall preparation. Am J Obstet ­Gynecol. 2002;187:1434; discussion 1436. 115. Strand CL, Wajsbort RR, Sturmann K. Effect of iodophor vs iodine tincture skin preparation on blood culture contamination rate. JAMA. 1993;269:1004. 116. Paterson DL, Ko WC, Von Gottberg A, et al. International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial infections. Ann Intern Med. 2004;140:26. 117. Wittmann DH, Schein M. Let us shorten antibiotic prophylaxis and therapy in surgery. Am J Surg. 1966;172:26S. 118. Dellinger EP. Duration of antibiotic treatment in surgical infections of the abdomen. Undesired effects of antibiotics and future studies. Eur J Surg Suppl. 1996;576:29; discussion 31. 119. Fry DE. Basic aspects of and general problems in surgical infections. Surg Infect (Larchmt). 2001;2(Suppl 1):S3. 120. Barie PS. Modern surgical antibiotic prophylaxis and ­therapy—less is more. Surg Infect (Larchmt). 2000;1:23. 121. Grobmyer SR, Graham D, Brennan MF, et al. High-pressure gradients generated by closed-suction surgical drainage systems. Surg Infect (Larchmt). 2002;3:245. 122. Power DA, Duggan J, Brady HR. Renal-dose (low-dose) dopamine for the treatment of sepsis-related and other forms of acute renal failure: ineffective and probably dangerous. Clin Exp Pharmacol Physiol Suppl. 1999;26:S23. 123. Vincent JL, Abraham, E, Annane D, et al. Reducing mortality in sepsis: new directions. Crit Care. 2002;6(Suppl 3):S1. 124. Malay MB, Ashton RC Jr., Landry DW, et al. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. 1999;47:699; discussion 703. 125. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862. 126. Dhainaut JF, Laterre PF, LaRosa SP, et al. The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results. Crit Care Med. 2003;31:2291; comment 2405. 127. Betancourt M, McKinnon PS, Massanari RM, et al. An evaluation of the cost effectiveness of drotrecogin alfa (activated) relative to the number of organ system failures. Pharmacoeconomics. 2003;21:1331. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 138. Kempainen RR, Brunette DD. The evaluation and management of accidental hypothermia. Respir Care. 2004;49:192. 139. Niven DJ, Stelfox HT, Léger C, et al. Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: a pilot randomized clinical trial. J Crit Care. 2013;28(3):296-302. 140. Schortgen F, Clabault K, Katsahian S, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Criti Care Med. 2012;185(10): 1088-1095. 141. Hoedemaekers CW, Ezzahti M, Gerritsen A, et al. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit Care (London). 2007;11(4):R91. 142. O’Donnell J, Axelrod P, Fisher C, et al. Use and effectiveness of hypothermia blankets for febrile patients in the intensive care unit. Clin Infect Dis. 1997;24(6):1208-1213. 143. Adelson PD, Wisniewski SR, Beca J, et al. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol. 2013;12(6):546-553. 144. Georgiou AP, Manara AR. Role of therapeutic hypothermia in improving outcome after traumatic brain injury: a systematic review. Br J Anaesth. 2013;110(3):357-367. 145. Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis. J Neurotrauma. 2008;25(1):62-71. 146. Schulman CI, Namias N, Doherty J, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect. 2005;6(4):369-375. 147. O’Donnell J, Axelrod P, Fisher C, et al. Use and effectiveness of hypothermia blankets for febrile patients in the intensive care unit. Clin Infect Dis. 1977;24:1208. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 397 CHAPTER 12 Patient Safety 128. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359. 129. Finney SJ, Zekveld C, Elia A, et al. Glucose control and mortality in critically ill patients. JAMA. 2003;290:2041. 130. Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003;125:1007. 131. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. 132. COIITSS Study Investigators, Annane D, Cariou A, et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010;303(4):341-348. 133. Saberi F, Heyland D, Lam M, et al. Prevalence, incidence, and clinical resolution of insulin resistance in critically ill patients: an observational study. JPEN J Parenter Enteral Nutr. 2008;32(3):227-235. 134. Arabi YM, Dabbagh OC, Tamim HM, et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med. 2008;36(12):3190-3197. 135. La Rochelle GE Jr., La Rochelle AG, Ratner RE, et al. Recovery of the hypothalamic-pituitary-adrenal axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med. 1993;95:258. 136. Bromberg JS, Alfrey EJ, Barker CF, et al. Adrenal suppression and steroid supplementation in renal transplant recipients. Transplantation. 1991;51:385. 137. Freidman RJ, Schiff CF, Bromberg JS. Use of supplemental steroids in patients having orthopaedic operations. J Bone Joint Surg. 1995;77:1801. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 13 chapter Introduction Arterial Blood Pressure 399 400 Noninvasive Measurement of Arterial Blood Pressure / 400 Invasive Monitoring of Arterial Blood Pressure / 401 Electrocardiographic Monitoring 401 Cardiac Output and Related Parameters 402 Determinants of Cardiac Performance / 402 Placement of the Pulmonary Artery Catheter / 402 Hemodynamic Measurements / 403 Physiologic Monitoring of the Surgical Patient Louis H. Alarcon and Mitchell P. Fink Measurement of Cardiac Output by Thermodilution / 403 Mixed Venous Oximetry / 404 Effect of Pulmonary Artery Catheterization on Outcome / 405 Minimally Invasive Alternatives to the Pulmonary Artery Catheter / 407 Respiratory Monitoring 409 Arterial Blood Gases / 409 Determinants of Oxygen Delivery / 409 Peak and Plateau Airway Pressure / 409 Pulse Oximetry / 410 Capnometry / 410 Renal Monitoring Introduction The Latin verb monere, which means “to warn, or advise” is the origin for the English word monitor. In modern medical practice, patients undergo monitoring to detect pathologic variations in physiologic parameters, providing advanced warning of impending deterioration in the status of one or more organ systems. The intended goal of this endeavor is to allow the clinician to take appropriate actions in a timely fashion to prevent or ameliorate the physiologic derangement. Furthermore, physiologic monitoring is used not only to warn, but also to titrate therapeutic interventions, such as fluid resuscitation or the infusion of vasoactive or inotropic drugs. The intensive care unit (ICU) and operating room are the two locations where the most advanced monitoring capabilities routinely are employed in the care of critically ill patients. In the broadest sense, physiologic monitoring encompasses a spectrum of endeavors, ranging in complexity from the routine and intermittent measurement of the classic vital signs (i.e., temperature, heart rate, arterial blood pressure, and respiratory rate) to the continuous recording of the oxidation state of cytochrome oxidase, the terminal element in the mitochondrial electron transport chain. The ability to assess clinically relevant parameters of tissue and organ status and employ this knowledge to improve patient outcomes represents the “holy grail” of critical care medicine. Unfortunately, consensus often is lacking regarding the most appropriate parameters to monitor in order to achieve this goal. Furthermore, making an inappropriate therapeutic decision Urine Output / 410 Bladder Pressure / 411 Neurologic Monitoring 411 Intracranial Pressure / 411 Electroencephalogram and Evoked Potentials / 411 Transcranial Doppler Ultrasonography / 411 Jugular Venous Oximetry / 412 Transcranial Near-Infrared Spectroscopy / 412 Brain Tissue Oxygen Tension / 412 Conclusions 412 410 due to inaccurate physiologic data or misinterpretation of good data can lead to a worse outcome than having no data at all. Of the highest importance is the integration of physio1 logic data obtained from monitoring into a coherent and evidenced-based treatment plan. Current technologies available to assist the clinician in this endeavor are summarized in this chapter. Also presented is a brief look at emerging techniques that may soon enter into clinical practice. In essence, the goal of hemodynamic monitoring is to ensure that the flow of oxygenated blood through the microcirculation is sufficient to support aerobic metabolism at the cellular level. In general, mammalian cells cannot store oxygen for subsequent use in oxidative metabolism, although a relatively tiny amount is stored in muscle tissue as oxidized myoglobin. Thus, aerobic synthesis of adenosine triphosphate (ATP), the energy “currency” of cells, requires the continuous delivery of oxygen by diffusion from hemoglobin in red blood cells to the oxidative machinery within mitochondria. Delivery of oxygen to mitochondria may be insufficient for several reasons. For example, cardiac output, hemoglobin concentration of blood, or the oxygen content of arterial blood each can be inadequate for independent reasons. Alternatively, despite adequate cardiac output, perfusion of capillary networks can be impaired as a consequence of dysregulation of arteriolar tone, microvascular thrombosis, or obstruction of nutritive vessels by sequestered leukocytes or platelets. Hemodynamic monitoring that does not take into account all of these factors will portray an incomplete and perhaps misleading picture of cellular physiology. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 The delivery of modern critical care is predicated on the ability to monitor a large number of physiologic variables and formulate evidenced-based therapeutic strategies to manage these variables. Technological advances in monitoring have at least a theoretical risk of exceeding our ability to understand the clinical implications of the derived information. This could result in the use of monitoring data to make inappropriate clinical decisions. Therefore, the implementation of any new monitoring technology must take into account the relevance and accuracy of the data obtained, the risks to the patient, as Under normal conditions when the supply of oxygen is plentiful, aerobic metabolism is determined by factors other than the availability of oxygen. These factors include the hormonal milieu and mechanical workload of contractile tissues. However, in pathologic circumstances when oxygen availability is inadequate, oxygen utilization (VO2) becomes dependent upon oxygen delivery (DO2). The relationship of VO2 to DO2 over a broad range of DO2 values is commonly represented as two intersecting straight lines. In the region of higher DO2 values, the slope of the line is approximately zero, indicating that VO2 is largely independent of DO2. In contrast, in the region of low DO2 values, the slope of the line is nonzero and positive, indicating that VO2 is supplydependent. The region where the two lines intersect is called the point of critical oxygen delivery (DO2crit), and represents the transition from supply-independent to supply-dependent oxygen uptake. Below a critical threshold of oxygen delivery, increased oxygen extraction cannot compensate for the delivery deficit; hence, oxygen consumption begins to decrease. The slope of the supply-dependent region of the plot reflects the maximal oxygen extraction capability of the vascular bed being evaluated. The subsequent sections will describe the techniques and utility of monitoring various physiologic parameters. Arterial Blood Pressure 400 The pressure exerted by blood in the systemic arterial system, commonly referred to as “blood pressure,” is a cardinal parameter measured as part of the hemodynamic monitoring of patients. Extremes in blood pressure are either intrinsically deleterious or are indicative of a serious perturbation in normal physiology. Arterial blood pressure is a complex function of both cardiac output and vascular input impedance. Thus, inexperienced clinicians may assume that the presence of a normal blood pressure is evidence that cardiac output and tissue perfusion are adequate. This assumption frequently is incorrect and is the reason why some critically ill patients may benefit from forms of hemodynamic monitoring in addition to measurement of arterial pressure. Blood pressure can be determined directly by measuring the pressure within the arterial lumen or indirectly using a cuff around an extremity. When the equipment is properly set up and calibrated, direct intra-arterial monitoring of blood pressure provides accurate and continuous data. Additionally, intra-arterial catheters provide a convenient way to obtain samples of blood for measurements of arterial blood gases and other laboratory 2 well as the evidence supporting any intervention directed at correcting the detected abnormality. The routine use of invasive monitoring devices, specifically the pulmonary artery catheter, must be questioned in light of the available evidence which does not demonstrate a clear benefit to its widespread use in various populations of critically ill patients. The future of physiologic monitoring will be dominated by the application of noninvasive and highly accurate devices which guide evidenced-based therapy. studies. Despite these advantages, intra-arterial catheters are invasive devices and occasionally are associated with serious complications. Noninvasive Measurement of Arterial Blood Pressure Both manual and automated means for the noninvasive determination of blood pressure use an inflatable sphygmomanometer cuff to increase pressure around an extremity, and a means for detecting the presence or absence of arterial pulsations. Several methods exist for this purpose. The time-honored approach is the auscultation of the Korotkoff sounds, which are heard over an artery distal to the cuff as the cuff is deflated from a pressure higher than systolic pressure to one less than diastolic pressure. Systolic pressure is defined as the pressure in the cuff when tapping sounds are first audible. Diastolic pressure is the pressure in the cuff when audible pulsations first disappear. Another means for pulse detection when measuring blood pressure noninvasively depends upon the detection of oscillations in the pressure within the bladder of the cuff. This approach is simple, and unlike auscultation, can be performed even in a noisy environment (e.g., a busy emergency room). Unfortunately, this approach is neither accurate nor reliable. Other methods, however, can be used to reliably detect the reappearance of a pulse distal to the cuff and thereby estimate systolic blood pressure. Two excellent and widely available approaches for pulse detection are use of a Doppler stethoscope (reappearance of the pulse produces an audible amplified signal) or a pulse oximeter (reappearance of the pulse is indicated by flashing of a light-emitting diode). A number of automated devices are capable of repetitively measuring blood pressure noninvasively. Some of these devices measure pressure oscillations in the inflatable bladder encircling the extremity to detect arterial pulsations as pressure in the cuff is gradually lowered from greater than systolic to less than diastolic pressure. Other automated noninvasive devices use a piezoelectric crystal positioned over the brachial artery as a pulse detector. The accuracy of these devices is variable, and often dependent on the size mismatch between the arm circumference and the cuff size.1 If the cuff is too narrow (relative to the extremity), the measured pressure will be artifactually elevated. Therefore, the width of the cuff should be approximately 40% of its circumference. Another noninvasive approach for measuring blood pressure relies on a technique called photoplethysmography. This VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Invasive Monitoring of Arterial Blood Pressure Direct and continuous monitoring of arterial pressure in critically ill patients may be performed by using fluid-filled tubing to connect an intra-arterial catheter to an external strain-gauge transducer. The signal generated by the transducer is electronically amplified and displayed as a continuous waveform by an oscilloscope. Digital values for systolic and diastolic pressure also are displayed. Mean pressure, calculated by electronically averaging the amplitude of the pressure waveform, also can be displayed. The fidelity of the catheter-tubing-transducer system is determined by numerous factors, including the compliance of the tubing, the surface area of the transducer diaphragm, and the compliance of the diaphragm. If the system is underdamped, then the inertia of the system, which is a function of the mass of the fluid in the tubing and the mass of the diaphragm, causes overshoot of the points of maximum positive and negative displacement of the diaphragm during systole and diastole, respectively. Thus, in an underdamped system, systolic pressure will be overestimated and diastolic pressure will be underestimated. In an overdamped system, displacement of the diaphragm fails to track the rapidly changing pressure waveform, and systolic pressure will be underestimated and diastolic pressure will be overestimated. It is important to note that even in an underdamped or over-damped system, mean pressure will be accurately recorded, provided the system has been properly calibrated. For these reasons, when using direct measurement of intra-arterial pressure to monitor patients, clinicians should make clinical decisions based primarily on the measured mean arterial blood pressure. The radial artery at the wrist is the site most commonly used for intra-arterial pressure monitoring. Other sites include the femoral and axillary artery. It is important to recognize, however, that measured arterial pressure is determined in part by the site where the pressure is monitored. Central (i.e., aortic) and peripheral (e.g., radial artery) pressures typically are different as a result of the impedance and inductance of the arterial tree. Systolic pressures typically are higher and diastolic pressures are lower in the periphery, whereas mean pressure is approximately the same in the aorta and more distal sites. Distal ischemia is an uncommon complication of intraarterial catheterization. The incidence of thrombosis is increased when larger-caliber catheters are employed and when catheters are left in place for an extended period of time. The incidence of thrombosis can be minimized by using a 20-gauge (or smaller) catheter in the radial artery and removing the catheter as soon as feasible. The risk of distal ischemic injury can be reduced by ensuring that adequate collateral flow is present prior to catheter insertion. At the wrist, adequate collateral flow can be documented by performing a modified version of the Allen test, wherein the artery to be cannulated is digitally compressed while using a Doppler stethoscope to listen for perfusion in the palmar arch vessels. Another potential complication of intra-arterial monitoring is retrograde embolization of air bubbles or thrombi into the intracranial circulation. In order to minimize this risk, care should be taken to avoid flushing arterial lines when air is present in the system, and only small volumes of fluid (less than 5 mL) should be employed for this purpose. Catheter-related infections can occur with any intravascular monitoring device. However, catheter-related bloodstream infection is a relatively uncommon complication of intra-arterial lines used for monitoring, occurring in 0.4% to 0.7% of catheterizations.3 The incidence increases with longer duration of arterial catheterization. Electrocardiographic Monitoring The electrocardiogram (ECG) records the electrical activity associated with cardiac contraction by detecting voltages on the body surface. A standard 3-lead ECG is obtained by placing electrodes that correspond to the left arm (LA), right arm (RA), and left leg (LL). The limb leads are defined as lead I (LA-RA), lead II (LL-RA), and lead III (LL-LA). The ECG waveforms can be continuously displayed on a monitor, and the devices can be set to sound an alarm if an abnormality of rate or rhythm is detected. Continuous ECG monitoring is widely available and applied to critically ill and perioperative patients. Monitoring of the ECG waveform is essential in patients with acute coronary syndromes or blunt myocardial injury, because dysrhythmias are the most common lethal complication. In patients with shock or sepsis, dysrhythmias can occur as a consequence of inadequate myocardial oxygen delivery or as a complication of vasoactive or inotropic drugs used to support blood pressure and cardiac output. Dysrhythmias can be detected by continuously monitoring the ECG tracing, and timely intervention may prevent serious complications. With appropriate computing hardware and software, continuous ST-segment analysis also can be performed to detect ischemia or infarction. Additional information can be obtained from a 12-lead ECG, which is essential for patients with potential myocardial ischemia or to rule out cardiac complications in other acutely ill patients. Continuous monitoring of the 12-lead ECG is now available and is proving to be beneficial in certain patient populations. In a study of 185 vascular surgical patients, continuous 12-lead ECG monitoring was able to detect transient myocardial ischemic episodes in 20.5% of the patients.4 This study demonstrated that the precordial lead V4, which is not routinely monitored on a standard 3-lead ECG, is the most sensitive for detecting perioperative ischemia and infarction. To detect 95% of the ischemic episodes, two or more precordial leads were necessary. Thus, continuous 12-lead ECG monitoring may provide greater sensitivity than 3-lead ECG for the detection of perioperative myocardial ischemia, and may become standard for monitoring high-risk surgical patients. Currently, there is considerable interest in using computerized approaches to analyze ECG waveforms and patterns to uncover hidden information that can be used to predict sudden cardiac death or the development of serious dysrhythmias. ECG patterns of interest include repetitive changes in the morphology of the T-wave [T-wave alternans (TWA)]5and heart rate variability.6 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 401 CHAPTER 13 PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENT method is capable of providing continuous information, since systolic and diastolic blood pressures are recorded on a beatto-beat basis. Photoplethysmography uses the transmission of infrared light to estimate the amount of hemoglobin (directly related to the volume of blood) in a finger placed under a servo-controlled inflatable cuff. A feedback loop controlled by a microprocessor continually adjusts the pressure in the cuff to maintain the blood volume of the finger constant. Under these conditions, the pressure in the cuff reflects the pressure in the digital artery. The measurements obtained using photoplethysmography generally agree closely with those obtained by invasive monitoring of blood pressure. 2 However, these readings may be less accurate in patients with hypotension or hypothermia. 402 PART I BASIC CONSIDERATIONS Integrated monitoring systems employ software that integrates vital signs to produce a single-parameter index which allows early detection of physiologic perturbations. The input variables include noninvasive measurements of heart rate, respiratory rate, blood pressure, blood oxygen saturation via pulse oximetry (SpO2), and temperature. The software uses sophisticated algorithms refined in an iterative fashion to develop a probabilistic model of normality, previously developed from a representative sample patient training set. Variance from these data set are used to evaluate the probability that the patient-derived vital signs are within the normal range. An abnormal index can occur while no single vital sign parameter is outside the range of normal if their combined patterns are consistent with known instability patterns. Employing such an integrated monitoring system in step-down unit patients has been shown to be a sensitive method to detect early physiologic abnormalities that may precede hemodynamic instability.7 Cardiac Output and Related Parameters Bedside catheterization of the pulmonary artery was introduced into clinical practice in the 1970s. Although the pulmonary artery catheter (PAC) initially was used primarily to manage patients with cardiogenic shock and other acute cardiac diseases, indications for this form of invasive hemodynamic monitoring gradually expanded to encompass a wide variety of clinical conditions. Clearly, many clinicians believe that information valuable for the management of critically ill patients is afforded by having a PAC in place. However, unambiguous data in support of this view are scarce, and several studies suggest that bedside PAC may not benefit most critically ill patients, and in fact lead to some serious complications (see next). Determinants of Cardiac Performance Preload. Starling’s law of the heart states that the force of muscle contraction depends on the initial length of the cardiac fibers. Using terminology that derives from early experiments using isolated cardiac muscle preparations, preload is the stretch of ventricular myocardial tissue just prior to the next contraction. Thus, cardiac preload is determined by end-diastolic volume (EDV). For the right ventricle, central venous pressure (CVP) approximates right ventricular end-diastolic pressure (EDP). For the left ventricle, pulmonary artery occlusion pressure (PAOP), which is measured by transiently inflating a balloon at the end of a pressure monitoring catheter positioned in a small branch of the pulmonary artery, approximates left ventricular end-diastolic pressure. The presence of atrioventricular valvular stenosis may alter this relationship. Clinicians frequently use EDP as a surrogate for EDV, but EDP is determined not only by volume but also by the diastolic compliance of the ventricular chamber. Ventricular compliance is altered by various pathologic conditions and pharmacologic agents. Furthermore, the relationship between EDP and true preload is not linear, but rather is exponential. Afterload. Afterload is another term derived from in vitro experiments using isolated strips of cardiac muscle, and is defined as the force resisting fiber shortening once systole begins. Several factors comprise the in vivo correlate of ventricular afterload, including ventricular intracavitary pressure, wall thickness, chamber radius, and chamber geometry. Since these factors are difficult to assess clinically, afterload is commonly approximated by calculating systemic vascular resistance, defined as mean arterial pressure (MAP) divided by cardiac output. Contractility. Contractility is defined as the inotropic state of the myocardium. Contractility is said to increase when the force of ventricular contraction increases at constant preload and afterload. Clinically, contractility is difficult to quantify, because virtually all of the available measures are dependent to a certain degree on preload and afterload. If pressure-volume loops are constructed for each cardiac cycle, small changes in preload and/or afterload will result in shifts of the point defining the end of systole. These end-systolic points on the pressure vs. volume diagram describe a straight line, known as the end-systolic pressure-volume line. A steeper slope of this line indicates greater contractility. Placement of the Pulmonary Artery Catheter In its simplest form, the pulmonary artery catheter (PAC) has four channels. One channel terminates in a balloon at the tip of the catheter. The proximal end of this channel is connected to a syringe to permit inflation of the balloon with air (saline should never be used). Prior to insertion of the PAC, the integrity of the balloon should be verified by inflating it. In order to minimize the risk of vascular or ventricular perforation by the relatively inflexible catheter, it also is important to verify that the inflated balloon extends just beyond the tip of the device. A second channel in the catheter contains wires that are connected to a thermistor located near the tip of the catheter. At the proximal end of the PAC, the wires terminate in a fitting that permits connection to appropriate hardware for the calculation of cardiac output using the thermodilution technique (see next). The final two channels are used for pressure monitoring and the injection of the thermal indicator for determinations of cardiac output. One of these channels terminates at the tip of the catheter. The other terminates 20 cm proximal to the tip. Placement of a PAC requires access to the central venous circulation. Such access can be obtained at a variety of sites, including the antecubital, femoral, jugular, and subclavian veins. Percutaneous placement through either the jugular or subclavian vein generally is preferred. Right internal jugular vein cannulation carries the lowest risk of complications, and the path of the catheter from this site into the right atrium is straight. In the event of inadvertent arterial puncture, local pressure is significantly more effective in controlling bleeding from the carotid artery compared to the subclavian artery. Nevertheless, it is more difficult to keep occlusive dressings in place on the neck than in the subclavian fossa. Furthermore, the anatomic landmarks in the subclavian position are quite constant, even in patients with anasarca or massive obesity; the subclavian vein always is attached to the deep (concave) surface of the clavicle. In contrast, the appropriate landmarks to guide jugular venous cannulation are sometimes difficult to discern in obese or very edematous patients. However, ultrasonic guidance, which should be used routinely, has been shown to facilitate bedside jugular venipuncture.8 Cannulation of the vein normally is performed percutaneously, using the Seldinger technique. A small-bore needle is inserted through the skin and subcutaneous tissue into the vein. After documenting return of venous blood, a guidewire with a flexible tip is inserted through the needle into the vein and the needle is withdrawn. A dilator/introducer sheath is passed over the wire, and the wire and the dilator are removed. The proximal terminus of the distal port of the PAC is connected through low-compliance tubing to a strain-gauge transducer, and the tubing-catheter system is flushed with fluid. While constantly VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Hemodynamic Measurements Even in its simplest embodiment, the PAC is capable of providing clinicians with a remarkable amount of information about the hemodynamic status of patients. Additional information may be obtained if various modifications of the standard PAC are employed. By combining data obtained through use of the PAC with results obtained by other means (i.e., blood hemoglobin concentration and oxyhemoglobin saturation), derived estimates of systemic oxygen transport and utilization can be calculated. Direct and derived parameters obtainable by bedside pulmonary arterial catheterization are summarized in Table 13-1. The equations used to calculate the derived parameters are summarized in Table 13-2. The approximate normal ranges for a number of these hemodynamic parameters (in adults) are shown in Table 13-3. Table 13-1 Directly Measured and Derived Hemodynamic Data Obtainable by Bedside Pulmonary Artery Catheterization Standard PAC PAC with Additional Feature(s) CVP Sˉvo2 (continuous) SV (or SVI) PAP QT or QT* (continuous) SVR (or SVRI) PAOP RVEF PVR (or PVRI) Derived Parameters Sˉvo2 (intermittent) RVEDV QT or QT* (intermittent) ḋo2 vˉ o2 ER QS/QT CVP = mean central venous pressure; ḋo2= systemic oxygen delivery; ER = systemic oxygen extraction ratio; PAOP = pulmonary artery occlusion (wedge) pressure; PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; QS/QT = fractional pulmonary venous admixture (shunt fraction); QT = cardiac output; QT* = cardiac output indexed to body surface area (cardiac index); RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; SV = stroke volume; SVI = stroke volume index; Sˉvo2 = fractional mixed venous (pulmonary artery) hemoglobin saturation; SVR = systemic vascular resistance; SVRI = systemic vascular resistance index; = vˉ o2 systemic oxygen utilization. Table 13-2 Formulas for calculation of hemodynamic parameters that can be derived by using data obtained by pulmonary artery catheterization QT* (L·min–1·m–2) = QT/BSA, where BSA is body surface area (m2) SV (mL) = QT/HR, where HR is heart rate (min–1) SVR (dyne·sec·cm–5) = [(MAP – CVP) × 80] /QT, where MAP is mean arterial pressure (mm Hg) SVRI (dyne·sec·cm–5m–2) = [(MAP – CVP) × 80] /QT* PVR (dyne·sec·cm–5) = [(PAP – PAOP) × 80] /QT, where PAP is mean pulmonary artery pressure PVRI (dyne·sec·cm–5m–2) = [(PAP – PAOP) × 80] /QT* RVEDV (mL) = SV/RVEF ḋo2(mL·min–1·m–2) = QT* × Cao2 × 10, where Cao2 is arterial oxygen content (mL/dL) vˉ o2(mL·min–1·m–2) = QT* × (Cao2 – Cˉvo2) × 10, where Cˉvo2 is mixed venous oxygen content (mL/dL) Cao2 = (1.36 × Hgb × Sao2) + (0.003 + Pao2), where Hgb is hemoglobin concentration (g/dL), Sao2 is fractional arterial hemoglobin saturation, and Pao2 is the partial pressure of oxygen in arterial blood Cˉvo2 = (1.36 × Hgb × Sˉvo2) + (0.003 + Pˉvo2), where Pvˉ o2 is the partial pressure of oxygen in pulmonary arterial (mixed venous) blood QS/QT = (Cco2 – Ca o2)/ (Cco2 – Cv o2), where Cc o2 (mL/dL) is the content of oxygen in pulmonary end capillary blood Cco2 = (1.36 × Hgb) + (0.003 + Pao2), where Pao2 is the alveolar partial pressure of oxygen Pao2 = [Fio2 × (PB – PH2O)] – Paco2/RQ, where Fio2 is the fractional concentration of inspired oxygen, PB is the barometric pressure (mm Hg), PH2O is the water vapor pressure (usually 47 mm Hg), Paco2 is the partial pressure of carbon dioxide in arterial blood (mm Hg), and RQ is respiratory quotient (usually assumed to be 0.8) Cˉvo2 = central venous oxygen pressure; CVP = mean central venous pressure; ḋo2 = systemic oxygen delivery; PAOP = pulmonary artery occlusion (wedge) pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; QS/QT = fractional pulmonary venous admixture (shunt fraction); QT = cardiac output; QT* = cardiac output indexed to body surface area (cardiac index); RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; SV = stroke volume; SVI = stroke volume index; Sˉvo2 = fractional mixed venous (pulmonary artery) hemoglobin saturation; SVR = systemic vascular resistance; SVRI = systemic vascular resistance index; vˉ o2 = systemic oxygen utilization. Measurement of Cardiac Output by Thermodilution Before the development of the PAC, determining cardiac output (QT) at the bedside required careful measurements of oxygen consumption (Fick method) or spectrophotometric determination of indocyanine green dye dilution curves. Measurements of QT using the thermodilution technique are simple and reasonably accurate. The measurements can be performed repetitively and the principle is straightforward. If a bolus of an indicator is rapidly and thoroughly mixed with a moving fluid upstream from a detector, then the concentration of the indicator at the detector will increase sharply and then exponentially diminish back VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 403 CHAPTER 13 PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENT observing the pressure tracing on an oscilloscope, the PAC is advanced with the balloon deflated until respiratory excursions are observed. The balloon is then inflated, and the catheter advanced further (“floated”), while monitoring pressures sequentially in the right atrium and right ventricle en route to the pulmonary artery. The pressure waveforms for the right atrium, right ventricle, and pulmonary artery are each characteristic. The catheter is advanced out into the pulmonary artery until a damped tracing indicative of the “wedged” position is obtained. The balloon is then deflated, taking care to ensure that a normal pulmonary arterial tracing is again observed on the monitor; leaving the balloon inflated can increase the risk of pulmonary infarction or perforation of the pulmonary artery. Unnecessary measurements of the pulmonary artery occlusion pressure are discouraged as rupture of the pulmonary artery may occur. 404 Parameter Normal Range CVP 0–6 mm Hg Right ventricular systolic pressure 20–30 mm Hg Right ventricular diastolic pressure 0–6 mm Hg PAOP 6–12 mm Hg Systolic arterial pressure 100–130 mm Hg Diastolic arterial pressure 60–90 mm Hg MAP 75–100 mm Hg QT 4–6 L/min QT* 2.5–3.5 L·min–1·m–2 SV 40–80 mL SVR 800–1400 dyne·sec·cm–5 SVRI 1500–2400 dyne·sec·cm–5·m–2 PVR 100–150 dyne·sec·cm–5 PVRI 200–400 dyne·sec·cm–5·m–2 Determination of cardiac output by the thermodilution method is generally quite accurate, although it tends to systematically overestimate QT at low values. Changes in blood temperature and QT during the respiratory cycle can influence the measurement. Therefore, results generally should be recorded as the mean of two or three determinations obtained at random points in the respiratory cycle. Using cold injectate widens the difference between TB and TI and thereby increases signal-tonoise ratio. Nevertheless, most authorities recommend using room temperature injectate (normal saline or 5% dextrose in water) to minimize errors resulting from warming of the fluid as it transferred from its reservoir to a syringe for injection. Technologic innovations have been introduced that permit continuous measurement of QT by thermodilution. In this approach, thermal transients are not generated by injecting a bolus of a cold indicator, but rather by heating the blood with a tiny filament located on the PAC upstream from the thermistor. By correlating the amount of current supplied to the heating element with the downstream temperature of the blood, it is possible to estimate the average blood flow across the filament and thereby calculate QT. Based upon the results of several studies, continuous determinations of QT using this approach agree well with data generated by conventional measurements using bolus injections of a cold indicator.9 Information is lacking regarding the clinical value of being able to monitor QT continuously. Cao2 16–22 mL/dL Cvo2 Mixed Venous Oximetry ~15 mL 02 dL blood ḋo2 400–660 mL·min ·m vˉ o2 115–165 mL·min–1·m–2 Table 13-3 Approximate normal ranges for selected hemodynamic parameters in adults PART I BASIC CONSIDERATIONS –1 –2 Cao2 = arterial oxygen content; Cvo2 = central venous oxygen pressure; CVP = mean central venous pressure; = ḋo2 systemic oxygen delivery; MAP = mean arterial pressure; PAOP = pulmonary artery occlusion (wedge) pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; QT = cardiac output; QT* = cardiac output indexed to body surface area (cardiac index); SV = stroke volume; SVI = stroke volume index; SVR = systemic vascular resistance; SVRI = systemic vascular resistance index; = vˉ o2 systemic oxygen utilization. to zero. The area under the resulting time-concentration curve is a function of the volume of indicator injected and the flow rate of the moving stream of fluid. Larger volumes of indicator result in greater areas under the curve, and faster flow rates of the mixing fluid result in smaller areas under the curve. When QT is measured by thermodilution, the indicator is heat and the detector is a temperature-sensing thermistor at the distal end of the PAC. The relationship used for calculating QT is called the Stewart-Hamilton equation: QT = [V × (TB – TI) × K1 × K2] /∫TB(t)dt where V is the volume of the indicator injected, TB is the temperature of blood (i.e., core body temperature), TI is the temperature of the indicator, K1 is a constant that is the function of the specific heats of blood and the indicator, K2 is an empirically derived constant that accounts for several factors (the dead space volume of the catheter, heat lost from the indicator as it traverses the catheter, and the injection rate of the indicator), and ∫TB(t)dt is the area under the time-temperature curve. In clinical practice, the Stewart-Hamilton equation is solved by a microprocessor. The Fick equation can be written as QT = VO2/(Cao2 – CVO2), where Cao2 is the content of oxygen in arterial blood and CVO2 is the content of oxygen in mixed venous blood. The Fick equation can be rearranged as follows: CVO2 = Cao2 – VO2/QT. If the small contribution of dissolved oxygen to CVO2 and Cao2 is ignored, the rearranged equation can be rewritten as SVO2 = Sao2 – VO2/ (QT × Hgb × 1.36), where SVO2 is the fractional saturation of hemoglobin in mixed venous blood, Sao2 is the fractional saturation of hemoglobin in arterial blood, and Hgb is the concentration of hemoglobin in blood. Thus it can be seen that SVO2 is a function of VO2 (i.e., metabolic rate), QT, Sao2, and Hgb. Accordingly, subnormal values of SVO2 can be caused by a decrease in QT (due, for example, to heart failure or hypovolemia), a decrease in Sao2 (due, for example, to intrinsic pulmonary disease), a decrease in Hgb (i.e., anemia), or an increase in metabolic rate (due, for example, to seizures or fever). With a conventional PAC, measurements of SVO2 require aspirating a sample of blood from the distal (i.e., pulmonary arterial) port of the catheter and injecting the sample into a blood gas analyzer. Therefore for practical purposes, measurements of SVO2 can be performed only intermittently. By adding a fifth channel to the PAC, it has become possible to monitor SVO2 continuously. The fifth channel contains two fiber-optic bundles, which are used to transmit and receive light of the appropriate wavelengths to permit measurements of hemoglobin saturation by reflectance spectrophotometry. Continuous SVO2 devices provide measurements of SVO2 that agree quite closely with those obtained by conventional analyses of blood aspirated from the pulmonary artery. Despite the theoretical value of being able to monitor SVO2 continuously, data are lacking to show that this capability favorably improves outcomes. In a prospective, observational study of 3265 patients undergoing cardiac surgery with either a standard PAC or a PAC with continuous SVO2 monitoring, the oximetric catheter was associated with fewer arterial blood gas and thermodilution cardiac output determinations, but no difference in patient VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Effect of Pulmonary Artery Catheterization on Outcome Despite initial enthusiasm for using the PAC in the management of critically-ill patients, several studies have failed to show improved outcomes with their use. Connors and colleagues reported results of a major observational study evaluating the value of PAC in critically ill patients.15 These researchers compared two groups of patients: those who did and those who did not undergo placement of a PAC during their first 24 hours of ICU care. The investigators recognized that the value of their intended analysis was completely dependent on the robustness of their methodology for case-matching, because sicker patients (i.e., those at greater risk of mortality based upon the severity of their illness) were presumably more likely to undergo pulmonary artery catheterization. Accordingly, the authors used sophisticated statistical methods for generating a cohort of study (i.e., PAC) patients, each one having a paired control matched carefully for severity of illness. Connors et al concluded that placement of a pulmonary artery catheter during the first 24 hours of stay in an ICU is associated with a significant increase in the risk of mortality, even when statistical methods are used to account for severity of illness.15 A number of prospective, randomized controlled trials of PAC are summarized in Table 13-4. The study by Pearson et al was underpowered with only 226 patients enrolled.16 In addition, the attending anesthesiologists were permitted to exclude patients from the CVP group at their discretion; thus, randomization was compromised. The study by Tuman et al was large (1094 patients were enrolled), but different anesthesiologists were assigned to the different groups.17 Furthermore, 39 patients in the CVP group underwent placement of a PAC because of hemodynamic complications. All of the individual Table 13-4 Summary of randomized, prospective clinical trials comparing pulmonary artery catheter with central venous pressure monitoring Author Study Population Groups Outcomes Pearson et al “Low risk” patients undergoing cardiac or vascular surgery CVP catheter (group 1); PAC (group 2); PAC with continuous Sˉvo2 readout (group 3) No differences among groups for mortality or length of ICU stay; significant differences in costs (group 1 < group 2 < group 3) Tuman et al17 Cardiac surgical patients PAC; CVP No differences between groups for mortality, length of ICU stay, or significant noncardiac complications Bender et al18 Vascular surgery patients PAC; CVP No differences between groups for mortality, length of ICU stay, or length of hospital stay Valentine et al19 Aortic surgery patients PAC + hemodynamic optimization in ICU night before surgery; CVP No differences between groups for mortality or length of ICU stay; significantly higher incidence of postoperative complications in PAC group Sandham et al20 “High risk” major surgery PAC; CVP No differences between groups for mortality, length of ICU stay; increased incidence of pulmonary embolism in PAC group 16 Harvey S, et al21 Medical and surgical PAC vs. no PAC, with option ICU patients for alternative CO measuring device in non-PAC group No differences in hospital mortality between the 2 groups, increased incidence of complications in the PAC group Binanay, et al23 Patients with CHF PAC vs. no PAC No difference in hospital mortality between the 2 groups, increased incidence of adverse events in the PAC group Wheeler, et al24 Patients with ALI PAC vs. CVC with a fluid and inotropic management protocol No difference in ICU or hospital mortality, or incidence of organ failure between the 2 groups; increased incidence of adverse events in the PAC group ALI = acute lung injury, CHF = congestive heart failure, CO = cardiac output, CVC = central venous catheter, ICU = intensive care unit, PAC = pulmonary artery catheter, = Sˉvo2 fractional mixed venous (pulmonary artery) hemoglobin saturation. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 405 CHAPTER 13 PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENT outcome.10 Since pulmonary artery catheters that permit continuous monitoring of SVO2 are more expensive than conventional PACs, the routine use of these devices cannot be recommended. The saturation of oxygen in the right atrium or superior vena cava (ScVO2) correlates closely with SVO2 over a wide range of conditions,11 although the correlation between ScVO2 and SVO2 has been questioned under certain conditions (e.g., septic shock).12 Since measurement of ScVO2 requires placement of a central venous catheter rather than a PAC, it is somewhat less invasive and easier to carry out. By using a central venous catheter equipped to permit fiber-optic monitoring of ScVO2, it may be possible to titrate the resuscitation of patients with shock using a less invasive device than the PAC.11,13 The Surviving Sepsis Campaign international guidelines for the management of severe sepsis and septic shock recommends that during the first 6 hours of resuscitation, the goals of initial resuscitation of sepsis-induced hypoperfusion should include all of the following: CVP 8–12 mm Hg, MAP ≥ 65 mm Hg, urine output ≥ 0.5 mL/kg/h. ScVO2 of 70% or SVO2of 65%.14 406 PART I BASIC CONSIDERATIONS single-institution studies of vascular surgery patients were relatively underpowered, and all excluded at least certain categories of patients (e.g., those with a history of recent myocardial infarction).18,19 In the largest randomized controlled trial of the PAC, Sandham et al randomized nearly 2000 American Society of Anesthesiologists (ASAs) class III and IV patients undergoing major thoracic, abdominal, or orthopedic surgery to placement of a PAC or CVP catheter.20 In the patients assigned to receive a PAC, physiologic goal-directed therapy was implemented by protocol. There were no differences in mortality at 30 days, 6 months, or 12 months between the two groups, and ICU length of stay was similar. There was a significantly higher rate of pulmonary emboli in the PAC group (0.9% vs. 0%). This study has been criticized because most of the patients enrolled were not in the highest risk category. In the “PAC-Man” trial, a multicenter, randomized trial in 65 United Kingdom hospitals, over 1000 ICU patients were managed with or without a PAC.21 The specifics of the clinical management were then left up to the treating clinicians. There was no difference in hospital mortality between the 2 groups (with PAC 68% vs. without PAC 66%, p = 0.39). However, a 9.5% complication rate was associated with the insertion or use of the PAC, although none of these complications were fatal. Clearly, these were critically ill patients, as noted by the high hospital mortality rates. Supporters of the PAC use cite methodology problems with this study, such as loose inclusion criteria and the lack of a defined treatment protocol. A meta-analysis of 13 randomized studies of the PAC included over 5000 patients was published in 2005.22 A broad spectrum of critically ill patients was included in these heterogeneous trials, and the hemodynamic goals and treatment strategies varied. While the use of the PAC was associated with an increased use of inotropes and vasodilators, there were no differences in mortality or hospital length of stay between the patients managed with a PAC and those managed without a PAC. The ESCAPE trial (which was one of the studies included in the previous meta-analysis)23 evaluated 433 patients with severe or recurrent congestive heart failure (CHF) admitted to the ICU. Patients were randomized to management by clinical assessment and a PAC or clinical assessment without a PAC. The goal in both groups was resolution of CHF, with additional PAC targets of a pulmonary capillary occlusion pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. There was no formal treatment protocol, but inotropic support was discouraged. Substantial reduction in symptoms, jugular venous pressure, and edema was noted in both groups. There was no significant difference in the primary end point of days alive and out of the hospital during the first 6 months, or hospital mortality (PAC 10%; vs. without PAC 9%). Adverse events were more common among patients in the PAC group (21.9% vs.11.5%; P = 0.04). Finally, the Fluids and Catheters Treatment Trial (FACTT) conducted by the Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network was published in 2006.24 The risks and benefits of PAC compared with central venous catheters (CVC) were evaluated in 1000 patients with acute lung injury. Patients were randomly assigned to receive either a PAC or a CVC to guide management for 7 days via an explicit protocol. Patients also were randomly assigned to a conservative or liberal fluid strategy in a 2 × 2 factorial design (outcomes based on the fluid management strategy were published separately). Mortality during the first 60 days was similar in the PAC and CVC groups (27% and 26%, respectively; P= 0.69). The duration of mechanical ventilation and ICU length of stay also were not influenced by the type of catheter used. The type of catheter employed did not affect the incidence of shock, respiratory or renal failure, ventilator settings, or requirement for hemodialysis or vasopressors. There was a 1% rate of crossover from CVC-guided therapy to PAC-guided therapy. The type of catheter used did not affect the administration of fluids or diuretics, and the net fluid balance was similar in the two groups. The PAC group had approximately twice as many catheter-related adverse events (mainly arrhythmias). Few subjects in critical care medicine have historically generated more emotional responses among experts in the field than the use of the PAC. As these studies demonstrate, it is not possible to show that therapy directed by use of the PAC saves lives when it is evaluated in a large population of patients. Certainly, given the available evidence, routine use of the PAC cannot be justified. Whether selective use of 2 the device in a few relatively uncommon clinical situations is warranted or valuable remains a controversial issue. Consequently, a marked decline in the use of the PAC from 5.66 per 1000 medical admissions in 1993 to 1.99 per 1000 medical admissions in 2004 has been seen.25 Based upon the results and exclusion criteria in these prospective randomized trials, reasonable criteria for perioperative monitoring without use of a PAC are presented in Table 13-5. One of the reasons for using a PAC to monitor critically ill patients is to optimize cardiac output and systemic oxygen delivery. Defining what constitutes the optimum cardiac output, however, has proven to be difficult. A number of randomized trials evaluating the effect on outcome of goal-directed compared to conventional hemodynamic resuscitation have been published. Some studies provide support for the notion that interventions designed to achieve supraphysiologic goals for DO2, VO2, and QT improve outcome.26,27 However, other published studies do not support this view, and a meta-analysis concluded that interventions designed to achieve supraphysiological goals for oxygen transport do not significantly reduce mortality rates in critically ill patients.28,29 At this time, supraphysiological resuscitation of patients in shock cannot be endorsed. There is no simple explanation for the apparent lack of effectiveness of pulmonary artery catheterization, although several concurrent possibilities exist. First, even though bedside pulmonary artery catheterization is quite safe, the procedure Table 13-5 Suggested criteria for perioperative monitoring without use of a pulmonary artery catheter in patients undergoing cardiac or major vascular surgical procedures No anticipated need for suprarenal or supraceliac aortic cross-clamping No history of myocardial infarction during 3 months prior to operation No history of poorly compensated congestive heart failure No history of coronary artery bypass graft surgery during 6 weeks prior to operation No history of ongoing symptomatic mitral or aortic valvular heart disease No history of ongoing unstable angina pectoris VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Minimally Invasive Alternatives to the Pulmonary Artery Catheter Because of the cost, risks and questionable benefit associated with bedside pulmonary artery catheterization, there has been interest in the development of practical means for less invasive monitoring of hemodynamic parameters. Several approaches have been developed, which have achieved variable degrees of success. None of these methods render the standard thermodilution technique of the pulmonary artery catheter obsolete. However, these strategies may contribute to improvements in the hemodynamic monitoring of critically ill patients. Doppler Ultrasonography. When ultrasonic sound waves are reflected by moving erythrocytes in the bloodstream, the frequency of the reflected signal is increased or decreased, depending on whether the cells are moving toward or away from the ultrasonic source. This change in frequency is called the Doppler shift, and its magnitude is determined by the velocity of the moving red blood cells. Therefore, measurements of the Doppler shift can be used to calculate red blood cell velocity. With knowledge of both the cross-sectional area of a vessel and the mean red blood cell velocity of the blood flowing through it, one can calculate blood flow rate. If the vessel in question is the aorta, then QT can be calculated as: QT = HR × A × ∫V(t)dt where A is the cross-sectional area of the aorta and ∫V(t)dt is the red blood cell velocity integrated over the cardiac cycle. Two approaches have been developed for using Doppler ultrasonography to estimate QT. The first approach uses an ultrasonic transducer, which is positioned manually in the suprasternal notch and focused on the root of the aorta. Aortic cross-sectional area can be estimated using a nomogram, which factors in age, height, and weight, back-calculated if an independent measure of QT is available, or by using twodimensional transthoracic or transesophageal ultrasonography. While this approach is completely noninvasive, it requires a highly-skilled operator in order to obtain meaningful results, and is laborintensive. Moreover, unless QT measured using thermodilution is used to back-calculate aortic diameter, accuracy using the suprasternal notch approach is not acceptable. Accordingly, this method is useful only for obtaining very intermittent estimates of QT, and has not been widely adopted by clinicians. A second more promising, albeit more invasive, approach has been introduced. In this method blood flow velocity is continuously monitored in the descending thoracic aorta using a continuous-wave Doppler transducer introduced into the esophagus. The probe is connected to a monitor, which continuously displays the blood flow velocity profile in the descending aorta as well as the calculated QT. In order to maximize the accuracy of the device, the probe position must be adjusted to obtain the peak velocity in the aorta. In order to transform blood flow in the descending aorta into QT, a correction factor is applied that is based on the assumption that only 70% of the flow at the root of the aorta is still present in the descending thoracic aorta. A meta-analysis of the available data show a good correlation between cardiac output estimates obtained by trans-esophageal Doppler and PAC in critically-ill patients.31 The ultrasonic device also calculates a derived parameter termed flow time corrected (FTc), which is the systolic flow time in the descending aorta corrected for heart rate. FTc is a function of preload, contractility, and vascular input impedance. Although it is not a pure measure of preload, Doppler-based estimates of SV and FTc have been used successfully to guide volume resuscitation in high-risk surgical patients undergoing major operations.30 Impedance Cardiography. The impedance to flow of alternating electrical current in regions of the body is commonly called bioimpedance. In the thorax, changes in the volume and velocity of blood in the thoracic aorta lead to detectable changes in bioimpedance. The first derivative of the oscillating component of thoracic bioimpedance (dZ/dt) is linearly related to aortic blood flow. On the basis of this relationship, empirically derived formulas have been developed to estimate SV, and subsequently QT, noninvasively. This methodology is called impedance cardiography. The approach is attractive because it is noninvasive, provides a continuous readout of QT, and does not require extensive training. Despite these advantages, measurements of QT obtained by impedance cardiography are not sufficiently reliable to be used for clinical decision making and have poor correlation with thermodilution.32 Because of the limitations of bioimpedance devices, a newer approach for processing the impedance signal was developed and commercialized. This approach is based on the recognition that the impedance signal has two components: amplitude and phase. Whereas the amplitude of the thoracic impedance signal is determined by all of the components of the thoracic cavity (bone, blood, muscle and other soft tissues), phase shifts are determined entirely by pulsatile flow. The vast majority of pulsatile flow is related to blood moving within the aorta. Therefore, the “bioreactance” signal correlates closely with aortic flow, and cardiac output determined using this approach agrees closely with cardiac output measured using conventional indicator dilution techniques.33 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 407 CHAPTER 13 PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENT is associated with a finite incidence of serious complications, including ventricular arrhythmias, catheter-related sepsis, central venous thrombosis, pulmonary arterial perforation, and pulmonary embolism.20 The adverse effects of these complications on outcome may equal or even outweigh any benefits associated with using a PAC to guide therapy. Second, the data generated by the PAC may be inaccurate, leading to inappropriate therapeutic interventions. Third, the measurements, even if accurate, may often be misinterpreted.29 Furthermore, the current state of understanding is primitive when it comes to deciding what is the best management for certain hemodynamic disturbances, particularly those associated with sepsis or septic shock. Taking all of this into consideration, it may be that interventions prompted by measurements obtained with a PAC are actually harmful to patients. As a result, the marginal benefit now available by placing a PAC may be quite small. Less invasive modalities are available that may provide clinically useful hemodynamic information. It may be true that aggressive hemodynamic resuscitation of patients, guided by various forms of monitoring, is valuable only during certain critical periods, such as the first few hours after presentation with septic shock or during surgery. For example, Rivers and colleagues reported that survival of patients with septic shock is significantly improved when resuscitation in the emergency department is guided by a protocol that seeks to keep ScVO2 greater than 70%.13 Similarly, a study using an ultrasound-based device (see Doppler Ultrasonography below) to assess cardiac filling and SV showed that maximizing SV intraoperatively results in fewer postoperative complications and shorter hospital length of stay.30 408 PART I BASIC CONSIDERATIONS Pulse Contour Analysis. Another method for determining cardiac output is an approach called pulse contour analysis for estimating SV on a beat-to-beat basis. The mechanical properties of the arterial tree and SV determine the shape of the arterial pulse waveform. The pulse contour method of estimating QT uses the arterial pressure waveform as an input for a model of the systemic circulation in order to determine beat-to-beat flow through the circulatory system. The parameters of resistance, compliance, and impedance are initially estimated based on the patient’s age and sex, and subsequently can be refined by using a reference standard measurement of QT. The reference standard estimation of QT is obtained periodically using the indicator dilution approach by injecting the indicator into a central venous catheter and detecting the transient increase in indicator concentration in the blood using an arterial catheter. In one commercially available embodiment of this approach, the lithium ion (Li+) is the indicator used for the periodic calibrations of the device. The lithium carbonate indicator can be injected into a peripheral vein, and the doses do not exert pharmacologically relevant effects in adult patients. The Li+ indicator dilution method has shown to be at least as reliable as other thermodilution methods over a broad range of CO in a variety of patients.33 In another commercially available system, a conventional bolus of cold fluid is used as the indicator for calibration. The thermodilution-based calibration requires central venous catheterization, although the temperature change is detected in a transpulmonary fashion (i.e., in a peripheral artery). Measurements of QT based on pulse contour monitoring using these two approaches are comparable in accuracy to standard PAC thermodilution methods, but are less invasive since transcardiac catheterization is not needed.34 Using on-line pressure waveform analysis, the computerized algorithms can calculate SV, QT, systemic vascular resistance, and an estimate of myocardial contractility, (i.e., the rate of rise of the arterial systolic pressure [dP/dT]). The use of pulse contour analysis has been applied using noninvasive photoplethysmographic measurements of arterial pressure. However, the accuracy of this technique has been questioned and its clinical utility remains to be determined.35 One commercially available device, which can be used for estimating cardiac output, does not require external calibration. Instead, the relationship between pulse pressure and stroke volume is determined using a proprietary algorithm that uses biometric data, such as age, gender, and height, as inputs. Although this methodology is gaining fairly wide acceptance in critical care medicine, reported accuracy (in comparison to “gold standard” approaches) is not very good.33 Partial Carbon Dioxide Rebreathing. Partial carbon dioxide (CO2) rebreathing uses the Fick principle to estimate QT noninvasively. By intermittently altering the dead space within the ventilator circuit via a rebreathing valve, changes in CO2 production (Vco2) and end-tidal CO2 (ETco2) are used to determine cardiac output using a modified Fick equation (QT = ΔVco2/ ΔETco2). Commercially available devices use this Fick principle to calculate QT using intermittent partial CO2 rebreathing through a disposable rebreathing loop. These devices consist of a CO2 sensor based on infrared light absorption, an airflow sensor, and a pulse oximeter. Changes in intrapulmonary shunt and hemodynamic instability impair the accuracy of QT estimated by partial CO2 rebreathing. Continuous in-line pulse oximetry and inspired fraction of inspired O2 (Fio2) are used to estimate shunt fraction to correct QT. Some studies of the partial CO2 rebreathing approach suggest that this technique is not as accurate as thermodilution, the gold standard for measuring QT.34,36 However, other studies suggest that the partial CO2 rebreathing method for determination of QT compares favorably to measurements made using a PAC in critically ill patients.37 Transesophageal Echocardiography. Transesophageal echocardiography (TEE) has made the transition from operating room to intensive care unit. TEE requires that the patient be sedated and usually intubated for airway protection. Using this powerful technology, global assessments of LV and RV function can be made, including determinations of ventricular volume, EF, and QT. Segmental wall motion abnormalities, pericardial effusions, and tamponade can be readily identified with TEE. Doppler techniques allow estimation of atrial filling pressures. The technique is somewhat cumbersome and requires considerable training and skill in order to obtain reliable results. Recently, a TEE probe has been introduced into practice that is small enough in diameter that it can be left in place for as long as 72 hours. While only limited data are currently available with this probe, it seems like it will be a useful cardiac monitoring tool for use in selected, patients with complex problems. Assessing Preload Responsiveness. Although pulse contour analysis or partial CO2 rebreathing may be able to provide estimates of SV and QT, these approaches alone can offer little or no information about the adequacy of preload. Thus, if QT is low, some other means must be employed to estimate preload. Many clinicians assess the adequacy of cardiac preload by determining CVP or PAOP. However, neither CVP nor PAOP correlate well with the true parameter of interest, left ventricular end-diastolic volume (LVEDV).38 Extremely high or low CVP or PAOP results are informative, but readings in a large middle zone (i.e., 5–20 mm Hg) are less useful. Furthermore, changes in CVP or PAOP fail to correlate well with changes in stroke volume.37,39 Echocardiography can be used to estimate LVEDV, but this approach is dependent on the skill and training of the individual using it, and isolated measurements of LVEDV fail to predict the hemodynamic response to alterations in preload.40 When intrathoracic pressure increases during the application of positive airway pressure in mechanically ventilated patients, venous return decreases, and as a consequence, left ventricular stroke volume (LVSV) also decreases. Therefore, pulse pressure variation (PPV) during a positive pressure episode can be used to predict the responsiveness of cardiac output to changes in preload.39,41 PPV is defined as the difference between the maximal pulse pressure and the minimum pulse pressure divided by the average of these two pressures. This approach has been validated by comparing PPV, CVP, PAOP, and systolic pressure variation as predictors of preload responsiveness in a cohort of critically ill patients. Patients were classified as being “preload responsive” if their cardiac index [QT/Body Surface Area (BSA)] increased by at least 15% after rapid infusion of a standard volume of intravenous fluid.42 Receiver-operating characteristic (ROC) curves demonstrated that PPV was the best predictor of preload responsiveness. Although atrial arrhythmias can interfere with the usefulness of this technique, PPV remains a useful approach for assessing preload responsiveness in most patients because of its simplicity and reliability.40 Near-infrared Spectroscopic Measurement of Tissue Hemoglobin Oxygen Saturation. Near-infrared spectroscopy (NIRS) allows continuous, noninvasive measurement of tissue VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Determinants of Oxygen Delivery The primary goal of the cardiovascular and respiratory systems is to deliver oxygenated blood to the tissues. DO2 is dependent to a greater degree on the oxygen saturation of hemoglobin (Hgb) in arterial blood (Sao2) than on the partial pressure of oxygen in arterial blood (Pao2). DO2 also is dependent on QT and Hgb. Dissolved oxygen in blood, which is proportional to the PaO2, makes only a negligible contribution to DO2, as is apparent from the equation: DO2 = QT × [(Hgb × Sao2 × 1.36) + (Pao2 × 0.0031)] Sao2 in mechanically ventilated patients depends on the mean airway pressure, the fraction of inspired oxygen (Fio2),and SVO2. Thus, when Sao2 is low, the clinician has only a limited number of ways to improve this parameter. The clinician can increase mean airway pressure by increasing positive-end expiratory pressure (PEEP) or inspiratory time. Fio2 can be increased to a maximum of 1.0 by decreasing the amount of room air mixed with the oxygen supplied to the ventilator. SVO2 can be increased by increasing Hgb or QT or decreasing oxygen utilization (e.g., by administering a muscle relaxant and sedation). Peak and Plateau Airway Pressure Respiratory Monitoring The ability to monitor various parameters of respiratory function is of utmost importance in critically ill patients. Many of these patients require mechanical ventilation. Monitoring of their respiratory physiology is necessary to assess the adequacy of oxygenation and ventilation, guide weaning and liberation from mechanical ventilation, and detect adverse events associated with respiratory failure and mechanical ventilation. These parameters include gas exchange, neuromuscular activity, respiratory mechanics, and patient effort. Arterial Blood Gases also can be measured. In recent years, efforts have been made to decrease the unnecessary use of arterial blood gas analysis. Serial arterial blood gas determinations are not necessary for routine weaning from mechanical ventilation in the majority of postoperative patients. Most bedside blood gas analyses still involve removal of an aliquot of blood from the patient, although continuous bedside arterial blood gas determinations are now possible without sampling via an indwelling arterial catheter that contains a biosensor. In studies comparing the accuracy of continuous arterial blood gas and pH monitoring with a conventional laboratory blood gas analyzer, excellent agreement between the two methods has been demonstrated.45 Continuous monitoring can reduce the volume of blood loss due to phlebotomy and dramatically decrease the time necessary to obtain blood gas results. Continuous monitoring, however, is expensive and is not widely employed. Blood gas analysis may provide useful information when caring for patients with respiratory failure. However, even in the absence of respiratory failure or the need for mechanical ventilation, blood gas determinations also can be valuable to detect alterations in acid-base balance due to low QT, sepsis, renal failure, severe trauma, medication or drug overdose, or altered mental status. Arterial blood can be analyzed for pH, Po2, Pco2, HCO3– concentration and calculated base deficit. When indicated, carboxyhemoglobin and methemoglobin levels Airway pressures routinely are monitored in mechanically ventilated patients. The peak airway pressure measured at the end of inspiration (Ppeak) is a function of the tidal volume, the resistance of the airways, lung/chest wall compliance, and peak inspiratory flow. The airway pressure measured at the end of inspiration when the inhaled volume is held in the lungs by briefly closing the expiratory valve is termed the plateau airway pressure (Pplateau). As a static parameter, plateau airway pressure is independent of the airway resistance and peak airway flow, and is related to the lung/chest wall compliance and delivered tidal volume. Mechanical ventilators monitor Ppeak with each breath and can be set to trigger an alarm if the Ppeak exceeds a predetermined threshold. Pplateau is not measured routinely with each delivered tidal volume, but rather is measured intermittently by setting the ventilator to close the exhalation circuit briefly at the end of inspiration and record the airway pressure when airflow is zero. If both Ppeak and Pplateau are increased (and tidal volume is not excessive), then the underlying problem is a decrease in the compliance in the lung/chest wall unit. Common causes of this problem include pneumothorax, hemothorax, lobar atelectasis, pulmonary edema, pneumonia, acute respiratory distress VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 409 CHAPTER 13 PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENT hemoglobin oxygen saturation (StO2) using near-infrared wavelengths of light (700–1000 nm). This technology is based on Beer’s law, which states that the transmission of light through a solution with a dissolved solute decreases exponentially as the concentration of the solute increases. In mammalian tissue, three compounds change their absorption pattern when oxygenated: cytochrome aa3, myoglobin, and hemoglobin. Because of the distinct absorption spectra of oxyhemoglobin and deoxyhemoglobin, Beer’s law can be used to detect their relative concentrations within tissue. Thus, the relative concentrations of the types of hemoglobin can be determined by measuring the change in light intensity as it passes through the tissue. Since about 20% of blood volume is intra-arterial and the StO2 measurements are taken without regard to systole or diastole, spectroscopic measurements are primarily indicative of the venous oxyhemoglobin concentration. NIRS has been evaluated to assess the severity of traumatic shock in animal models and in trauma patients. Studies have shown that peripheral muscle StO2, as determined by NIRS, is as accurate as other end points of resuscitation (i.e., base deficit, mixed venous oxygen saturation) in a porcine model of hemorrhagic shock.43 Continuously-measured StO2 has been evaluated in blunt trauma patients as a predictor of the development of multiple organ dysfunction syndrome (MODS) and mortality.44 Exactly 383 patients were studied at seven level 1 trauma centers. StO2was monitored for 24 hours after admission along with vital signs and other endpoints of resuscitation, such as base deficit (BD). Minimum StO2(using a minimum StO2≤ 75% as a cutoff) had a similar sensitivity and specificity in predicting the development of MODS as BD ≥ 6 mEq/L. StO2 and BD were also comparable in predicting mortality. Thus, NIRS-derived muscle StO2 measurements perform similarly to BD in identifying poor perfusion and predicting the development of MODS or death after severe torso trauma, yet have the additional advantages of being continuous and noninvasive. Ongoing prospective studies will help determine the clinical utility of continuous monitoring of StO2 in clinical scenarios such as trauma, hemorrhagic shock, and sepsis. 410 PART I BASIC CONSIDERATIONS syndrome (ARDS), active contraction of the chest wall or diaphragmatic muscles, abdominal distention, and intrinsic PEEP, such as occurs in patients with bronchospasm and insufficient expiratory times. When Ppeak is increased but Pplateau is relatively normal, the primary problem is an increase in airway resistance, such as occurs with bronchospasm, use of a small-caliber endotracheal tube, or kinking or obstruction of the endotracheal tube. A low Ppeak also should trigger an alarm, as it suggests a discontinuity in the airway circuit involving the patient and the ventilator. Ventilator-induced lung injury (VILI) is now an established clinical entity of great relevance to the care of critically ill patients. Excessive airway pressure and tidal volume adversely affect pulmonary and possibly systemic responses to critical illness. Subjecting the lung parenchyma to excessive pressure, known as barotrauma, can result in parenchymal lung injury, diffuse alveolar damage similar to ARDS, and pneumothorax, and can impair venous return and therefore limit cardiac output. Lung-protective ventilation strategies have been developed to prevent the development of VILI and improve patient outcomes. In a large, multicenter randomized trial of patients with ARDS from a variety of etiologies, limiting plateau airway pressure to less than 30 cm H2O and tidal volume to less than 6 mL/kg of ideal body weight reduced 28-day mortality by 22% relative to a ventilator strategy that used a tidal volume of 12 mL/kg.46 For this reason, monitoring of plateau pressure and using a low tidal volume strategy in patients with ARDS is now the standard of care. Recent data also suggest that a lung-protective ventilation strategy is associated with improved clinical outcomes in ventilated patients without ARDS.47 Pulse Oximetry The pulse oximeter is a microprocessor-based device that integrates oximetry and plethysmography to provide continuous noninvasive monitoring of the oxygen saturation of arterial blood (Sao2). It is considered one of the most important and useful technologic advances in patient monitoring. Continuous, noninvasive monitoring of arterial oxygen saturation is possible using light-emitting diodes and sensors placed on the skin. Pulse oximetry employs two wavelengths of light (i.e., 660 nm and 940 nm) to analyze the pulsatile component of blood flow between the light source and sensor. Because oxyhemoglobin and deoxyhemoglobin have different absorption spectra, differential absorption of light at these two wavelengths can be used to calculate the fraction of oxygen saturation of hemoglobin. Under normal circumstances, the contributions of carboxyhemoglobin and methemoglobin are minimal. However, if carboxyhemoglobin levels are elevated, the pulse oximeter will incorrectly interpret carboxyhemoglobin as oxyhemoglobin and the arterial saturation displayed will be falsely elevated. When the concentration of methemoglobin is markedly increased, the Sao2 will be displayed as 85%, regardless of the true arterial saturation.48 The accuracy of pulse oximetry begins to decline at Sao2 values less than 92%, and tends to be unreliable for values less than 85%.49 Several studies have assessed the frequency of arterial oxygen desaturation in hospitalized patients and its effect on outcome. Monitoring pulse oximetry in surgical patients is associated with a reduction in unrecognized deterioration, rescue events and transfers to the ICU.50 Because of its clinical relevance, ease of use, noninvasive nature, and cost-effectiveness, pulse oximetry has become a routine monitoring strategy in patients with respiratory disease, intubated patients, and those undergoing surgical intervention under sedation or general anesthesia. Pulse oximetry is especially useful in the titration of Fio2 and PEEP for patients receiving mechanical ventilation, and during weaning from mechanical ventilation. The widespread use of pulse oximetry has decreased the need for arterial blood gas determinations in critically ill patients. Capnometry Capnometry is the measurement of carbon dioxide in the airway throughout the respiratory cycle. Capnometry is most commonly measured by infrared light absorption. CO2 absorbs infrared light at a peak wavelength of approximately 4.27 μm. Capnometry works by passing infrared light through a sample chamber to a detector on the opposite side. More infrared light passing through the sample chamber (i.e., less CO2) causes a larger signal in the detector relative to the infrared light passing through a reference cell. Capnometric determination of the partial pressure of CO2 in end-tidal exhaled gas (Petco2) is used as a surrogate for the partial pressure of CO2 in arterial blood (Paco2) during mechanical ventilation. In healthy subjects, Petco2 is about 1 to 5 mm Hg less than Paco2.51 Thus, Petco2 can be used to estimate Paco2 without the need for blood gas determination. However, changes in Petco2 may not correlate with changes in Paco2 during a number of pathologic conditions (see next). Capnography allows the confirmation of endotracheal intubation and continuous assessment of ventilation, integrity of the airway, operation of the ventilator, and cardiopulmonary function. Capnometers are configured with either an in-line sensor or a sidestream sensor. The sidestream systems are lighter and easy to use, but the thin tubing that samples the gas from the ventilator circuit can become clogged with secretions or condensed water, preventing accurate measurements. The in-line devices are bulky and heavier, but are less likely to become clogged. Continuous monitoring with capnography has become routine during surgery under general anesthesia and for some intensive care patients. A number of situations can be promptly detected with continuous capnography. A sudden reduction in Petco2 suggests either obstruction of the sampling tubing with water or secretions, or a catastrophic event such as loss of the airway, airway disconnection or obstruction, ventilator malfunction, or a marked decrease in QT. If the airway is connected and patent and the ventilator is functioning properly, then a sudden decrease in Petco2 should prompt efforts to rule out cardiac arrest, massive pulmonary embolism, or cardiogenic shock. Petco2 can be persistently low during hyperventilation or with an increase in dead space such as occurs with pulmonary embolization (even in the absence of a change in QT). Causes of an increase in Petco2 include reduced minute ventilation or increased metabolic rate. Renal Monitoring Urine Output Bladder catheterization with an indwelling catheter allows the monitoring of urine output, usually recorded hourly by the nursing staff. With a patent Foley catheter, urine output is a gross indicator of renal perfusion. The generally accepted normal urine output is 0.5 mL/kg per hour for adults and 1 to 2 mL/ kg per hour for neonates and infants. Oliguria may reflect inadequate renal artery perfusion due to hypotension, hypovolemia, or low QT. Low urine flow also can be a sign of intrinsic renal VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ dysfunction. It is important to recognize that normal urine output does not exclude the possibility of impending renal failure. The triad of oliguria, elevated peak airway pressures, and elevated intra-abdominal pressure is known as the abdominal compartment syndrome (ACS). This syndrome, first described in patients after repair of ruptured abdominal aortic aneurysm, is associated with interstitial edema of the abdominal organs, resulting in elevated intra-abdominal pressure (IAP). When IAP exceeds venous or capillary pressures, perfusion of the kidneys and other intra-abdominal viscera is impaired. Oliguria is a cardinal sign. While the diagnosis of ACS is a clinical one, measuring IAP is useful to confirm the diagnosis. Ideally, a catheter inserted into the peritoneal cavity could measure IAP to substantiate the diagnosis. In practice, transurethral bladder pressure measurement reflects IAP and is most often used to confirm the presence of ACS. After instilling 50 to 100 mL of sterile saline into the bladder via a Foley catheter, the tubing is connected to a transducing system to measure bladder pressure. Intra-abdominal hypertension is defined as an IAP ≥ 12 mm Hg recorded on three standard measurements conducted 4 to 6 hours apart, while the diagnosis of ACS is the presence of an IAP ≥ 20 mm Hg recorded by three measurements 1 to 6 hours apart.52,60 Less commonly, gastric or inferior vena cava pressures can be monitored with appropriate catheters to detect elevated intra-abdominal pressures. Neurologic Monitoring Intracranial Pressure Because the brain is rigidly confined within the bony skull, cerebral edema or mass lesions increase intracranial pressure (ICP). Monitoring of ICP currently is recommended in patients with severe traumatic brain injury (TBI), defined as a Glasgow Coma Scale (GCS) score less than or equal to 8 with an abnormal CT scan, and in patients with severe TBI and a normal CT scan if two or more of the following are present: age greater than 40 years, unilateral or bilateral motor posturing, or systolic blood pressure less than 90 mm Hg.53 ICP monitoring also is indicated in patients with acute subarachnoid hemorrhage with coma or neurologic deterioration, intracranial hemorrhage with intraventricular blood, ischemic middle cerebral artery stroke, fulminant hepatic failure with coma and cerebral edema on CT scan, and global cerebral ischemia or anoxia with cerebral edema on CT scan. The goal of ICP monitoring is to ensure that cerebral perfusion pressure (CPP) is adequate to support perfusion of the brain. CPP is equal to the difference between MAP and ICP: CPP = MAP – ICP. One type of ICP measuring device, the ventriculostomy catheter, consists of a fluid-filled catheter inserted into a cerebral ventricle and connected to an external pressure transducer. This device permits measurement of ICP, but also allows drainage of cerebrospinal fluid (CSF) as a means to lower ICP and sample CSF for laboratory studies. Other devices locate the pressure transducer within the central nervous system and are used only to monitor ICP. These devices can be placed in the intraventricular, parenchymal, subdural, or epidural spaces. Ventriculostomy catheters are the accepted standard for monitoring ICP in patients with TBI due to their accuracy, ability to drain CSF, and low complication rate. The associated complications include infection (5%), hemorrhage (1.1%), catheter Electroencephalogram and Evoked Potentials Electroencephalogram offers the capacity to monitor global neurologic electrical activity, while evoked potential monitoring can assess pathways not detected by the conventional EEG. Continuous EEG (CEEG) monitoring in the intensive care unit (ICU) permits ongoing evaluation of cerebral cortical activity. It is especially useful in obtunded and comatose patients. CEEG also is useful for monitoring of therapy for status epilepticus and detecting early changes associated with cerebral ischemia. CEEG can be used to adjust the level of sedation, especially if high-dose barbiturate therapy is being used to manage elevated ICP. Somatosensory and brain stem evoked potentials are less affected by the administration of sedatives than is the EEG. Evoked potentials are useful for localizing brain stem lesions or proving the absence of such structural lesions in cases of metabolic or toxic coma. They also can provide prognostic data in posttraumatic coma. An advance in EEG monitoring is the use of the bispectral index (BIS) to titrate the level of sedative medications. While sedative drugs are usually titrated to the clinical neurologic examination, the BIS device has been used in the operating room to continuously monitor the depth of anesthesia. The BIS is an empirical measurement statistically derived from a database of over 5000 EEGs.59 The BIS is derived from bifrontal EEG recordings and analyzed for burst suppression ratio, relative alpha:beta ratio, and bicoherence. Using a multivariate regression model, a linear numeric index (BIS) is calculated, ranging from 0 (isoelectric EEG) to 100 (fully awake). Its use has been associated with lower consumption of anesthetics during surgery and earlier awakening and faster recovery from anesthesia.60 The BIS also has been validated as a useful approach for monitoring the level of sedation for ICU patients, using the revised Sedation-Agitation Scale as a gold standard.61 Transcranial Doppler Ultrasonography This modality provides a noninvasive method for evaluating cerebral hemodynamics. Transcranial Doppler (TCD) measurements of middle and anterior cerebral artery blood flow velocity are useful for the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. Qureshi et al demonstrated that an increase in the middle cerebral artery mean flow velocity as VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 411 CHAPTER 13 PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENT Bladder Pressure malfunction or obstruction (6.3%–10.5%), and malposition with injury to cerebral tissue.54 The purpose of ICP monitoring is to detect and treat abnormal elevations of ICP that may be detrimental to cerebral perfusion and function. In TBI patients, ICP >20 mm Hg is associated with unfavorable outcomes.55 However, few studies have shown that treatment of elevated ICP improves clinical outcomes in human trauma patients. In a randomized, controlled, double-blind trial, Eisenberg and colleagues demonstrated that maintaining ICP less than 25 mm Hg in patients without craniectomy and less than 15 mm Hg in patients with craniectomy is associated with improved outcome.56 In patients with low CPP, therapeutic strategies to correct CPP can be directed at increasing MAP, decreasing ICP, or both. While it has been recommended that CPP be maintained between 50 and 70 mm Hg, the evidence to support this recommendation is not overly compelling.57 Furthermore, a retrospective cohort study of patients with severe TBI found that ICP/CPP-targeted neuro-intensive care was associated with prolonged mechanical ventilation and increased therapeutic interventions, without evidence for improved outcome in patients who survive beyond 24 hours.58 412 PART I assessed by TCD is an independent predictor of symptomatic vasospasm in a prospective study of patients with aneurysmal subarachnoid hemorrhage.62 In addition, while some have proposed using TCD to estimate ICP, studies have shown that TCD is not a reliable method for estimating ICP and CPP, and currently cannot be endorsed for this purpose.63 TCD also is useful to confirm the clinical examination for determining brain death in patients with confounding factors such as the presence of CNS depressants or metabolic encephalopathy. BASIC CONSIDERATIONS Jugular Venous Oximetry When the arterial oxygen content, hemoglobin concentration, and the oxyhemoglobin dissociation curve are constant, changes in jugular venous oxygen saturation (Sjo2) reflect changes in the difference between cerebral oxygen delivery and demand. Generally, a decrease in Sjo2 reflects cerebral hypoperfusion, whereas an increase in Sjo2 indicates the presence of hyperemia. Sjo2 monitoring cannot detect decreases in regional cerebral blood flow if overall perfusion is normal or above normal. This technique requires the placement of a catheter in the jugular bulb, usually via the internal jugular vein. Catheters that permit intermittent aspiration of jugular venous blood for analysis or continuous oximetry catheters are available. Low Sjo2 is associated with poor outcomes after TBI.64 Nevertheless, the value of monitoring Sjo2 remains unproven. If it is employed, it should not be the sole monitoring technique, but rather should be used in conjunction with ICP and CPP monitoring. By monitoring ICP, CPP, and Sjo2, early intervention with volume, vasopressors, and hyperventilation has been shown to prevent ischemic events in patients with TBI.65 Transcranial Near-Infrared Spectroscopy Transcranial near-infrared spectroscopy (NIRS) is a noninvasive continuous monitoring method to determine cerebral oxygenation. It employs technology similar to that of pulse oximetry to determine the concentrations of oxy- and deoxyhemoglobin with near-infrared light and sensors, and takes advantage of the relative transparency of the skull to light in the near-infrared region of the spectrum. Continuous monitoring of cerebral perfusion via transcranial NIRS may provide a method to detect early cerebral ischemia in patients with traumatic brain injury.66 Nevertheless, this form of monitoring remains largely a research tool at the present time. Brain Tissue Oxygen Tension While the standard of care for patients with severe TBI includes ICP and CPP monitoring, this strategy does not always prevent secondary brain injury. Growing evidence suggests that monitoring local brain tissue oxygen tension (PbtO2) may be a useful adjunct to ICP monitoring in these patients. Normal values for PbtO2 are 20 to 40 mm Hg, and critical levels are 8 to 10 mm Hg. A recent clinical study sought to determine whether the addition of a PbtO2 monitor to guide therapy in severe traumatic brain injury was associated with improved patient outcomes.67 Twenty-eight patients with severe traumatic brain injury (GCS score ≤8) were enrolled in an observational study at a level I trauma center. These patients received invasive ICP and PbtO2monitoring and were compared with 25 historical controls matched for age, injuries, and admission GCS score that had undergone ICP monitoring alone. Goals of therapy in both groups included maintaining an ICP <20 mm Hg and a CPP >60 mm Hg. Among patients with PbtO2 monitoring, therapy also was directed at maintaining PbtO2>25 mm Hg. The groups had similar mean daily ICP and CPP levels. The mortality rate in the historical controls treated with standard ICP and CPP management was 44%. Mortality was significantly lower in the patients who had therapy guided by PbtO2 monitoring in addition to ICP and CPP (25%; P<0.05). The benefits of PbtO2 monitoring may include the early detection of brain tissue ischemia despite normal ICP and CPP. In addition, PbtO2-guided management may reduce potential adverse effects associated with therapies to maintain ICP and CPP. CONCLUSIONS Modern intensive care is predicated by the need and ability to continuously monitor a wide range of physiologic parameters. This capability has dramatically improved the care of critically ill patients and advanced the development of the specialty of critical care medicine. In some cases, the technological ability to measure such variables has surpassed our understanding of the significance or the knowledge of the appropriate intervention to ameliorate such pathophysiologic changes. In addition, the development of less invasive monitoring methods has been promoted by the recognition of complications associated with invasive monitoring devices. The future portends the continued development of noninvasive monitoring devices along with their application in an evidenced-based strategy to guide rational therapy. REFERENCES Entries highlighted in bright blue are key references. 1. Bur A, Herkner H, Vlcek M, et al. Factors influencing the accuracy of oscillometric blood pressure measurement in critically ill patients. Crit Care Med. 2003;31(3):793-799. 2. Fischer MO, Avram R, Carjaliu I, et al. 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Curr Opin Crit Care. 2005;11(3): 235-239. 40. Gunn SR, Pinsky MR. Implications of arterial pressure variation in patients in the intensive care unit. Curr Opin Crit Care. 2001;7(3):212-217. 41. Mesquida J, Kim HK, Pinsky MR. Effect of tidal volume, intrathoracic pressure, and cardiac contractility on variations in pulse pressure, stroke volume, and intrathoracic blood volume. Intensive Care Med. 2011;37(10):1672-1679. 42. Michard F, Boussat S, Chemla D, et al. Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med. 2000;162(1):134-138. 43. Crookes BA, Cohn SM, Burton EA, Nelson J, Proctor KG. Noninvasive muscle oxygenation to guide fluid resuscitation after traumatic shock. Surgery. 2004;135(6):662-670. 44. Cohn SM, Nathens AB, Moore FA, et al. Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation. J Trauma. 2007;62(1):44-54; discussion 54-5. 45. Haller M, Kilger E, Briegel J, Forst H, Peter K. Continuous intra-arterial blood gas and pH monitoring in critically ill patients with severe respiratory failure: a prospective, criterion standard study. Crit Care Med. 1994;22(4):580-587. 46. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301-1308. 47. Serpa Neto A, Cardoso SO, Manetta JA, et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012;308(16):1651-1659. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 413 CHAPTER 13 PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENT in the Department of Veterans Affairs: a prospective, observational, multicenter analysis. Anesthesiology. 2002;96(4): 860-870. 11. Rivers EP, Ander DS, Powell D. Central venous oxygen saturation monitoring in the critically ill patient. Curr Opin Crit Care. 2001;7(3):204-211. 12. Varpula M, Karlsson S, Ruokonen E, Pettila V. Mixed venous oxygen saturation cannot be estimated by central venous oxygen saturation in septic shock. Intens Care Med. 2006;32(9): 1336-1343. 13. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. 14. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med. 2013;41(2):580-637. 15. Connors AF Jr., Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA. 1996;276(11): 889-897. 16. Pearson KS, Gomez MN, Moyers JR, Carter JG, Tinker JH. A cost/benefit analysis of randomized invasive monitoring for patients undergoing cardiac surgery. Anesth Analg. 1989;69(3):336-341. 17. Tuman KJ, McCarthy RJ, Spiess BD, et al. Effect of pulmonary artery catheterization on outcome in patients undergoing coronary artery surgery. Anesthesiology. 1989;70(2):199-206. 18. Bender JS, Smith-Meek MA, Jones CE. Routine pulmonary artery catheterization does not reduce morbidity and mortality of elective vascular surgery: results of a prospective, randomized trial. Ann Surg. 1997;226(3):229-236. 19. Valentine RJ, Duke ML, Inman MH, et al. Effectiveness of pulmonary artery catheters in aortic surgery: a randomized trial. J Vasc Surg. 1998;27(2):203-211; discussion 11-2. 20. Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in highrisk surgical patients. N Engl J Med. 2003;348(1):5-14. 21. Harvey S, Harrison DA, Singer M, et al. Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial. Lancet. 2005;366(9484):472-477. 22. Shah MR, Hasselblad V, Stevenson LW, et al. Impact of the pulmonary artery catheter in critically ill patients: meta-analysis of randomized clinical trials. JAMA. 2005;294(13):1664-1670. 23. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005;294(13): 1625-1633. 24. National Heart Lung, Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wheeler AP, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006;354(21):2213-2224. 25. Wiener RS, Welch HG. Trends in the use of the pulmonary artery catheter in the United States, 1993-2004. JAMA. 2007;298(4):423-429. 26. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective Trial of Supranormal Values of Survivors as Therapeutic Goals in High-Risk Surgical Patients. Chest. 1988;94(6):1176-1186. 27. Bishop MH, Shoemaker WC, Appel PL, et al. Prospective, randomized trial of survivor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation endpoints in severe trauma. J Trauma. 1995;38(5):780-787. 28. Heyland DK, Cook DJ, King D, Kernerman P, Brun-Buisson C. Maximizing oxygen delivery in critically ill patients: a methodologic appraisal of the evidence. Crit Care Med. 1996;24(3):517-524. 414 PART I BASIC CONSIDERATIONS 48. Tremper KK. Pulse oximetry. Chest. 1989;95(4):713-715. 49. Shoemaker WC, Belzberg H, Wo CCJ, et al. Multicenter study of noninvasive monitoring systems as alternatives to invasive monitoring of acutely ill emergency patients. Chest. 1998;114(6):1643-1652. 50. Taenzer AH, Pyke JB, McGrath SP, Blike GT. Impact of pulse oximetry surveillance on rescue events and intensive care unit transfers: a before-and-after concurrence study. Anesthesiology. 2010;112(2):282-287. 51. Jubran A, Tobin MJ. Monitoring during mechanical ventilation. Clin Chest Med. 1996;17(3):453-473. 52. Sugrue M. Abdominal compartment syndrome. Curr Opin Crit Care. 2005;11(4):333-338. 53. Brain Trauma F, American Association of Neurological S, Congress of Neurological S, et al. Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma. 2007;24 Suppl: 1S37-1S44. 54. Brain Trauma F, American Association of Neurological S, Congress of Neurological S, et al. Guidelines for the management of severe traumatic brain injury. VII. Intracranial pressure monitoring technology. J Neurotrauma. 2007;24 Suppl: 1S45-1S54. 55. Juul N, Morris GF, Marshall SB, Marshall LF. Intracranial hypertension and cerebral perfusion pressure: influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial. J Neurosurg. 2000;92(1):1-6. 56. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg. 1988;69(1):15-23. 57. Brain Trauma F, American Association of Neurological S, Congress of Neurological S, et al. Guidelines for the management of severe traumatic brain injury. IX. Cerebral perfusion thresholds. J Neurotrauma. 2007;24 Suppl: 1S59-1S64. 58. Cremer OL, van Dijk GW, van Wensen E, et al. Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med. 2005;33(10):2207-2213. 59. Sigl JC, Chamoun NG. An introduction to bispectral analysis for the electroencephalogram. J Clin Monit. 1994;10(6):392-404. 60. Gan TJ, Glass PS, Windsor A, et al. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology. 1997;87(4):808-815. 61. Simmons LE, Riker RR, Prato BS, Fraser GL. Assessing sedation during intensive care unit mechanical ventilation with the Bispectral Index and the Sedation-Agitation Scale. Crit Care Med. 1999;27(8):1499-1504. 62. Qureshi AI, Sung GY, Razumovsky AY, et al. Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. Crit Care Med. 2000;28(4):984-990. 63. Czosnyka M, Matta BF, Smielewski P, Kirkpatrick PJ, Pickard JD. Cerebral perfusion pressure in head-injured patients: a noninvasive assessment using transcranial Doppler ultrasonography. J Neurosurg. 1998;88(5):802-808. 64. Feldman Z, Robertson CS. Monitoring of cerebral hemodynamics with jugular bulb catheters. Crit Care Clin. 1997;13(1):51-77. 65. Vigue B, Ract C, Benayed M, et al. Early SjvO2 monitoring in patients with severe brain trauma. Intens Care Med. 1999;25(5):445-451. 66. Murkin JM, Arango M. Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J Anaesth. 2009;103 Suppl: 1i3-li13. 67. Stiefel MF, Spiotta A, Gracias VH, et al. Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg. 2005;103(5):805-811. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 14 chapter Introduction 415 Historical Background 415 Physiology and Pathophysiology of Minimally Invasive Surgery 417 Laparoscopy / 417 Thoracoscopy / 419 Extracavitary Minimally Invasive Surgery / 419 Anesthesia / 419 The Minimally Invasive Team / 419 Room Setup and the Minimally Invasive Suite / 420 Patient Positioning / 420 General Principles of Access / 421 Laparoscopic Access / 421 Access for Subcutaneous and Minimally Invasive Surgery, Robotics, Natural Orifice Transluminal Endoscopic Surgery, and SingleIncision Laparoscopic Surgery Donn H. Spight, John G. Hunter, and Blair A. Jobe Extraperitoneal Surgery / 422 Hand-Assisted Laparoscopic Access / 423 Natural Orifice Transluminal Endoscopic Surgery Access / 423 Single-Incision Laparoscopic Surgery Access / 423 Port Placement / 424 Imaging Systems / 425 Energy Sources for Endoscopic and Endoluminal Surgery / 426 Instrumentation / 429 Robotic Surgery / 429 Endoluminal and Endovascular Surgery / 431 Natural Orifice Transluminal Endoscopic Surgery / 432 INTRODUCTION Minimally invasive surgery describes an area of surgery that crosses all traditional disciplines, from general surgery to neurosurgery. It is not a discipline unto itself, but more a philosophy of surgery, a way of thinking. Minimally invasive surgery is a 1 means of performing major operations through small incisions, often using miniaturized, high-tech imaging systems, to minimize the trauma of surgical exposure. Some believe that the term minimal access surgery more accurately describes the small incisions generally necessary to gain access to surgical sites in high-tech surgery, but John Wickham’s term minimally invasive surgery (MIS) is widely used because it describes the paradox of postmodern high-tech surgery—small holes, big operations. Robotic surgery today is practiced using a single platform (Intuitive, Inc., Sunnyvale, CA) and should better be termed computer-enhanced surgery because the term robotics assumes autonomous action that is not a feature of the da Vinci robotic system. Instead, the da Vinci robot couples an ergonomic workstation that features stereoptic video imaging and intuitive micromanipulators (surgeon side) with a set of arms delivering specialized laparoscopic instruments enhanced with more degrees of freedom than are allowed by laparoscopic surgery alone (patient side). A computer between the surgeon side and patient side removes surgical tremor and scales motion to allow precise microsurgery, which is helpful for microdissection and difficult anastomoses. Single-incision laparoscopic surgery (SILS), also called laparoendoscopic single-site surgery (LESS), is a recent addition to the armamentarium of the minimally invasive surgeon. Single-Incision Laparoscopic Surgery / 433 Special Considerations 435 Pediatric Laparoscopy / 435 Laparoscopy during Pregnancy / 435 Minimally Invasive Surgery and Cancer Treatment / 436 Considerations in the Elderly and Infirm / 436 Cirrhosis and Portal Hypertension / 436 Economics of Minimally Invasive Surgery / 436 Education and Skill Acquisition / 437 Telementoring / 437 Innovation and Introduction of New Procedures / 437 As ­public awareness has grown, so too has its spread outside of larger institutions. SILS challenges the well-established paradigm of standard laparoscopic surgery by placing multiple trocars within the fascia at the umbilicus or through a single multichannel trocar at the umbilicus. The manipulation of tightly spaced instruments across the fulcrum of the abdominal wall requires that the surgeon either operate in a crossed hands fashion or use specialized curved instruments to avoid clashing outside the body while working intra-abdominally. The primary advantage of SILS is the reduction to one surgical scar. Greater efficacy, safety, and cost savings have yet to be fully elucidated in the increasing number of procedures that are being attempted in this manner. The advent of a robotic SILS platform now enables the computer reassignment of the surgeon’s hands, thus eliminating the difficult ergonomic challenges making the technique far more accessible. Natural orifice transluminal endoscopic surgery (NOTES) is an extension of interventional endoscopy. Using the mouth, anus, vagina, and urethra (natural orifices), flexible endoscopes are passed through the wall of the esophagus, stomach, colon, bladder, or vagina entering the mediastinum, the pleural space, or the peritoneal cavity. The advantage of this method of minimal access is principally the elimination of the scar associated with laparoscopy or thoracoscopy. Other advantages have yet to be elucidated, including pain reduction, need for hospitalization, and cost savings. HISTORICAL BACKGROUND Although the term minimally invasive surgery is relatively recent, the history of its component parts is nearly 100 years old. What is considered the newest and most popular variety VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 416 Minimally invasive surgery describes a philosophical approach to surgery in which access trauma is minimized without compromising the quality of the surgical procedure. The carbon dioxide pneumoperitoneum used for laparoscopy induces some unique pathophysiologic consequences. Robotic surgery has been most valuable in the pelvis for performance of minimally invasive prostatectomy and gynecologic and fertility procedures. Natural orifice transluminal endoscopic surgery represents a new opportunity to develop truly scar-free surgery. of MIS, laparoscopy, is, in fact, the oldest. Primitive laparoscopy, placing a cystoscope within an inflated abdomen, was first performed by Kelling in 1901.1 Illumination of the abdomen required hot elements at the tip of the scope and was dangerous. In the late 1950s, Hopkins described the rod lens, a method of transmitting light through a solid quartz rod with no heat and little light loss.1 Around the same time, thin quartz fibers were discovered to be capable of trapping light internally and conducting it around corners, opening the field of fiber optics and allowing the rapid development of flexible endoscopes.2,3 In the 1970s, the application of flexible endoscopy grew faster than that of rigid endoscopy except in a few fields such as gynecology and orthopedics.4 By the mid1970s, rigid and flexible endoscopes made a rapid transition from diagnostic instruments to therapeutic ones. The explosion of video-assisted surgery in the past 20 years was a result of the development of compact, high-resolution, charge-coupled devices (CCDs) that could be mounted on the internal end of flexible endoscopes or on the external end of a Hopkins telescope. Coupled with bright light sources, fiber-optic cables, and high-definition video monitors, the videoendoscope has changed our understanding of surgical anatomy and reshaped surgical practice. Flexible endoscopic imaging started in the 1960s with the first bundling of many quartz fibers into bundles, one for illumination and one for imaging. The earliest upper endoscopes revolutionized the diagnosis and treatment of gastroesophageal reflux and peptic ulcer disease and made possible early detection of upper and lower gastrointestinal (GI) cancer at a stage that could be cured. The first endoscopic surgical procedure was the colonoscopic polypectomy, developed by Shinya and Wolfe, two surgeons from New York City. The percutaneous endoscopic gastrostomy (PEG) invented by Gauderer and Ponsky may have been the first NOTES procedure, reported in 1981.5 Endoscopic pancreatic pseudocyst drainage is thought to be the next NOTES procedure developed; however, there was little energy and money put into the development of NOTES until a number of gastroenterologists claimed the ability to remove the gallbladder with a flexible endoscope, using a transgastric technique. With this pronouncement, the surgical community took notice and seized the momentum for NOTES research and development. Today most intra-abdominal NOTES procedures remain within the realm of research or incorporate a hybrid laparoscopic technique outside of highly specialized centers. Clinically the 5 6 7 8 Single-incision laparoscopic surgery reduces the amount of abdominal wall trauma but presents unique challenges to the traditional tenets of laparoscopic ergonomics. Laparoscopy during pregnancy is best performed in the second trimester and is safe if appropriate monitoring is performed. Laparoscopic surgery for cancer is also appropriate if good tissue handling techniques are maintained. Training for laparoscopy requires practice outside of the operating room in a simulation laboratory. transvaginal approach has been studied the most extensively. Evaluation of 551 female patients from the ­German NOTES registry has shown conversion and complication rates similar to conventional laparoscopic surgery for cholecystectomy and appendectomy procedures.6 Endoscopic mucosal resection (EMR) of early-stage esophageal and gastric lesions has revolutionized the management of these malignancies. The peroral endoscopic myotomy (POEM) procedure for achalasia is showing clinical efficacy and gaining popularity. As the race to minimize the size and increase the functionality of laparoscopic instruments progressed, the notion of using fewer access points to accomplish the same operations resulted in the development of single-incision laparoscopic surgery (SILS), synonymously termed laparoendoscopic single-site surgery (LESS). Viewed as a progression of laparoscopic surgery, SILS has recently garnered greater enthusiasm over its transvisceral NOTES counterpart.7 Currently the single-incision technique is used regularly across a wide variety of surgical areas including general, urologic, gynecologic, colorectal, and bariatric surgery.8 Although optical imaging produced the majority of MIS procedures, other (traditionally radiologic) imaging technologies allowed the development of innovative procedures in the 1970s. Fluoroscopic imaging allowed the adoption of percutaneous vascular procedures, the most revolutionary of which was balloon angioplasty. Balloonbased procedures spread into all fields of medicine used to open up clogged lumens with minimal access. Stents were then developed that were used in many disciplines to keep the newly ballooned segment open. The culmination of fluoroscopic balloon and stent proficiency is exemplified by the transvenous intrahepatic portosystemic shunt and by the aortic stent graft, which has nearly replaced open elective abdominal aortic aneurysm repair. MIS procedures using ultrasound imaging have been limited to fairly crude exercises, such as fragmenting kidney stones and freezing liver tumors, because of the relatively low resolution of ultrasound devices. Newer, high-resolution ultrasound methods with high-frequency crystals may act as a guide while performing minimally invasive resections of individual layers of the intestinal wall. Axial imaging, such as computed tomography (CT), has allowed the development of an area of MIS that often is not recognized because it requires only a CT scanner and a long needle. CT-guided drainage of abdominal fluid collections and percutaneous biopsy of abnormal tissues are minimally invasive VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ PHYSIOLOGY AND PATHOPHYSIOLOGY OF MINIMALLY INVASIVE SURGERY Even with the least invasive of the MIS procedures, physiologic changes occur. Many minimally invasive procedures require minimal or no sedation, and there are few adverse consequences to the cardiovascular, endocrinologic, or immunologic systems. The least invasive of such procedures include stereotactic biopsy of breast lesions and flexible GI endoscopy. Minimally invasive procedures that require general anesthesia have a greater physiologic impact because of the anesthetic agent, the incision (even if small), and the induced pneumoperitoneum. Laparoscopy The unique feature of laparoscopic surgery is the need to lift the abdominal wall from the abdominal organs. Two methods have been devised for achieving this.10 The first, used by most surgeons, is a pneumoperitoneum. Throughout the early twentieth century, intraperitoneal visualization was achieved by inflating the abdominal cavity with air, using a sphygmomanometer bulb.11 The problem with using air insufflation is that nitrogen is poorly soluble in blood and is slowly absorbed across the peritoneal surfaces. Air pneumoperitoneum was believed to be more painful than nitrous oxide (N2O) pneumoperitoneum, but less painful than carbon dioxide (CO2) pneumoperitoneum. ­Subsequently, CO and N2O were used for inflating the 2 abdomen. N2O had2 the advantage of being physiologically inert and rapidly absorbed. It also provided better analgesia for laparoscopy performed under local anesthesia when compared with CO2 or air.12 Despite initial concerns that N2O would not suppress combustion, controlled clinical trials have established its safety within the peritoneal cavity.13 In addition, N2O has been shown to reduce the intraoperative end-tidal CO2 and minute ventilation required to maintain homeostasis when compared to CO2 pneumoperitoneum.13 The effect of N2O on tumor biology and the development of port site metastasis are unknown. As such, caution should be exercised when performing laparoscopic cancer surgery with this agent. Finally, the safety of N2O pneumoperitoneum in pregnancy has yet to be elucidated. The physiologic effects of CO2 pneumoperitoneum can be divided into two areas: (a) gas-specific effects and (b) pressurespecific effects (Fig. 14-1). CO2 is rapidly absorbed across the peritoneal membrane into the circulation. In the circulation, CO2 creates a respiratory acidosis by the generation of carbonic acid.14 Body buffers, the largest reserve of which lies in bone, absorb CO2 (up to 120 L) and minimize the development of hypercarbia or respiratory acidosis during brief endoscopic procedures.14 Once the body buffers are saturated, respiratory acidosis develops rapidly, and the respiratory system assumes the burden of keeping up with the absorption of CO2 and its release from these buffers. CO2 Local effects Systemic effects Peritoneal distention Vagal reaction Elevated diaphragm Altered venous return Pain Hypercarbia Acidosis Increased afterload Increased catecholamines Myocardial stress Figure 14-1. Carbon dioxide gas insufflated into the peritoneal cavity has both local and systemic effects that cause a complex set of hemodynamic and metabolic alterations. (Reproduced with permission from Hunter JG, ed. Bailliere’s Clinical Gastroenterology Laparoscopic Surgery. London/Philadelphia: Bailliere Tindall; 1993:758. Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 417 CHAPTER 14 Minimally Invasive Surgery means of performing procedures that previously required a celiotomy. CT-guided percutaneous radiofrequency (RF) ablation has emerged as a useful treatment for primary and metastatic liver tumors. This procedure also is performed laparoscopically under ultrasound guidance.9 A powerful, noninvasive method of imaging that will allow the development of the least invasive—and potentially noninvasive—surgery is magnetic resonance imaging (MRI). MRI is an extremely valuable diagnostic tool, but it is only slowly coming to be of therapeutic value. One obstacle to the use of MRI for MIS is that image production and refreshment of the image as a procedure progresses are slow. Another is that all instrumentation must be nonmetallic when working with the powerful magnets of an MRI scanner. Moreover, MRI magnets are bulky and limit the surgeon’s access to the patient. Open magnets have been developed that allow the surgeon to stand between two large MRI coils, obtaining access to the portion of the patient being scanned. The advantage of MRI, in addition to the superb images produced, is that there is no radiation exposure to patient or surgeon. Some neurosurgeons are accumulating experience using MRI to perform frameless stereotactic surgery. Robotic surgery has been dreamed about for some time, and many science fiction–like devices have been developed over the years to provide mechanical assistance for the surgeon. The first computer-assisted robot was designed to accurately drill femoral shaft bone for wobble-free placement of hip prostheses. Although the concept was appealing, the robot proved no better than a skilled orthopedic surgeon and was a good deal slower. Following this, the first and only two commercially successful robots for laparoscopic surgery were developed in California. Computer Motion, founded by Yulun Wang in Santa Barbara, used National Science Foundation funds to create a mechanical arm, the Aesop robot, which held and moved the laparoscope with voice, foot, or hand control. In Northern California, a master-slave system first developed for surgery on the multinational space station by Philip Green was purchased by Fred Moll and Lonnie Smith, and then reengineered with the surgeon in mind to create a remarkably intuitive computer-enhanced surgical platform. The company, Intuitive Surgical, was aptly named, and their primary product, the da Vinci robot, is currently the only major robotic platform on the market. Although eschewed by many experienced laparoscopists, the da Vinci achieved a toehold among many skilled surgeons who found that the robot could facilitate MIS procedures that were difficult with standard laparoscopic procedures. The latest iteration of the da Vinci platform released in 2009 features high-definition, three-dimensional vision and a dualconsole capability allowing greater visualization, assistance, and instruction capabilities. 418 PART I BASIC CONSIDERATIONS In patients with normal respiratory function, this is not difficult; the anesthesiologist increases the ventilatory rate or vital capacity on the ventilator. If the respiratory rate required exceeds 20 breaths per minute, there may be less efficient gas exchange and increasing hypercarbia.15 Conversely, if vital capacity is increased substantially, there is a greater opportunity for barotrauma and greater respiratory motion–induced disruption of the upper abdominal operative field. In some situations, it is advisable to evacuate the pneumoperitoneum or reduce the intra-abdominal pressure to allow time for the anesthesiologist to adjust for hypercarbia.16 Although mild respiratory acidosis probably is an insignificant problem, more severe respiratory acidosis leading to cardiac arrhythmias has been reported.17 Hypercarbia also causes tachycardia and increased systemic vascular resistance, which elevates blood pressure and increases myocardial oxygen demand.14,17 The pressure effects of the pneumoperitoneum on cardiovascular physiology also have been studied. In the hypovolemic individual, excessive pressure on the inferior vena cava and a reverse Trendelenburg position with loss of lower extremity muscle tone may cause decreased venous return and decreased cardiac output.14,18 This is not seen in the normovolemic patient. The most common arrhythmia created by laparoscopy is bradycardia. A rapid stretch of the peritoneal membrane often causes a vagovagal response with bradycardia and, occasionally, hypotension.19 The appropriate management of this event is desufflation of the abdomen, administration of vagolytic agents (e.g., atropine), and adequate volume replacement.20 With the increased intra-abdominal pressure compressing the inferior vena cava, there is diminished venous return from the lower extremities. This has been well documented in the patient placed in the reverse Trendelenburg position for upper abdominal operations. Venous engorgement and decreased venous return promote venous thrombosis.21,22 Many series of advanced laparoscopic procedures in which deep venous thrombosis (DVT) prophylaxis was not used demonstrate the frequency of pulmonary embolus. This usually is an avoidable complication with the use of sequential compression stockings, subcutaneous heparin, or low molecular weight heparin.20,23 In short-duration laparoscopic procedures, such as appendectomy, hernia repair, or cholecystectomy, the risk of DVT may not be sufficient to warrant extensive DVT prophylaxis. The increased pressure of the pneumoperitoneum is transmitted directly across the paralyzed diaphragm to the thoracic cavity, creating increased central venous pressure and increased filling pressures of the right and left sides of the heart. If the intra-abdominal pressures are kept under 20 mmHg, the cardiac output usually is well maintained.22–24 The direct effect of the pneumoperitoneum on increasing intrathoracic pressure increases peak inspiratory pressure, pressure across the chest wall, and also, the likelihood of barotrauma. Despite these concerns, disruption of blebs and consequent pneumothoraces are rare after uncomplicated laparoscopic surgery.24 Pneumothoraces occurring with laparoscopic esophageal surgery may be very significant. The pathophysiology and management are discussed at the end of this section. Increased intra-abdominal pressure decreases renal blood flow, glomerular filtration rate, and urine output. These effects may be mediated by direct pressure on the kidney and the renal vein.25,26 The secondary effect of decreased renal blood flow is to increase plasma renin release, thereby increasing sodium retention. Increased circulating antidiuretic hormone levels also are found during the pneumoperitoneum, increasing free water reabsorption in the distal tubules.27 Although the effects of the pneumoperitoneum on renal blood flow are immediately reversible, the hormonally mediated changes such as elevated antidiuretic hormone levels decrease urine output for up to 1 hour after the procedure has ended. Intraoperative oliguria is common during laparoscopy, but the urine output is not a reflection of intravascular volume status; intravenous (IV) fluid administration during an uncomplicated laparoscopic procedure should not be linked to urine output. Because insensible fluid losses through the open abdomen are eliminated with laparoscopy, the need for supplemental fluid during a laparoscopic surgical procedure should only keep up with venous pooling in the lower limbs, third-space losses into the bowel, and blood loss, which is generally less than occurs with an equivalent open operation. The hemodynamic and metabolic consequences of pneumoperitoneum are well tolerated by healthy individuals for a prolonged period and by most individuals for at least a short period. Difficulties can occur when a patient with compromised cardiovascular function is subjected to a long laparoscopic procedure. It is during these procedures that alternative approaches should be considered or insufflation pressure reduced. Alternative gases that have been suggested for laparoscopy include the inert gases helium, neon, and argon. These gases are appealing because they cause no metabolic effects, but are poorly soluble in blood (unlike CO2 and N2O) and are prone to create gas emboli if the gas has direct access to the venous system.22 Gas emboli are rare but serious complications of laparoscopic surgery.23,28 They should be suspected if hypotension develops during insufflation. Diagnosis may be made by listening (with an esophageal stethoscope) for the characteristic “mill wheel” murmur. The treatment of gas embolism is to place the patient in a left lateral decubitus position with the head down to trap the gas in the apex of the right ventricle.23 A rapidly placed central venous catheter then can be used to aspirate the gas out of the right ventricle. In some situations, minimally invasive abdominal surgery should be performed without insufflation. This has led to the development of an abdominal lift device that can be placed through a 10- to 12-mm trocar at the umbilicus.29 These devices have the advantage of creating little physiologic derangement, but they are bulky and intrusive. The exposure and working room offered by lift devices also are inferior to those accomplished by pneumoperitoneum. Lifting the anterior abdominal wall reduces space available laterally and thereby displaces the bowel medially and anteriorly into the operative field. A pneumoperitoneum, with its well-distributed intra-abdominal pressure, provides better exposure. Abdominal lift devices also cause more postoperative pain, but they do allow the performance of MIS with standard (nonlaparoscopic) surgical instruments. Endocrine responses to laparoscopic surgery are not always intuitive. Serum cortisol levels after laparoscopic operations are often higher than after the equivalent operation performed through an open incision.30 The greatest difference between the endocrine response of open and laparoscopic surgery is the more rapid equilibration of most stress-mediated hormone levels after laparoscopic surgery. Immune suppression also is less after laparoscopy than after open surgery. There is a trend toward more rapid normalization of cytokine levels after a laparoscopic procedure than after the equivalent procedure performed by celiotomy.31 Transhiatal mobilization of the distal esophagus is commonly performed as a component of many laparoscopic upper VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 419 A B Thoracoscopy The physiology of thoracic MIS (thoracoscopy) is different from that of laparoscopy. Because of the bony confines of the thorax, it is unnecessary to use positive pressure when working in the thorax.32 The disadvantages of positive pressure in the chest include decreased venous return, mediastinal shift, and the need to keep a firm seal at all trocar sites. Without positive pressure, it is necessary to place a double-lumen endotracheal tube so that the ipsilateral lung can be deflated when the operation starts. By collapsing the ipsilateral lung, working space within the thorax is obtained. Because insufflation is unnecessary in thoracoscopic surgery, it can be beneficial to use standard instruments via extended port sites in conjunction with thoracoscopic instruments. This approach is particularly useful when performing advanced procedures such as thoracoscopic anatomic pulmonary resection. Extracavitary Minimally Invasive Surgery Many MIS procedures create working spaces in extrathoracic and extraperitoneal locations. Laparoscopic inguinal ­hernia repair usually is performed in the anterior extraperitoneal Retzius space.33,34 Laparoscopic nephrectomy often is performed with retroperitoneal laparoscopy. Endoscopic retroperitoneal approaches to pancreatic necrosectomy have seen some limited use.35 Lower extremity vascular procedures and plastic surgical endoscopic procedures require the development of working space in unconventional planes, often at the level of the fascia, sometimes below the fascia, and occasionally in nonanatomic regions.36 Some of these techniques use insufflation of gas, but many use balloon inflation to develop the space, followed by low-pressure gas insufflation or lift devices to maintain the space (Fig. 14-2). These techniques produce fewer and less severe adverse physiologic consequences than does the pneumoperitoneum, but the insufflation of carbon dioxide into extraperitoneal locations can spread widely, causing subcutaneous emphysema and metabolic acidosis. Anesthesia Proper anesthesia management during laparoscopic surgery requires a thorough knowledge of the pathophysiology of the CO2 pneumoperitoneum.20 The laparoscopic surgeon can C Figure 14-2. Balloons are used to create extra-anatomic working spaces. In this example (A through C), a balloon is introduced into the space between the posterior rectus sheath and the rectus abdominal muscle. The balloon is inflated in the preperitoneal space to create working room for extraperitoneal endoscopic hernia repair. i­nfluence cardiovascular performance by reducing or removing the CO2 pneumoperitoneum. Insensible fluid losses are negligible, and therefore, IV fluid administration should not exceed that necessary to maintain circulating volume. MIS procedures are often outpatient procedures, so short-acting anesthetic agents are preferable. Because the factors that require hospitalization after laparoscopic procedures include the management of nausea, pain, and urinary retention, the anesthesiologist should minimize the use of agents that provoke these conditions and maximize the use of medications that prevent such problems. Critical to the anesthesia management of these patients is the use of nonnarcotic analgesics (e.g., ketorolac) when hemostasis allows it and the liberal use of antiemetic agents, including ondansetron and steroids. The Minimally Invasive Team From the beginning, the tremendous success of MIS was founded on the understanding that a team approach was necessary. The many laparoscopic procedures performed daily range from basic to advanced complexity, and require that the surgical team have an intimate understanding of the operative conduct (Table 14-1). Minimally invasive procedures require complicated and fragile equipment that demands constant maintenance. In addition, multiple intraoperative adjustments to the equipment, camera, insufflator, monitors, and patient/surgeon VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 14 Minimally Invasive Surgery abdominal procedures. If there is compromise of the mediastinal pleura with resultant CO2 pneumothorax, the defect should be enlarged so as to prevent a tension pneumothorax. Even with such a strategy, tension pneumothorax may develop, as mediastinal structures may seal the hole during inspiration, allowing the chest to fill during expiration. In addition to enlargement of the hole, a thoracostomy tube (chest tube) should be placed across the breach into the abdomen with intra-abdominal pressures reduced below 8 mmHg, or a standard chest tube may be placed. When a pneumothorax occurs with laparoscopic Nissen fundoplication or Heller myotomy, it is preferable to place an 18-French red rubber catheter with multiple side holes cut out of the distal end across the defect. At the end of the procedure, the distal end of the tube is pulled out a 10-mm port site (as the port is removed), and the pneumothorax is evacuated to a primitive water seal using a bowl of sterile water or saline. During laparoscopic esophagectomy, it is preferable to leave a standard chest tube, as residual intra-abdominal fluid will tend to be siphoned through the defect postoperatively, if the tube is removed at the end of the case. 420 Table 14-1 Laparoscopic surgical procedures PART I Basic Appendectomy Advanced Nissen fundoplication Lymph node dissection BASIC CONSIDERATIONS Cholecystectomy Heller myotomy Robotics Hernia repair Gastrectomy Stereo imaging Esophagectomy Telemedicine Enteral access Laparoscopy-assisted procedures Bile duct exploration Hepatectomy Colectomy Pancreatectomy Splenectomy Prostatectomy Adrenalectomy Hysterectomy Nephrectomy p­ osition are made during these procedures. As such, a coordinated team approach is mandated to ensure patient safety and excellent outcomes. More and more, flexible endoscopes are used to guide or provide quality control for laparoscopic procedures. As NOTES, SILS, and robotic surgery penetrate the operative theatre, hybrid procedures (laparoscopy and endoscopy) and complicated robotics cases will require a nursing staff capable of maintaining flexible endoscopes and understanding the operation of sophisticated technology. A typical MIS team may consist of a laparoscopic surgeon and an operating room (OR) nurse with an interest in laparoscopic and endoscopic surgery. Adding dedicated assistants and circulating staff with an intimate knowledge of the equipment will add to and enhance the team nucleus. Studies have demonstrated that having a designated laparoscopic team increases the efficiency and safety of laparoscopic surgery, which is translated into a benefit for patient and hospital.37 Room Setup and the Minimally Invasive Suite Nearly all MIS, whether using fluoroscopic, ultrasound, or optical imaging, incorporates a video monitor as a guide. Occasionally, two images are necessary to adequately guide the operation, as in procedures such as endoscopic retrograde cholangiopancreatography, laparoscopic common bile duct exploration, and laparoscopic ultrasonography. When two images are necessary, the images should be displayed on two adjacent video monitors or projected on a single screen with a picture-in-picture effect. The video monitor(s) should be set across the operating table from the surgeon. The patient should be interposed between the surgeon and the video monitor; ideally, the operative field also lies between the surgeon and the monitor. In pelviscopic surgery, it is best to place the video monitor at the patient’s feet, and in laparoscopic cholecystectomy, the monitor is placed at the 10 o’clock position (relative to the patient) while the surgeon stands on the patient’s left at the 4 o’clock position. The insufflating and patient-monitoring equipment ideally also is placed across the table from the surgeon, so that the insufflating pressure and the patient’s vital signs and end-tidal CO2 tension can be monitored. The development of the minimally invasive surgical suite has been a tremendous contribution to the field of laparoscopy Figure 14-3. An example of a typical minimally invasive surgery suite. All core equipment is located on easily movable consoles. in that it has facilitated the performance of advanced procedures and techniques (Fig. 14-3). By having the core equipment (monitors, insufflators, and imaging equipment) located within mobile, ceiling-mounted consoles, the surgery team is able to accommodate and make small adjustments rapidly and continuously throughout the procedure. The specifically designed minimally invasive surgical suite serves to decrease equipment and cable disorganization, ease the movements of operative personnel around the room, improve ergonomics, and facilitate the use of advanced imaging equipment such as laparoscopic ultrasound.38 Although having a minimally invasive surgical suite available is very useful, it is not essential to successfully carry out advanced laparoscopic procedures. Patient Positioning Patients usually are placed in the supine position for laparoscopic surgery. When the operative field is the gastroesophageal junction or the left lobe of the liver, it is easiest to operate from between the legs. The legs may be elevated in Allen stirrups or abducted on leg boards to achieve this position. When pelvic procedures are performed, it usually is necessary to place the legs in Allen stirrups to gain access to the perineum. A lateral decubitus position with the table flexed provides the best access to the retroperitoneum when performing nephrectomy or adrenalectomy. For laparoscopic splenectomy, a 45° tilt of the patient provides excellent access to the lesser sac and the lateral peritoneal attachments to the spleen. For thoracoscopic surgery, the patient is placed in the lateral position with table flexion to open the intercostal spaces and the distance between the iliac crest and costal margin (Fig. 14-4). Additional consideration must be made in robotic operations to position the patient appropriately before starting. Clashing of the robotic arms with surrounding equipment or each other can occur if not positioned correctly. Once the robot is docked to the patient, the bed cannot be moved without undocking. When the patient’s knees are to be bent for extended periods or the patient is going to be placed in a reverse Trendelenburg position for more than a few minutes, DVT prophylaxis should be used. Sequential compression of the lower extremities during prolonged (>90 minutes) laparoscopic procedures increases venous return and provides inhibition of thromboplastin activation. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ General Principles of Access The most natural ports of access for MIS and NOTES are the anatomic portals of entry and exit. The nares, mouth, urethra, and anus are used to access the respiratory, GI, and urinary systems. The advantage of using these points of access is that no incision is required. The disadvantages lie in the long distances between the orifice and the region of interest. For NOTES procedures, the vagina may serve as another point of access, entering the abdomen via the posterior cul-de-sac of the pelvis. Similarly, the peritoneal cavity may be reached through the side wall of the stomach or colon. Access to the vascular system may be accomplished under local anesthesia by cutting down and exposing the desired Laparoscopic Access The requirements for laparoscopy are more involved, because the creation of a pneumoperitoneum requires that instruments of access (trocars) contain valves to maintain abdominal inflation. Two methods are used for establishing abdominal access during laparoscopic procedures.39,40 The first, direct puncture laparoscopy, begins with the elevation of the relaxed abdominal wall with two towel clips or a well-placed hand. A small incision is made in the umbilicus, and a specialized spring-loaded (Veress) needle is placed in the abdominal cavity (Fig. 14-5). With the Veress needle, two distinct pops are felt as the surgeon passes the needle through the abdominal wall fascia and the peritoneum. The umbilicus usually is selected as the preferred Figure 14-5. A. Insufflation of the abdomen is accomplished with a Veress needle held at its serrated collar with a thumb and forefinger. B. Because the linea alba is fused to the umbilicus, the abdominal wall is grasped with fingers or penetrating towel clip to elevate the abdominal wall away from the underlying structures. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 421 CHAPTER 14 Minimally Invasive Surgery Figure 14-4. Proper padding and protection of pressure points is an essential consideration in laparoscopic and thoracoscopic approaches. In preparation for thoracoscopy, this patient is placed in left lateral decubitus position with the table flexed, which serves to open the intercostal spaces and increase the distance between the iliac crest and the inferior costal margin. vessel, usually in the groin. Increasingly, vascular access is obtained with percutaneous techniques using a small incision, a needle, and a guidewire, over which are passed a variety of different-sized access devices. This approach, known as the Seldinger technique, is most frequently used by general surgeons for placement of Hickman catheters, but also is used to gain access to the arterial and venous system for performance of minimally invasive procedures. Guidewire-assisted, Seldingertype techniques also are helpful for gaining access to the gut for procedures such as PEG, for gaining access to the biliary system through the liver, and for gaining access to the upper urinary tract. In thoracoscopic surgery, the access technique is similar to that used for placement of a chest tube. In these procedures, general anesthesia and single lung ventilation are essential. A small incision is made over the top of a rib and, under direct vision, carried down through the pleura. The lung is collapsed, and a trocar is inserted across the chest wall to allow access with a telescope. Once the lung is completely collapsed, subsequent access may be obtained with direct puncture, viewing all entry sites through the videoendoscope. Because insufflation of the chest is unnecessary, simple ports that keep the small incisions open are all that is required to allow repeated access to the thorax. 422 Peritoneum Blunt tip Hasson trocar Linea alba PART I BASIC CONSIDERATIONS Figure 14-6. It is essential to be able to interpret the insufflator pressure readings and flow rates. These readings indicate proper intraperitoneal placement of the Veress needle. point of access because, in this location, the abdominal wall is quite thin, even in obese patients. The abdomen is inflated with a pressure-limited insufflator. CO2 gas usually is used, with maximal pressures in the range of 14 to 15 mmHg. During the process of insufflation, it is essential that the surgeon observe the pressure and flow readings on the monitor to confirm an intraperitoneal location of the Veress needle tip (Fig. 14-6). Laparoscopic surgery can be performed under local anesthesia, but general anesthesia is preferable. Under local anesthesia, N2O is used as the insufflating agent, and insufflation is stopped after 2 L of gas is insufflated or when a pressure of 10 mmHg is reached. After peritoneal insufflation, direct access to the abdomen is obtained with a 5- or 10-mm trocar. The critical issues for safe direct-puncture laparoscopy include the use of a vented stylet for the trocar, or a trocar with a safety shield or dilating tip. The trocar must be pointed away from the sacral promontory and the great vessels.41 Patient position should be surveyed before trocar placement to ensure a proper trajectory. For performance of laparoscopic cholecystectomy, the trocar is angled toward the right upper quadrant. Occasionally, the direct peritoneal access (Hasson) technique is advisable.42 With this technique, the surgeon makes a small incision just below the umbilicus and under direct vision locates the abdominal fascia. Two Kocher clamps are placed on the fascia, and with curved Mayo scissors, a small incision is made through the fascia and underlying peritoneum. A finger is placed into the abdomen to make sure that there is no adherent bowel. A sturdy suture is placed on each side of the fascia and secured to the wings of a specialized trocar, which is then passed directly into the abdominal cavity (Fig. 14-7). Rapid insufflation can make up for some of the time lost with the initial dissection. This technique is preferable for the abdomen of patients who have undergone previous operations in which small bowel may be adherent to the undersurface of the abdominal wound. The close adherence of bowel to the peritoneum in the previously operated abdomen does not eliminate the possibility of intestinal injury but should make great vessel injury extremely unlikely. Because of the difficulties in visualizing the abdominal region immediately adjacent to the primary trocar, it is recommended that the telescope be passed through a Figure 14-7. The open laparoscopy technique involves identification and incision of the peritoneum, followed by the placement of a specialized trocar with a conical sleeve to maintain a gas seal. Specialized wings on the trocar are attached to sutures placed through the fascia to prevent loss of the gas seal. secondary trocar to inspect the site of initial abdominal access.40 Secondary punctures are made with 5- and 10-mm trocars. For safe access to the abdominal cavity, it is critical to visualize all sites of trocar entry.41,42 At the completion of the operation, all trocars are removed under direct vision, and the insertion sites are inspected for bleeding. If bleeding occurs, direct pressure with an instrument from another trocar site or balloon tamponade with a Foley catheter placed through the trocar site generally stops the bleeding within 3 to 5 minutes. When this is not successful, a full-thickness abdominal wall suture has been used successfully to tamponade trocar site bleeding. It is generally agreed that 5-mm trocars need no site suturing. Ten-millimeter trocars placed off the midline and above the transverse mesocolon do not require repair. Conversely, if the fascia has been dilated to allow the passage of the gallbladder or other organ, it should be repaired at the fascial level with interrupted sutures. The port site may be closed with suture delivery systems similar to crochet needles enabling mass closure of the abdominal wall. This is especially helpful in obese patients where direct fascial closure may be challenging, through a small skin incision. Failure to close lower abdominal trocar sites that are 10 mm in diameter or larger can lead to an incarcerated hernia. Access for Subcutaneous and Extraperitoneal Surgery There are two methods for gaining access to nonanatomic spaces. For retroperitoneal locations, balloon dissection is effective. This access technique is appropriate for the extraperitoneal repair of inguinal hernias and for retroperitoneal surgery for adrenalectomy, nephrectomy, lumbar discectomy, pancreatic necrosectomy, or para-aortic lymph node dissection.43,44 The initial access to the extraperitoneal space is performed in a way similar to direct puncture laparoscopy, except that the last layer (the peritoneum) is not traversed. Once the transversalis fascia has been punctured, a specialized trocar with a balloon on the end is introduced. The balloon is inflated in the extraperitoneal space to create a working chamber. The balloon then is deflated VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ A located, a long retractor that holds a 5-mm laparoscope allows the coaxial dissection of the vein and coagulation or clipping of each side branch. A small incision above the knee also can be used to ligate perforating veins in the lower leg. Subcutaneous access also is used for plastic surgery procedures.46 Minimally invasive approaches are especially well suited to cosmetic surgery, in which attempts are made to hide the incision. It is easier to hide several 5-mm incisions than one long incision. The technique of blunt dissection along fascial planes combined with lighted retractors and endoscope-holding retractors is most successful for extensive subcutaneous surgery. Some prefer gas insufflation of these soft tissue planes. The primary disadvantage of soft tissue insufflation is that subcutaneous emphysema can be created. Hand-Assisted Laparoscopic Access Hand-assisted laparoscopic surgery is thought to combine the tactile advantages of open surgery with the minimal access of laparoscopy and thoracoscopy. This approach commonly is used to assist with difficult cases before conversion to celiotomy is necessary. Additionally, hand-assisted laparoscopic surgery is used to help surgeons negotiate the steep learning curve associated with advanced laparoscopic procedures.47 This technology uses an entryway for the hand that preserves the pneumoperitoneum and enables laparoscopic visualization in combination with the use of minimally invasive instruments (Fig. 14-9). Formal investigation of this modality has been limited primarily to case reports and small series and has focused primarily on solid organ and colon surgery. Intraperitoneal, intrathoracic, and retroperitoneal access for robotic surgery adheres to the principles of laparoscopic and thoracoscopic access; however, the port size for the primary puncture is 12 mm to allow placement of the stereo laparoscope. Remaining trocars are 8 mm. Natural Orifice Transluminal Endoscopic Surgery Access Multiple studies have shown safety in the performance of NOTES procedures. Transvaginal, transvesicle, transanal, transcolonic, transgastric, and transoral approaches have all been attempted with varying success. The ease of decontamination, entry, and closure of these structures create variable challenges. The transvaginal approach for resection of the uterus has been employed for many years by gynecologists and has been modified by laparoscopists with great success. Extraction of the gallbladder, kidney, bladder, large bowel, and stomach can be performed via the vagina. The esophagus can be traversed to enter the mediastinum. Leaving the orifice or organ of entry with an endoscope requires the use of an endoscopic needle knife followed by submucosal tunneling or direct puncture and balloon dilation (Fig. 14-10). Closure has been performed using endoscopic clips or sutures with advanced endoscopic platforms. B Figure 14-8. A. With two small incisions, virtually the entire saphenous vein can be harvested for bypass grafting. B. The lighted retractor in the subcutaneous space during saphenous vein harvest is seen illuminating the skin. (Reproduced with permission of­ Taylor & Francis, LLC from Jones GE, Eaves FE III, Howell RL, et al. Harvest of muscle, nerve, fascia, and vein. In: Bostwick J III, Eaves FE III, Nahai F, eds. Endoscopic Plastic Surgery. St Louis: Quality Medical Publishing, Inc.: Quality Medical Publishing, Inc.; 1995:542. Permission conveyed through Copyright Clearance Center, Inc.) Single-Incision Laparoscopic Surgery Access There is no standardized approach for SILS, and access techniques vary by surgeon preference. Traditionally, a single skin incision is made directly through the umbilical scar ranging from 1 to 3 cm. Through this single incision, multiple low-profile trocars can be placed separately into the fascia to allow insufflation, camera, and working instruments. The advantage of this technique is that conventional laparoscopic tools can be employed. The disadvantage becomes apparent when an extraction site VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 423 CHAPTER 14 Minimally Invasive Surgery and a Hasson trocar is placed. An insufflation pressure of 10 mmHg usually is adequate to keep the extraperitoneal space open for dissection and will limit subcutaneous emphysema. Higher gas pressures force CO2 into the soft tissues and may contribute to hypercarbia. Extraperitoneal endosurgery provides less working space than laparoscopy but eliminates the possibility of intestinal injury, intestinal adhesion, herniation at the trocar sites, and ileus. These issues are important for laparoscopic hernia repair because extraperitoneal approaches prevent the small bowel from sticking to the prosthetic mesh.34 Subcutaneous surgery has been most widely used in cardiac, vascular, and plastic surgery.36 In cardiac surgery, subcutaneous access has been used for saphenous vein harvesting, and in vascular surgery for ligation of subfascial perforating veins (Linton procedure). With minimally invasive techniques, the entire saphenous vein above the knee may be harvested through a single incision (Fig. 14-8).45,46 Once the saphenous vein is 424 PART I BASIC CONSIDERATIONS Figure 14-9. This is an example of hand-assisted laparoscopic surgery during left colectomy. The surgeon uses a hand to provide retraction and counter tension during mobilization of the colon from its retroperitoneal attachments, as well as during division of the mesocolon. This technique is particularly useful in the region of the transverse colon. is needed. A variety of specialized multilumen trocars are on the market that can be placed through the umbilical ring48 (Fig. 14-11A,B). The advantages of these devices include faster access, improved safety, minimization of air leaks, and platform-derived instrument triangulation. The major disadvantage is cost. A Port Placement Trocars for the surgeon’s left and right hand should be placed at least 10 cm apart. For most operations, it is possible to o­ rient the telescope between these two trocars and slightly back from them. The ideal trocar orientation creates an equilateral ­triangle B C D E Figure 14-10. Submucosal tunnel technique for transesophageal mediastinoscopy. (Reproduced with permission from Khashab MA, Kalloo AN. NOTES: current status and new horizons. Gastroenterology. 2012;142:704-710. © 2012 by the AGA Institute.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 425 A Multiple trocars through single skin incision B Figure 14-11. A. Specialized multilumen trocars can facilitate instrument placement. B. For single-incision laparoscopic surgery, multiple fascial punctures can be performed via a single skin incision. (Illustration by Corinne Sandone. © 2014 JHU. Reprinted with permission.) between the surgeon’s right hand, left hand, and the telescope, with 10 to 15 cm on each leg. If one imagines the target of the operation (e.g., the gallbladder or gastroesophageal junction) oriented at the apex of a second equilateral triangle built on the first, these four points of reference create a diamond (Fig. 14-12). The surgeon stands behind the telescope, which provides optimal ergonomic orientation but frequently requires that a camera operator (or mechanical camera holder) reach between the surgeon’s hands to guide the telescope. SILS is challenging for even the experienced laparoscopist because it violates most of the aforementioned ergonomic principles. Having only a single point of entry into the abdominal cavity creates an inherently crowded port and hand position. The inability to space trocars severely limits the ability to triangulate the left and right hand instruments. As a result, the surgeon must often work in a crossed hands fashion (Fig. 14-13). Additionally, the axis of the camera view is often in line with the working instruments, making visualization difficult without a deflectable tip laparoscope. The position of the operating table should permit the surgeon to work with both elbows in at the sides, with arms bent 90° at the elbow.49 It usually is necessary to alter the operating table position with left or right tilt with the patient in the Trendelenburg or reverse Trendelenburg position, depending on the operative field.50,51 Imaging Systems Two methods of videoendoscopic imaging are widely used. Both methods use a camera with a CCD, which is an array of photosensitive sensor elements (pixels) that convert the incoming light intensity to an electric charge. The electric charge is subsequently converted into a black-and-white image.52 With videoendoscopy, the CCD chip is placed on the internal end of a long, flexible endoscope. With older f­lexible endoscopes, thin quartz fibers are packed together in a bundle, and the CCD camera is mounted on the external end of the endoscope. Most standard GI endoscopes have the CCD chip at the distal THE DIAMOND OF SUCCESS "Second base" (hiatal hernia) "Third base" (L hand) 15 cm "First base" (R hand) "Home plate" (telescope) Figure 14-12. The diamond configuration created by placing the telescope between the left and the right hand, recessed from the target by about 15 cm. The distance between the left and the right hand is also ideally 10 to 15 cm. In this “baseball diamond” configuration, the surgical target occupies the second base position. Figure 14-13. The single point of abdominal entry for trocars often requires that the surgeon work in a crossed hands fashion. (Illustration by Corinne Sandone. © 2014 JHU. Reprinted with permission.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 14 Minimally Invasive Surgery Single port accommodates multiple trocars 426 PART I BASIC CONSIDERATIONS end, but small, delicate choledochoscopes and nephroscopes are equipped with fiber-optic bundles.53 Distally mounted CCD chips were developed for laparoscopy as well but remain very expensive and therefore have not become as widely used. Video cameras come in two basic designs. Nearly all laparoscopic cameras contain a red, green, and blue input, and are identical to the color cameras used for television production.52 An additional feature of many video cameras is digital enhancement. Digital enhancement detects edges, areas where there are drastic color or light changes between two adjacent pixels.54 By enhancing this difference, the image appears sharper and surgical resolution is improved. New laparoscopic cameras contain a high-definition (HD) chip, which increases the lines of resolution from 480 to 1080 lines. To enjoy the benefit of the clarity of HD video imaging, HD monitors also are necessary. Priorities in a video imaging system for MIS are illumination first, resolution second, and color third. Without the first two attributes, video surgery is unsafe. Illumination and resolution are as dependent on the telescope, light source, and light cable as on the video camera used. Imaging for laparoscopy, thoracoscopy, and subcutaneous surgery uses a rigid metal telescope, usually 30 cm in length. Longer telescopes are available for obese patients and for reaching the mediastinum and deep in the pelvis from a periumbilical entry site. The standard telescope contains a series of quartz optical rods and focusing lenses.55 Telescopes vary in size from 2 to 12 mm in diameter. Because light transmission is dependent on the cross-sectional area of the quartz rod, when the diameter of a rod/lens system is doubled, the illumination is quadrupled. Little illumination is needed in highly reflective, small spaces such as the knee, and a very small telescope will suffice. When working in the abdominal cavity, especially if blood is present, the full illumination of a 10-mm telescope usually is necessary. Rigid telescopes may have a flat or angled end. The flat end provides a straight view (0°), and the angled end provides an oblique view (30° or 45°).52 Angled telescopes allow greater flexibility in viewing a wider operative field through a single trocar site (Fig. 14-14A); rotating an angled telescope changes the field of view. The use of an angled telescope has distinct advantages for most videoendoscopic procedures, particularly in visualizing the common bile duct during laparoscopic Figure 14-14. A. The laparoscope tips come in a variety of angled configurations. All laparoscopes have a 70° field of view. A 30°-angled scope enables the surgeon to view this field at a 30° angle to the long axis of the scope. cholecystectomy or visualizing the posterior esophagus or the tip of the spleen during laparoscopic fundoplication. Flexible tip laparoscopes offer even greater optical freedom. Light is delivered to the endoscope through a fiber-optic light cable. These light cables are highly inefficient, losing >90% of the light delivered from the light source. Extremely bright light sources (300 watts) are necessary to provide adequate illumination for laparoscopic surgery. The quality of the videoendoscopic image is only as good as the weakest component in the imaging chain (Fig. 14-15). Therefore, it is important to use a video monitor that has a ­resolution equal to or greater than the camera being used.55 ­Resolution is the ability of the optical system to distinguish between line pairs. The larger the number of line pairs per millimeter, the sharper and more detailed the image. Most high-­resolution monitors have up to 700 horizontal lines. HD television can deliver up to eight times more resolution than standard monitors; when combined with digital enhancement, a very sharp and well-defined image can be achieved.52,55 A heads-up display is a high-resolution liquid crystal monitor that is built into eyewear worn by the surgeon.56 This technology allows the surgeon to view the endoscopic image and operative field simultaneously. The proposed advantages of headsup display include a high-resolution monocular image, which affords the surgeon mobility and reduces vertigo and eyestrain. However, this technology has not yet been widely adopted. Interest in three-dimensional (3-D) laparoscopy has waxed and waned. 3-D laparoscopy provides the additional depth of field that is lost with two-dimensional endosurgery and improves performance of novice laparoscopists performing complex tasks of dexterity, including suturing and knot tying.57 The advantages of 3-D systems are less obvious to experienced laparoscopists. Additionally, because 3-D systems require the flickering of two similar images, which are resolved with special glasses, the images’ edges become fuzzy and resolution is lost. The optical accommodation necessary to rectify these slightly differing images is tiring and may induce headaches when one uses these systems for a long period of time. The da Vinci robot uses a specialized laparoscope with two optical bundles on opposite sides of the telescope. A specialized binocular eyepiece receives input from two CCD chips, each capturing the image from one of the two quartz rod lens systems, thereby creating true 3-D imaging without needing to employ active or passive technologies that have made 3-D laparoscopy so disappointing. Single-incision laparoscopy presents new challenges to visualization of the operative field. In the traditional laparoscope, the light source enters the scope at a 90° angle. That position coupled with a bulky scope handle creates crowding in an already limited space. Additionally, because the scope and instruments enter the abdomen at the same point, an adequate perspective is often unobtainable even with a 30° scope. The advent of increased length laparoscopes with lighting coming from the end and a deflectable tip now allows the surgeon to re-create a sense of internal triangulation with little compromise externally. The ability to move the shaft of the scope off line while maintaining the same image provides a greater degree of freedom for the working ports. Energy Sources for Endoscopic and Endoluminal Surgery Many MIS procedures use conventional energy sources, but the benefits of bloodless surgery to maintain optimal visualization VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 427 Lamp Light source Monitor Light guide cable Camera controller Image formed by objective lens Illumination light guide Adaption optic Relayed image Camera objective lens Observation position Focus ring Objective lens section Relay lens section CCD chip Eyepiece lens section Figure 14-15. The Hopkins rod lens telescope includes a series of optical rods that effectively transmit light to the eyepiece. The video camera is placed on the eyepiece to provide the working image. The image is only as clear as the weakest link in the image chain. CCD = charge-coupled device. (Reproduced with permission from Prescher et al.52 Copyright Elsevier.) have spawned new ways of applying energy. The most common energy source is RF electrosurgery using an alternating current with a frequency of 500,000 cycles/s (Hz). Tissue ­heating ­progresses through the well-known phases of coagulation (60°C [140°F]), vaporization and desiccation (100°C [212°F]), and carbonization (>200°C [392°F]).58 The two most common methods of delivering RF electrosurgery are with monopolar and bipolar electrodes. With monopolar electrosurgery, a remote ground plate on the patient’s leg or back receives the flow of electrons that originate at a point source, the surgical electrode. A fine-tipped electrode causes a high current density at the site of application and rapid tissue heating. Monopolar electrosurgery is inexpensive and easy to modulate to achieve different tissue effects.59 A short-duration, high-voltage discharge of current (coagulation current) provides extremely rapid tissue heating. Lower-voltage, higher-wattage current (cutting current) is better for tissue desiccation and vaporization. When the surgeon desires tissue division with the least amount of thermal injury and least coagulation necrosis, a cutting current is used. With bipolar electrosurgery, the electrons flow between two adjacent electrodes. The tissue between the two electrodes is heated and desiccated. There is little opportunity for tissue cutting when bipolar current is used alone, but the ability to coapt the electrodes across a vessel provides the best method of small-vessel coagulation without thermal injury to adjacent tissues60 (Fig. 14-16). Advanced laparoscopic device manufacturers have leveraged the ability to selectively use bipolar energy and combined it with compressive force and a controllable blade to create a number of highly functional dissection and vesselsealing tools. To avoid thermal injury to adjacent structures, the laparoscopic field of view must include all uninsulated portions of the electrosurgical electrode. In addition, the integrity of the insulation must be maintained and assured. Capacitive coupling occurs when a plastic trocar insulates the abdominal wall from the current; in turn, the current is bled off of a metal sleeve or laparoscope into the viscera54 (Fig. 14-17A). This may result in thermal necrosis and a delayed fecal fistula. Another potential mechanism for unrecognized visceral injury may occur with the direct coupling of current to the laparoscope and adjacent bowel58 (Fig. 14-17B). Another method of delivering RF electrosurgery is argon beam coagulation. This is a type of monopolar electrosurgery in which a uniform field of electrons is distributed across a tissue surface by the use of a jet of argon gas. The argon gas jet distributes electrons more evenly across the surface than does spray Figure 14-16. An example of bipolar coagulation devices. The flow of electrons passes from one electrode to the other, and the intervening tissue is heated and desiccated. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 14 Minimally Invasive Surgery Condensor lens 428 Conduction through ungrounded telescope Capacitive coupled fault condition PART I Plastic collar over metal trocar Cannula Te les co p e Plastic cannula B A Figure 14-17. A. Capacitive coupling occurs as a result of high current density bleeding from a port sleeve or laparoscope into adjacent bowel. B. Direct coupling occurs when current is transmitted directly from the electrode to a metal instrument or laparoscope, and then into adjacent tissue. (Reproduced with permission from Odell.58) electrofulguration. This technology has its greatest application for coagulation of diffusely bleeding surfaces such as the cut edge of liver or spleen. It is of less value in laparoscopic procedures because the increased intra-abdominal pressures created by the argon gas jet can increase the chances of a gas embolus. It is paramount to vent the ports and closely monitor insufflation pressure when using this source of energy within the context of laparoscopy. With endoscopic endoluminal surgery, RF alternating current in the form of a monopolar circuit represents the mainstay for procedures such as snare polypectomy, sphincterotomy, lower esophageal sphincter ablation, and biopsy. 61,62 A grounding (return) electrode is necessary for this form of energy. B ­ ipolar electrocoagulation is used primarily for thermal hemostasis. The electrosurgical generator is activated by a foot pedal so the endoscopist may keep both hands free during the ­endoscopic procedure. Gas, liquid, and solid-state lasers have been available for medical application since the mid-1960s.63 The CO2 laser (wavelength 10.6 μm) is most appropriately used for cutting and superficial ablation of tissues. It is most helpful in locations unreachable with a scalpel such as excision of vocal cord granulomas. The CO2 laser beam must be delivered with a series of mirrors and is therefore somewhat cumbersome to use. The next most popular laser is the neodymium yttrium-aluminum garnet (Nd:YAG) laser. Nd:YAG laser light is 1.064 μm (1064 nm) in wavelength. It is in the near-infrared portion of the spectrum and, like CO2 laser light, is invisible to the naked eye. A unique feature of the Nd:YAG laser is that 1064-nm light is poorly absorbed by most tissue pigments and therefore travels deep into tissue.64 Deep tissue penetration provides deep tissue heating (Fig. 14-18). For this reason, the Nd:YAG laser is capable of the greatest amount of tissue destruction with a single application.63 Such capabilities make it the ideal laser for destruction of large fungating tumors of the rectosigmoid, tracheobronchial tree, or esophagus. A disadvantage is that the deep tissue heating may cause perforation of a hollow viscus. When it is desirable to coagulate flat lesions in the cecum, a different laser should be chosen. The frequency-doubled Nd:YAG laser, also known as the KTP laser (potassium thionyl phosphate crystal is used to double the Nd:YAG frequency), provides 532-nm light. This is in the green portion of the spectrum, and at this wavelength, selective absorption by red pigments in tissue (such as hemangiomas and arteriovenous malformations) is optimal. The depth of tissue heating is intermediate, between those of the CO2 and the Nd:YAG lasers. Coagulation (without vaporization) of superficial vascular lesions can be obtained without intestinal perforation.64 106 105 Absorption coefficient BASIC CONSIDERATIONS Capacitively coupled energy to metal cannula H2O 1064 nm 104 H2O 103 Me 102 lan in 101 HbO2 1 10–1 10–2 100 UV Visible Infared 1000 Wavelength (nm) 10,000 Figure 14-18. This graph shows the absorption of light by various tissue compounds (water, melanin, and oxyhemoglobin) as a function of the wavelength of the light. The nadir of the oxyhemoglobin and melanin curves is close to 1064 nm, the wavelength of the neodymium yttrium-aluminum garnet laser. (Reproduced with permission from Hunter JG, Sackier JM, eds. Minimally Invasive Surgery. New York: McGraw-Hill; 1993:28.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Instrumentation Hand instruments for MIS usually are duplications of conventional surgical instruments made longer, thinner, and smaller at the tip. It is important to remember that when grasping tissue with laparoscopic instruments, a greater force is applied over a smaller surface area, which increases the risk for perforation or injury.69 Certain conventional instruments such as scissors are easy to reproduce with a diameter of 3 to 5 mm and a length of 20 to 45 cm, but other instruments such as forceps and clamps cannot provide remote access. Different configurations of graspers were developed to replace the various configurations of surgical forceps and clamps. Standard hand instruments are 5 mm in diameter and 30 cm in length, but smaller and shorter hand instruments are now available for pediatric surgery, for microlaparoscopic surgery, and for arthroscopic procedures.69 A unique laparoscopic hand instrument is the monopolar electrical hook. This device usually is configured with a suction and irrigation apparatus to eliminate smoke and blood from the operative field. The monopolar hook allows tenting of tissue over a bare metal wire with subsequent coagulation and division of the tissue. Instrumentation for NOTES is still evolving, but many long micrograspers, microscissors, electrocautery adapters, suturing devices, clip appliers, and visceral closure devices are in design and application. These instruments often require an entirely different endoscopic platform requiring manipulation by a surgeon and assistant to accomplish complex maneuvers. Techniques such as mucosotomy, hydrodissection, and clip application require specialized training. The sheer size of the instrumentation often requires an overtube to allow easy exchange throughout the procedure. Instrumentation for SILS seeks to restore the surgeon’s ability to triangulate the left and right hands through variation in length, mechanical articulation, or curved design. Additionally, a lower profile camera head helps reduce the instrument crowding that occurs at the single point of abdominal entry. Robotic Surgery The term robot defines a device that has been programmed to perform specific tasks in place of those usually performed by people. The devices that have earned the title “surgical robots” would be more aptly termed computer-enhanced surgical devices, as they are controlled entirely by the surgeon for the purpose of improving performance. The first computerassisted surgical device was the laparoscopic camera holder (Aesop, Computer Motion, Goleta, CA), which enabled the surgeon to maneuver the laparoscope either with a hand control, foot control, or voice activation. Randomized studies with such camera holders demonstrated a reduction in operative time, steadier image, and a reduction in the number of required laparoscope cleanings.70 This device had the advantage of eliminating the need for a human camera holder, which served to free valuable OR personnel for other duties. This technology has now been eclipsed by simpler systems using passive positioning of the camera with a mechanical arm, but the benefits of a steadier image and fewer members of the OR team remain. The major revolution in robotic surgery was the development of a master-slave surgical platform that returned the wrist to laparoscopic surgery and improved manual dexterity by developing an ergonomically comfortable work station, with 3-D imaging, tremor elimination, and scaling of movement (e.g., large, gross hand movements can be scaled down to allow suturing with microsurgical precision) (Fig. 14-19). The most recent iteration of the robotic platform features a second console slave enabling greater assisting and teaching opportunities. The surgeon is physically separated from the operating table, and the working arms of the device are placed over the patient (Fig. 14-20). An assistant remains at the bedside and changes the instruments as needed, providing retraction as needed to facilitate the procedure. The robotic platform (da Vinci, Intuitive Surgical, Sunnyvale, CA) was initially greeted with VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 429 CHAPTER 14 Minimally Invasive Surgery In flexible GI endoscopy, the CO2 and Nd:YAG lasers have largely been replaced by heater probes and endoluminal stents. The heater probe is a metal ball that is heated to a temperature (60–100°C [140°–212°F]) that allows coagulation of bleeding lesions without perforation. Photodynamic therapy is a palliative treatment for obstructing cancers of the GI tract.65 Patients are given an IV dose of porfimer sodium, which is a photosensitizing agent that is taken up by malignant cells. Two days after administration, the drug is endoscopically activated using a laser. The activated porfimer sodium generates oxygen free radicals, which kill the tumor cells. The tumor is later endoscopically débrided. The use of this modality for definitive treatment of early cancers is in experimental phases and has yet to become established. A unique application of laser technology provides extremely rapid discharge (<10–6 s) of large amounts of energy (>103 volts). These high-energy lasers, of which the pulsed dye laser has seen the most clinical use, allow the conversion of light energy to mechanical disruptive energy in the form of a shock wave. Such energy can be delivered through a quartz fiber, and with rapid repetitive discharges, can provide sufficient shock-wave energy to fragment kidney stones and gallstones.66 Shock waves also may be created with miniature electric sparkplug discharge systems known as electrohydraulic lithotriptors. These devices also are inserted through thin probes for e­ ndoscopic application. Lasers have the advantage of pigment selectivity, but electrohydraulic lithotriptors are more popular because they are substantially less expensive and are more compact. Methods of producing shock waves or heat with ultrasonic energy are also of interest. Extracorporeal shockwave lithotripsy creates focused shock waves that intensify as the focal point of the discharge is approached. When the focal point is within the body, large amounts of energy are capable of fragmenting stones. Slightly different configurations of this energy can be used to provide focused internal heating of tissues. Potential applications of this technology include the ability to noninvasively produce sufficient internal heating to destroy tissue without an incision. A third means of using ultrasonic energy is to create rapidly oscillating instruments that are capable of heating tissue with friction; this technology represents a major step forward in energy technology.67 An example of its application is the laparoscopic coagulation shears device (Harmonic Scalpel), which is capable of coagulating and dividing blood vessels by first occluding them and then providing sufficient heat to weld the blood vessel walls together and to divide the vessel. This nonelectric method of coagulating and dividing tissue with a minimal amount of collateral damage has facilitated the performance of numerous endosurgical procedures.68 It is especially useful in the control of bleeding from medium-sized vessels that are too big to manage with monopolar electrocautery and require bipolar desiccation followed by cutting. 430 PART I BASIC CONSIDERATIONS Figure 14-19. Robotic instruments and hand controls. The surgeon is in a sitting position, and the arms and wrists are in an ergonomic and relaxed position. some skepticism by expert laparoscopists, as it was difficult to prove additional value for operations performed with the da Vinci robot. Not only were the operations longer and the equipment more expensive, but additional quality could not be demonstrated. Two randomized controlled trials compared robotic and conventional laparoscopic approaches to Nissen fundoplication.71,72 In both of these trials, the operative time was longer for robotic surgery, and there was no difference in ultimate outcome. Similar results were achieved for laparoscopic cholecystectomy.73 Nevertheless, the increased dexterity provided by the da Vinci robot convinced many surgeons and health administrators that robotic platforms were worthy of investment, for marketing purposes if for no other reason. The success story for computer-enhanced surgery with the da Vinci started with cardiac surgery and migrated to the 3 ­pelvis. Mitral valve surgery, performed with right thoracoscopic access, became one of the more popular procedures performed with the robot.74 To date, a myriad of publications have demonstrated success performing procedures from thyroidectomies to colectomies with total mesorectal excision. Almost any procedure performed laparoscopically has been attempted robotically, although true advantage is demonstrated only very sparingly. In most cases, increased cost and operative time challenge the notion of “better.” The tidal wave of enthusiasm for robotic surgery came when most minimally invasive urologists declared robotic prostatectomy to be preferable to laparoscopic and open prostatectomy.75 The great advantage—it would appear—of robotic Figure 14-20. Room setup and position of surgeon and assistant for robotic surgery. (©2013 Intuitive Surgical, Inc. Reprinted with permission.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Endoluminal and Endovascular Surgery The fields of vascular surgery, interventional radiology, neuroradiology, gastroenterology, general surgery, pulmonology, and urology all encounter clinical scenarios that require the urgent restoration of luminal patency. Based on this need, fundamental techniques have been pioneered that are applicable to all specialties and virtually every organ system. As a result, all minimally invasive surgical procedures, from coronary artery angioplasty to palliation of pancreatic malignancy, involve the use of access devices, catheters, guidewires, balloon dilators, stents, and other devices (e.g., lasers, atherectomy catheters) that are capable of opening up the occluded biologic cylinder77 (Table 14-2). Endoluminal balloon dilators may be inserted through an endoscope, or they may be fluoroscopically guided. Balloon dilators all have low compliance—that is, the balloons do not stretch as the pressure within the balloon is increased. The high pressures achievable in the balloon create radial expansion of the narrowed vessel or orifice, usually disrupting the atherosclerotic plaque, the fibrotic stricture, or the muscular band (e.g., esophageal achalasia).78 Once the dilation has been attained, it is frequently beneficial to hold the lumen open with a stent.79 Stenting is particularly valuable in treating malignant lesions and atherosclerotic occlusions or aneurysmal disease (Fig. 14-21). Stenting is also of value to seal leaky cylinders, including aortic dissections, traumatic vascular injuries, leaking GI anastomoses, and fistulas. Stenting usually is not applicable for long-term management of benign GI strictures except in patients with limited life expectancy (Fig. 14-22).79–81 A variety of stents are available that are divided into six basic categories: plastic stents, metal stents, drug-eluting stents (to decrease fibrovascular hyperplasia), covered metal stents, anchored stent grafts, and removable covered plastic stents80 (Fig. 14-23). Plastic stents came first and are used widely as endoprostheses for temporary bypass of obstructions in the biliary or urinary systems. Metal stents generally are delivered over a balloon and expanded with the balloon to the desired size. These metal stents usually are made of titanium or nitinol and are still used in coronary stenting. A chemotherapeutic agent Guidewire Guid Gu ide id ew Balloon Ballllo Ba Bal llo Sheath She Sh Table 14-2 Modalities and techniques of restoring luminal patency Modality Technique Core out Photodynamic therapy Laser Coagulation Endoscopic biopsy forceps Chemical Ultrasound Ultrasound Endoscopic biopsy Balloon Fracture Balloon Ball lloon with stent Stent Sten St e t expanded Dilate Balloon Bougie Angioplasty Endoscope Bypass Transvenous intrahepatic portosystemic shunt Surgical (synthetic or autologous conduit) Stent Self-expanding metal stent Plastic stent Stent in place Figure 14-21. The deployment of a metal stent across an ­isolated vessel stenosis is illustrated. (Reproduced with permission from Hunter JG, Sackier JM, eds. Minimally Invasive Surgery. New York: McGraw-Hill; 1993:235.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 431 CHAPTER 14 Minimally Invasive Surgery prostatectomy is the ability to visualize and spare the pelvic nerves responsible for erectile function. In addition, the creation of the neocystourethrotomy, following prostatectomy, was greatly facilitated by needle holders and graspers with a wrist in them. Female pelvic surgery with the da Vinci robot is also reaching wide appeal. The magnified imaging provided makes this approach ideal for microsurgical tasks such as reanastomosis of the Fallopian tubes. The final frontier for computer-enhanced surgery is the promise of telesurgery, in which the surgeon is a great distance from the patient (e.g., combat or space). This application has rarely been used, as the safety provided by having the surgeon at bedside cannot be sacrificed to prove the concept. However, remote laparoscopic cholecystectomy has been performed when a team of surgeons located in New York performed a cholecystectomy on a patient located in France.76 metal stents are use to prevent tissue ingrowth. Ingrowth may be an advantage in preventing stent migration, but such tissue ingrowth may occlude the lumen and cause obstruction anew. This is a particular problem when stents are used for palliation of GI malignant growth and may be a problem for the longterm use of stents in vascular disease. Filling the interstices with Silastic or other materials may prevent tumor ingrowth but also makes stent migration more likely. In an effort to minimize stent migration, stents have been incorporated with hooks and barbs at the proximal end of the stent to anchor it to the wall of the vessel. Endovascular stenting of aortic aneurysms has nearly replaced open surgery for this condition. Lastly, selfexpanding plastic stents have been developed as temporary devices to be used in the GI tract to close internal fistulas and bridge leaking anastomoses. 432 PART I BASIC CONSIDERATIONS Natural Orifice Transluminal Endoscopic Surgery Figure 14-22. This is an esophagram in a patient with severe dysphagia secondary to advanced esophageal cancer (A) before and (B) after placement of a covered self-expanding metal stent. was added to coronary stents several years ago to decrease endothelial proliferation. These drug-eluting stents provide greater long-term patency but require long-term anticoagulation with antiplatelet agents to prevent thrombosis.82 Coated Figure 14-23. Covered self-expanding metal stents. These devices can be placed fluoroscopically or endoscopically. The use of the flexible endoscope to enter the GI, urinary, or reproductive tracts and then traverse the wall of the structure to enter the peritoneal cavity, the mediastinum, or the chest has strong appeal to patients wishing to avoid scars and pain caused by abdominal wall trauma. In truth, transluminal surgery 4 has been performed in the stomach for a long time, either from the inside out (e.g., percutaneous, PEG, and transgastric pseudocyst drainage) or from the outside in (e.g., laparoscopic assisted intragastric tumor resection). The catalyzing events for NOTES were the demonstration that a porcine gallbladder could be removed with a flexible endoscope passed through the wall of the stomach and then removed through the mouth, and the demonstration in a series of 10 human cases from India of the ability to perform transgastric appendectomy. Since that time, a great deal of money has been invested by endoscopic and MIS companies to help surgeons and gastroenterologists explore this new territory. Systemic inflammatory markers such as C-reactive protein, tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6 have been shown to be similar in transgastric and transcolonic NOTES when compared to laparoscopy in porcine models.83 Concerns about the safety of transluminal access and limitations in equipment remain the greatest barriers to expansion. To date, the most headline-grabbing procedures have been the transvaginal and transgastric removal of the gallbladder84–86 (Fig. 14-24). To ensure safety, all human cases thus far have involved laparoscopic assistance to aid in retraction and ensure adequate closure of the stomach or vagina. To date, thousands of transvaginal and transgastric procedures have been performed internationally, with two large registries demonstrating noninferiority to conventional laparoscopy.87 The fact that the vast majority of these procedures are being done transvaginally creates an obvious limitation in applicability. The rapid growth of endoscopic technology catalyzed by NOTES has already spun off new technologies capable of performing a wide variety of endoscopic surgical procedures from EMR, to ablation of Barrett’s esophagus, to creation of competent antireflux valves in patients with gastroesophageal reflux disease. POEM has shown promise as a NOTES treatment for esophageal achalasia.88 In this procedure, a 1.5- to 2-cm mucosotomy is created within the anterior esophagus 10 cm proximal to the gastroesophageal junction. A submucosal tunnel is then created using a combination of electrocautery, hydrodissection, and carbon dioxide insufflation. The scope is advanced VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 433 CHAPTER 14 Minimally Invasive Surgery Figure 14-24. Transgastric cholecystectomy using natural orifice transluminal endoscopic surgery technology and one to three laparoscopic ports has been performed occasionally in several locations around the world. (Illustration by Jennifer Fairman. © 2007 JHU. Reprinted with permission.) beyond the gastroesophageal junction, and a circular myotomy is performed avoiding disruption of the longitudinal fibers. The mucosotomy is then closed using endoscopic clips (Fig. 14-25). Over 1000 clinical POEM cases have been performed worldwide. Data from expert NOTES surgeons s­ uggest that this selective myotomy avoids abdominal trauma and minimally disrupts the normal anatomic characteristics of the gastroesophageal junction while providing significant relief of symptoms.89 Randomized clinical trials and long-term follow-up need to be performed to further evaluate efficacy. Although this application is still considered experimental, there is little doubt that when equivalent operations can be performed with less pain, fewer scars, and less disability, patients will flock to it. NOTES procedures are associated with an increased mental workload and significant learning curve for even experienced surgical endoscopists. Surgeons should engage only when they can perform these procedures with the safety and efficacy demanded by our profession. Single-Incision Laparoscopic Surgery As a surgical technique, SILS seems to be a natural progression from conventional laparoscopic surgery. As surgeons sought to reduce the number and size of abdominal wall trocars and NOTES procedures necessitated laparoscopic surveillance, the idea of a hybridization took off. An incision in the umbilicus, a preexisting scar, is thought to be less painful, have fewer wound complications, lead to quicker return to activity, and have a better cosmetic appearance than conventional laparoscopy. P ­ erhaps one of the earliest examples of SILS is the application of laparoscopic instrumentation to resect lesions in the rectum or sigmoid colon. Using the anus as the portal of entry, transanal endoscopic microsurgery (TEMS) employs a specialized multichannel trocar to reach lesions located 8 to 18 cm away from the anal verge (Fig. 14-26). More deformable versions of these complex trocars have been developed with features to allow insufflation and be amenable to maintaining a seal within the natural orifice of the umbilicus (see Fig. 14-11). Ports typically contain three or four channels. The latter often affords the ability to place a dedicated retractor. There are many challenges faced by the operating surgeon in SILS procedures. These include crowded trocar placement, a lack of triangulation of left and right hand instruments, 5 frequent crossing or clashing of instruments, limited visualization, and limited retraction ability. These challenges are mitigated by surgeon experience and the development of specialized instruments. Articulating or curved instruments of varying lengths and an extended length can improve working space. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 434 PART I BASIC CONSIDERATIONS A Figure 14-27. Example of curved instruments used in single-incision laparoscopic surgery. (©2013 Intuitive Surgical, Inc. Reprinted with permission.) B Figure 14-25. A. Peroral endoscopic esophageal myotomy for the treatment of achalasia. B. Serial images showing overtube in submucosal tunnel, using needle knife to divide circular muscle fibers of esophagus, and closure of myotomy with clips. (A. From Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy. 2010;42:265271. Thieme. B. From Rieder E, Dunst CM, Kastenmeier AS, et al. Development and technique of peroral endoscopic myotomy (POEM) for achalasia. Eur Surg. 2011;43/3:140-145. With kind permission from Springer Science + Business Media.) Curved instruments are typically reusable and offer less clutter than their more sophisticated counterparts, providing some cost reduction (Fig. 14-27). A low-profile HD scope with or without a deflectable tip can improve visualization greatly. Even with such instrumentation, the learning curve is very steep, particularly when the surgeon is forced to work in a cross-handed technique. The accomplished SILS surgeon will possess a tool bag of innovative strategies to retract structures like the gallbladder away from the operative field. These tricks may range from the use of percutaneous needlescopic instruments to the application of transfascial sutures. Expert consensus recommendations for efficient SILS are shown in Tables 14-3 and 14-4.8 When performing SILS procedures, it is imperative to follow proven tenets of operative conduct such as visualizing the “critical view” of safety in a laparoscopic cholecystectomy. As safety should always be the paramount concern, the addition of extra trocars or conversion to traditional laparoscopy should not be considered a failure. Contraindications include those true of traditional laparoscopy. Relative contraindications include previous surgery and high body mass index (BMI). Patients with a high BMI or Table 14-3 Expert panel recommendations for accomplishing ­single-incision laparoscopic surgery efficiently Multichannel port preferably to be placed intraumbilically, but an extraumbilical approach can be used in certain cases Extra ports should be used where there is a clinical need When applicable, sutures can be useful for added retraction Closure should be accomplished using sutures of absorbable material placed either continuously or interrupted Skin should be closed with absorbable sutures or glue Figure 14-26. Transanal endoscopic microsurgery scope. (Illustration by Corinne Sandone. © 2014 JHU. Reprinted with permission.) Source: Ahmed I, Cianco F, Ferrar V, et al. Current status of singleincision laparoscopic surgery: European experts’ views. Surg Laparosc Endosc Percutan Tech. 2012;22(3):194-199. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 435 Table 14-4 Recommended Equipment/ Instrumentation Benefit to Surgeon Slimline instruments with low-profile design Reduces internal and external clashing Varied-length instruments Reduces extracorporeal clashing Longer instruments Advantageous for reaching the surgical field Articulating (or prebent) instruments Restore triangulation Small-diameter, low-profile angle scope Reduces clashing by providing additional space High-definition camera Achieves high-quality images for intraoperative visualization CHAPTER 14 Minimally Invasive Surgery Expert panel recommendations for single-incision laparoscopic surgery equipment and instrumentation Source: Ahmed I, Cianco F, Ferrar V, et al. Current status of singleincision laparoscopic surgery: European experts’ views. Surg Laparosc Endosc Percutan Tech. 2012;22(3):194-199. A central obesity can pose a challenge because the umbilicus may be located far from operative target. Size and morphology of the target organ should always be considered when doing SILS. Many studies have demonstrated equivalency to standard laparoscopic procedures regarding intraoperative and postoperative complications. However, it is questionable what the full benefit of the dramatic reduction in ergonomics and the increase in complexity provide beyond an improved cosmetic appearance. This is in large part due to the already improved benefits of laparoscopic surgery. A meta-analysis performed by Ahmed and colleagues in 2010 found the conversion rate from SILS to conventional laparoscopy to be 0% to 24% for cholecystectomies, 0% to 41% for appendectomies, and 0% to 33% for nephrectomies.90 The most common complications were intra-abdominal abscesses and wound infections. The recently released robotics application may provide the bridge necessary to bypass the significant technical skills learning curve required to operate through a single site (Fig. 14-28). SPECIAL CONSIDERATIONS Pediatric Laparoscopy The advantages of MIS in children may be more significant than in the adult population. MIS in the adolescent is little different from that in the adult, and standard instrumentation and ­trocar positions usually can be used. However, laparoscopy in the infant and young child requires specialized instrumentation. The instruments are shorter (15–20 cm), and many are 3 mm in diameter rather than 5 mm. Because the abdomen of the child is much smaller than that of the adult, a 5-mm telescope provides sufficient illumination for most operations. The development of 5-mm clippers and bipolar devices has obviated the need for 10-mm trocars in pediatric laparoscopy.91 Because B Figure 14-28. A and B. Robotic single-incision surgery platform. (©2013 Intuitive Surgical, Inc. Reprinted with permission.) the abdominal wall is much thinner in infants, a pneumoperitoneum pressure of 8 mmHg can provide adequate exposure. DVT is rare in children, so prophylaxis against thrombosis probably is unnecessary. A wide variety of pediatric surgical procedures are frequently performed with MIS access, from pull-through procedures for colonic aganglionosis (Hirschsprung’s disease) to repair of congenital diaphragmatic hernias.92 Laparoscopy during Pregnancy Concerns about the safety of laparoscopic cholecystectomy or appendectomy in the pregnant patient have been thoroughly investigated and are readily managed. Access to the abdomen in the pregnant patient should take into consideration the height of the uterine fundus, which reaches the umbilicus at VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 436 PART I BASIC CONSIDERATIONS 20 weeks. In order not to damage the uterus or its blood supply, most surgeons feel that the open (Hasson) approach should be used in favor of direct puncture laparoscopy. The patient should be positioned slightly on the left side to avoid compression of the vena cava by the uterus. Because pregnancy poses a risk for thromboembolism, sequential compression devices are essential for all procedures. Fetal acidosis induced by maternal hypercarbia also has been raised as a concern. The arterial pH of the fetus follows the pH of the mother linearly; and therefore, fetal acidosis may be prevented by avoiding a respiratory acidosis in the mother.93 The pneumoperitoneum pressure induced by laparoscopy is not a safety issue either as it has been proved that midpregnancy uterine contractions provide a much greater pressure in utero than a pneumoperitoneum of 15 mmHg. More than 100 cases of laparoscopic cholecystectomy in pregnancy have been reported with uniformly good results.94 The operation should be performed during the second trimester of pregnancy if possible. Protection of the fetus against intraoperative x-rays is imperative. Some believe it advisable to track fetal pulse rates with a transvaginal ultrasound probe; however, the significance of fetal tachycardia or bradycardia is a bit unclear in the second trimester of pregnancy. To be prudent, however, heart rate decelerations reversibly associated with pneumoperitoneum creation might signal the need to convert to open cholecystectomy or appendectomy. 6 Minimally Invasive Surgery and Cancer Treatment MIS techniques have been used for many decades to provide palliation for the patient with an obstructive cancer. Laser treatment, intracavitary radiation, stenting, and dilation are outpatient techniques that can be used to reestablish the continuity of an obstructed esophagus, bile duct, ureter, or airway. MIS techniques also have been used in the staging of cancer. Mediastinoscopy is still used occasionally before thoracotomy to assess the status of the mediastinal lymph nodes. Laparoscopy also is used to assess the liver in patients being evaluated for pancreatic, gastric, or hepatic resection. New technology and greater surgical skills allow for accurate minimally invasive staging of cancer.95 Occasionally, it is appropriate to perform palliative measures (e.g., laparoscopic gastrojejunostomy to bypass a pancreatic cancer) at the time of diagnostic laparoscopy if diagnostic findings preclude attempts at curative resection. Initially controversial, the role of MIS to provide a safe curative treatment of cancer has proven to be no different from the principles of open surgery. All gross and microscopic 7 tumor should be removed (an R0 resection), and an adequate lymphadenectomy should be performed to allow accurate staging. Generally, this number has been 10 to 15 lymph nodes, although there is still debate as to the value of more extensive lymphadenectomy. All of the major abdominal cancer operations have been performed with laparoscopy. Of the three major cancer resections of GI cancer (liver lobe, pancreatic head, and esophagus), only esophagectomy is routinely performed by a fair number of centers.96,97 Laparoscopic hepatectomy has attracted a loyal following, and distal pancreatectomy frequently is performed with laparoscopic access. In Japan, laparoscopicassisted gastrectomy has become quite popular for early gastric cancer, an epidemic in Japan far exceeding that of colon cancer in North America and Northern Europe. The most common cancer operation performed laparoscopically is segmental colectomy, which has proven itself safe and efficacious in a multicenter controlled randomized trial.98 Considerations in the Elderly and Infirm Laparoscopic cholecystectomy has made possible the removal of a symptomatic gallbladder in many patients previously thought to be too elderly or too ill to undergo a laparotomy. Older patients are more likely to require conversion to celiotomy because of disease chronicity.98 Operations on these patients require close monitoring of anesthesia. The intraoperative management of these patients may be more difficult with laparoscopic access than with open access. The advantage of MIS lies in what happens after the operation. Much of the morbidity of surgery in the elderly is a result of impaired mobility. In addition, pulmonary complications, urinary tract sepsis, DVT, pulmonary embolism, congestive heart failure, and myocardial infarction often are the result of improper fluid management and decreased mobility. By allowing rapid and early mobilization, laparoscopic surgery has made possible the safe performance of procedures in the elderly and infirm. Cirrhosis and Portal Hypertension Patients with hepatic insufficiency pose a significant challenge for any type of surgical intervention.99 The ultimate surgical outcome in this population relates directly to the degree of underlying hepatic dysfunction.100 Often, this group of patients has minimal reserve, and the stress of an operation will trigger complete hepatic failure or hepatorenal syndrome. These patients are at risk for major hemorrhage at all levels, including trocar insertion, operative dissection in a field of dilated veins, and secondary to an underlying coagulopathy. Additionally, ascitic leak from a port site may occur, leading to bacterial peritonitis. Therefore, a watertight port site closure should be carried out in all patients. It is essential that the surgeon be aware of the severity of hepatic cirrhosis as judged by a Model of End-Stage Liver Disease (MELD) score or Child’s classification. Additionally, the presence of portal hypertension is a relative contraindication to laparoscopic surgery until the portal pressures are reduced with portal decompression. For example, if a patient has an incarcerated umbilical hernia and ascites, a preoperative paracentesis or transjugular intrahepatic portosystemic shunt procedure in conjunction with aggressive diuresis may be considered. Because these patients commonly are intravascularly depleted, insufflation pressures should be reduced to prevent a decrease in cardiac output, and minimal amounts of Na+-sparing IV fluids should be given. Economics of Minimally Invasive Surgery Minimally invasive surgical procedures reduce the costs of surgery most when length of hospital stay can be shortened and return to work is quickened. For example, shorter hospital stays can be demonstrated in laparoscopic cholecystectomy, Nissen fundoplication, splenectomy, and adrenalectomy. Procedures such as inguinal herniorrhaphy that are already performed as outpatient procedures are less likely to provide cost savings. Procedures that still require a 4- to 7-day hospitalization, such as laparoscopy-assisted colectomy, are less likely to deliver a lower bottom line than their open surgery counterparts. Nonetheless, with responsible use of disposable instrumentation and a commitment to the most effective use of the inpatient setting, most laparoscopic procedures can be made less expensive than their conventional equivalents. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Education and Skill Acquisition Telementoring In response to the Institute of Medicine’s call for the development of unique technologic solutions to deliver health care to rural and underserved areas, surgeons are beginning to explore the feasibility of telementoring. Teleconsultation or telementoring Innovation and Introduction of New Procedures The revolution in minimally invasive general surgery, which occurred in 1990, created ethical challenges for the profession. The problem was this: If competence is gained from experience, how was the surgeon to climb the competence curve (otherwise known as the learning curve) without injuring patients? If it was indeed impossible to achieve competence without making mistakes along the way, how should one effectively communicate this to patients such that they understand the weight of their decisions? Even more fundamentally important is determining the path that should be followed before one recruits the first patient for a new procedure. Although procedure development is fundamentally different than drug development (i.e., there is great individual ­variation in the performance of procedures, but no difference between one tablet and the next), adherence to a process similar to that used to develop a new drug is a reasonable path for a surgical innovator. At the outset, the surgeon must identify the problem that is not solved with current surgical procedures. For example, although the removal of a gallbladder through a Kocher incision is certainly effective, it creates a great deal of disability, pain, and scarification. As a result of those issues, many patients with very symptomatic biliary colic delayed operation until life-threatening complications occurred. Clearly, there was a need for developing a less invasive approach (Fig. 14-29). Once the opportunity has been established, the next step involves a search through other disciplines for technologies and techniques that might be applied. Again, this is analogous to the drug industry, where secondary drug indications have often turned out to be more therapeutically important than the primary indication for drug development. The third step is in vivo studies in the most appropriate animal model. These types of studies are controversial because of the resistance to animal experimentation, and yet without such studies, many humans would be Progress in Surgery Performance Open surgery Laparoscopic surgery Seamless surgery ? Video optics General anesthesia sterile technique 1880 1900 1920 1940 1960 1980 1985 1990 1995 2000 ? VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 14-29. The progress of general surgery can be reflected by a series of performance curves. General anesthesia and sterile technique allowed the development of maximally invasive open surgery over the last 125 years. Video optics allowed the development of minimally invasive surgery over the last 25 years. Noninvasive (seamless) surgery will result when a yet undiscovered transformational event allows surgery to occur without an incision, and perhaps ? without anesthesia. 437 CHAPTER 14 Minimally Invasive Surgery Historically, surgeons in training (residents, registrars, and fellows) acquired their skills in minimally invasive techniques through a series of operative experiences of graded complexity. This training occurred on patients. Although such a paradigm did not compromise patient safety, learning in the OR is costly. In addition, the recent worldwide constraint placed on resident work hours makes it attractive to teach laparoscopic skills outside of the OR. Skills labs started at nearly every surgical training center in the 1990s with low fidelity box-type trainers. These were rudimentary simulated abdominal cavities with a video camera, monitor, trocars, laparoscopic instruments, and target models. These targets were often as simple as a pegboard and rubber rings, or a latex drain to practice suturing and knot tying. Virtual reality training devices present a unique opportunity to improve and enhance experiential learning in endoscopy and laparoscopy for all surgeons. This technology has the advantage of enabling objective measurement of psychomotor skills, which can be used to determine progress in skill acquisition and, ultimately, technical competency.101 Several of these devices have been validated as a means of measuring proficiency in skill performance. More importantly, training on virtual reality platforms has proven to translate to improved operative performance in randomized trials.102,103 Currently surgical skills labs are mandatory for Residency Review Committee credentialing. 8 ­Successful completion of the Fundamentals of Laparoscopic Surgery (FLS) technical and cognitive examination became a mandatory prerequisite for the American Board of Surgery qualification examination in general surgery in 2010. In the future, institutions may require simulator training to the expert level as a prerequisite for performance of laparoscopic procedures in the OR. The Fundamental of Endoscopic Surgery (FES) and Fundamentals of Robotic Surgery (FRS) high stakes exams are both on the horizon for future surgical trainees. The American College of Surgeons has taken a leadership position in accrediting skills labs across the world as American College of Surgeons–accredited educational institutes. is two-way audio and visual communication between two geographically separated providers. This communication can take place in the office setting or directly in the OR when complex scenarios are encountered. Although local communication channels may limit its performance in rural areas, the technology is available and currently is being used, especially in states and provinces with large geographically remote populations.103 438 PART I BASIC CONSIDERATIONS injured or killed during the developmental phase of medical drugs, devices, and techniques. These steps often are called the preclinical phase of procedure development. The decision as to when such procedures are ready to come out of the lab is a difficult one. Put simply, the procedure should be reproducible, provide the desired effect, and not have serious side effects. Once these three criteria are reached, the time for human application has arrived. Before the surgeon discusses the new procedure with patients, it is important to achieve full institutional support. Involvement of the medical board, the chief of the medical staff, and the institutional review board is essential before commencing on a new procedure. These bodies are responsible for the use of safe, highquality medical practices within their institution, and they will demand that great caution and all possible safeguards are in place before proceeding. The dialogue with the patient who is to be first must be thorough, brutally honest, and well documented. The psychology that allows a patient to decide to be first is quite interesting, and may, under certain circumstances, require psychiatric evaluation. Certainly if a dying cancer patient has a chance with a new drug, this makes sense. Similarly, if the standard surgical procedure has a high attendant morbidity and the new procedure offers a substantially better outcome, the decision to be first is understandable. On the other hand, when the benefits of the new approach are small and the risks are largely unknown, a more complete psychological profile may be necessary before proceeding. For new surgical procedures, it generally is wise to assemble the best possible operative team, including a surgeon experienced with the old technique, and assistants who have participated in the earlier animal work. This initial team of experienced physicians and nurses should remain together until full competence with the procedure is attained. This may take 10 procedures, or it may take 50 procedures. The team will know that it has achieved competence when the majority of procedures take the same length of time and the team is relaxed and sure of the flow of the operation. This will complete phase I of the procedure development. In phase II, the efficacy of the procedure is tested in a nonrandomized fashion. Ideally, the outcome of new techniques must be as good as or better than the procedure that is being replaced. This phase should occur at several medical centers to prove that good outcomes are achievable outside of the pioneering institution. These same requirements may be applied to the introduction of new technology into the OR. The value equation requires that the additional measurable procedure quality exceeds the additional measurable cost to the patient or healthcare system. In phase III, a randomized trial pits the new procedure against the old. Once the competence curve has been climbed, it is appropriate for the team to engage in the education of others. During the ascension of the competence curve, other learners in the institution (i.e., surgical residents) may not have the opportunity to participate in the first case series. Although this may be difficult for them, the best interest of the patient must be put before the education of the resident. The second stage of learning occurs when the new procedure has proven its value and a handful of experts exist, but the majority of surgeons have not been trained to perform the new procedure. In this setting, it is relatively unethical for surgeons to forge ahead with a new procedure in humans as if they had spent the same amount of time in intensive study that the first team did. The fact that one or several surgical teams were able to perform an operation does not ensure that all others with the same medical degrees can perform the operation with equal skill. It behooves the learners to contact the experts and request their assistance to ensure an optimal outcome at the new center. Although it is important that the learners contact the experts, it is equally important that the experts be willing to share their experience with their fellow professionals. As well, the experts should provide feedback to the learners as to whether they feel the learners are equipped to forge ahead on their own. If not, further observation and assistance from the experts are required. Although this approach may sound obvious, it is fraught with difficulties. In many situations, ego, competitiveness, and monetary concerns have short-circuited this process and led to poor patient outcomes. To a large extent, MIS has recovered from the black eye it received early in development, when inadequately trained surgeons caused an excessive number of significant complications. If innovative procedures and technologies are to be developed and applied without the mistakes of the past, surgeons must be honest when they answer these questions: Is this procedure safe? Would I consider undergoing this procedure if I developed a surgical indication? Is the procedure as good as or better than the procedure it is replacing? Do I have the skills to apply this procedure safely and with equivalent results to the more experienced surgeon? Answering these questions in the affirmative should be a professional obligation. A negative response should motivate the surgeon to seek an alternative procedure or outside assistance before subjecting a patient to the new procedure. REFERENCES Entries highlighted in bright blue are key references. 1. Hopkins HH. Optical principles of the endoscope. In: Berci G, ed. Endoscopy. New York: Appleton-Century-Crofts; 1976:3. 2. Katzir A. Optical fibers in medicine. Sci Am. 1989;260:120. 3. Hirschowitz BI. A personal history of the fiberscope. Gastroenterology. 1979;76:864. 4. Veritas TF. Coelioscopy: a synthesis of Georg Kelling’s work with insufflation, endoscopy, and luft tamponade. In: Litynski GS, ed. 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Subtotal cholecystectomy: for the difficult gallbladder in portal hypertension and cholecystitis. Surgery. 1985;98:1. 100. Litwin DWM, Pham Q. Laparoscopic surgery in the complicated patient. In: Eubanks WS, Swanstrom LJ, Soper NJ, eds. Mastery of Endoscopic and Laparoscopic Surgery. Philadelphia: Lippincott, Williams & Wilkins; 2000:57. 101. Gallagher AG, Smith CD, Bowers SP, et al. Psychomotor skills assessment in practicing surgeons experienced in This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 15 chapter Overview of Molecular Cell Biology 443 Basic Concepts of Molecular Research / 443 Molecular Approaches to Surgical Research / 444 Fundamentals of Molecular and Cell Biology 444 Molecular and Genomic Surgery Xin-Hua Feng, Xia Lin, Juehua Yu, John Nemunaitis, and F. Charles Brunicardi Gene Regulation / 446 Human Genome / 449 Cell Cycle and Apoptosis / 450 Signal Transduction Pathways / 450 Gene Therapy and Molecular Drugs in Cancer / 453 Stem Cell Research / 456 The Atomic Theory of Disease / 456 DNA and Heredity / 444 OVERVIEW OF MOLECULAR CELL BIOLOGY The beginning of modern medicine can be traced back to centuries ago when physicians and scientists began studying human anatomy from cadavers in morgues and animal physiology following hunting expeditions. Gradually, from the study of animals and plants in greater detail and the discovery of microbes, scientific principles governing life lead to the emergence of the biological sciences. As biological science developed and expanded, scientists and physicians began to utilize the principles of biological sciences to solve challenges of human diseases while continuing to explore the fundamentals of life in greater detail. With ever-evolving state-of-the-art scientific tools, our understanding of how cells, tissues, organs, and entire organisms function, down to the level of molecular and subatomic structure, has resulted in modern biology with an enormous impact on modern healthcare and the discovery of amazing treatments for disease at an exponential pace. Significant progress has been made in molecular studies of organ development, cell signaling, and gene regulation. The advent of recombinant DNA technology, polymerase chain reaction (PCR) techniques, and next-generation genomic sequencing, which resulted in the sequencing of the human genome, holds the potential to have a transformational influence on healthcare and society this century by not only broadening our understanding of the pathophysiology of disease, but also by bringing about necessary changes in personalized medicine. Today’s practicing surgeons are becoming increasingly aware that many modern surgical procedures rely on the information gained through molecular research (i.e., personalized surgery). Genomic information, such as deleterious BRCA and RET proto-oncogene mutations, is being used to help direct prophylactic procedures to remove potentially harmful tissues before they do damage to patients. Molecular engineering has led to cancer-specific gene therapy that could serve in the near future as a more effective adjunct to surgical debulking of tumors than radiation or chemotherapy, so surgeons will benefit Technologies of Molecular and Cell Biology 456 DNA Cloning / 456 Detection of Nucleic Acids and Proteins / 457 Cell Manipulations / 462 Genetic Manipulations / 463 Personalized Genomic Medicine and Surgery / 463 from a clear introduction to how basic biochemical and biological principles relate to the developing area of molecular biology. This chapter reviews the current information on modern molecular biology for the surgical community. Basic Concepts of Molecular Research The modern era of molecular biology, which has been mainly concerned with how genes govern cell activity, began in 1953 when James D. Watson and Francis H. C. Crick made one of the greatest scientific discoveries by deducing the double-helical structure of deoxyribonucleic acid (DNA).1,2 The year 1 2003 marked the 50th anniversary of this great discovery. In the same year, the Human Genome Project completed with sequencing approximately 20,000 to 25,000 genes and 3 billion base pairs in human DNA.3 Before 1953, one of the most 2 mysterious aspects of biology was how genetic material was precisely duplicated from one generation to the next. Although DNA had been implicated as genetic material, it was the base-paired structure of DNA that provided a logical interpretation of how a double helix could “unzip” to make copies of itself. This DNA synthesis, termed replication, immediately gave rise to the notion that a template was involved in the transfer of information between generations, and thus confirmed the suspicion that DNA carried an organism’s hereditary information. Within cells, DNA is packed tightly into chromosomes. One important feature of DNA as genetic material is its ability to encode important information for all of a cell’s functions (Fig. 15-1). Based on the principles of base complementarity, scientists also discovered how information in DNA is accurately transferred into the protein structure. DNA serves as a template for RNA synthesis, termed transcription, including messenger RNA (mRNA, or the protein-encoding RNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). mRNA carries the information from DNA to make proteins, termed translation, with the assistance of rRNA and tRNA. Each of these steps is precisely controlled in such a way that genes are properly expressed in each cell at a specific time and location. In recent years, new VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 Biological sciences developed drastically in last 60 years after the uncovering of DNA structure by Watson and Crick The completion of the human genome sequence in 2003 represents a great milestone in modern science. The technology emerging from molecular and cellular biology has revolutionized the understanding of disease and will radically transform the practice of surgery. The use of genetically modified mouse models and cell lines using gene therapy and RNA interference therapy has greatly classes of noncoding RNAs (ncRNA), for example, microRNA (or miRNA), Piwi-interacting RNA (or piRNA), and long intergenic noncoding RNA (or lincRNA), have been identified. Although the number of ncRNAs encoded in the human genome is unknown and a lot of ncRNAs have not been validated for their functions, ncRNAs have been associated to regulate gene expression through posttranscriptional gene regulation such as mRNA degradation or epigenetic regulation such as chromatin structure modification and DNA methylation induction.4 Consequently, the differential gene activity in a cell determines its actions, properties, and functions. Molecular Approaches to Surgical Research Rapid advances in molecular and cellular biology over the past half century have revolutionized the understanding of disease and will radically transform the practice of surgery. In the future, molecular techniques will be increasingly applied to surgical disease and will lead to new strategies for the selection and implementation of operative therapy. Surgeons should be familiar with the fundamental principles of molecular and cellular biology so that emerging scientific breakthroughs can be translated into improved care of the surgical patient. DNA Transcription Genomics Proteomics Proteins Structure Cell functions Functional genomics Signaling Metabolism 444 6 The greatest advances in the field of molecular biology have been in the areas of analysis and manipulation of DNA.1 Since Watson and Crick’s discovery of DNA structure, an intensive effort has been made to unlock the deepest biologic secrets of DNA. Among the avalanche of technical advances, one discovery in particular has drastically changed the world of molecular biology: the uncovering of the enzymatic and microbiologic techniques that produce recombinant DNA. Recombinant DNA technology involves the enzymatic manipulation of DNA and, subsequently, the cloning of DNA. DNA molecules are cloned for a variety of purposes including safeguarding DNA samples, facilitating sequencing, generating probes, and expressing recombinant proteins in one or more host organisms. DNA can be produced by a number of means, including restricted digestion of an existing vector, PCR, and cDNA synthesis. As DNA cloning techniques have developed over the last quarter century, researchers have moved from studying DNA to studying the functions of proteins, and from cell and animal models to molecular therapies in humans. Expression of recombinant proteins provides a method for analyzing gene regulation, structure, and function. In recent years, the uses for recombinant proteins have expanded to include a variety of new applications, including gene therapy and biopharmaceuticals. The basic molecular approaches for modern surgical research include DNA cloning, cell manipulation, disease modeling in animals, and clinical trials in human patients. FUNDAMENTALS OF MOLECULAR AND CELL BIOLOGY RNA Translation 5 contributed to the understanding of the molecular basis for human diseases and targeted therapies. The sequencing of each individual’s genome has the potential to improve the predication, prevention, and targeted treatment of disease, resulting in personalized medicine and surgery. The use of functional genomics and modern molecular analyses will facilitate the discovery of actionable genes to guide choice of care. Figure 15-1. The flow of genetic information from DNA to protein to cell functions. The process of transmission of genetic information from DNA to RNA is called transcription, and the process of transmission from RNA to protein is called translation. Proteins are the essential controlling components for cell structure, cell signaling, and metabolism. Genomics and proteomics are the study of the genetic composition of a living organism at the DNA and protein level, respectively. The study of the relationship between genes and their cellular functions is called functional genomics. DNA and Heredity DNA forms a right-handed, double-helical structure that is composed of two antiparallel strands of unbranched polymeric deoxyribonucleotides linked by phosphodiester bonds between the 5′ carbon of one deoxyribose moiety to the 3′ carbon of the next (Fig. 15-2). DNA is composed of four types of deoxyribonucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T). The nucleotides are joined together by phosphodiester bonds. In the double-helical structure deduced by Watson and Crick, the two strands of DNA are complementary to each other. Because of size, shape, and chemical composition, A always pairs with T, and C with G, through the formation of hydrogen bonds between complementary bases that stabilize the double helix. Recognition of the hereditary transmission of genetic information is attributed to the Austrian monk, Gregor Mendel. His seminal work, ignored upon publication until its rediscovery in 1900, established the laws of segregation and of independent VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Building blocks of DNA Base G + Nucleotide DNA strand 5' 3' G G C T A Sugar Phosphate Double-stranded DNA 3' 5' 5' Table 15-1 DNA double helix 3' Historical events in genetics and molecular biology 5' A T C G T A G C G C C G A T A T T T A T G C A T C T Sugar-phosphate backbone 1865 Mendel Laws of genetics established Miescher DNA isolated A 1905 Garrod Human inborn errors of metabolism 1913 Sturtevant Linear map of genes 1927 Muller X-rays cause inheritable genetic damage 1928 Griffith Transformation discovered 1941 Beadle and Tatum “One gene, one enzyme” concept 1944 Avery, MacLeod, McCarty DNA as material of heredity 1950 McKlintock Existence of transposons confirmed 1953 Watson and Crick Double-helical structure of DNA 1957 Benzer and Kornberg Recombination and DNA polymerase 1966 Nirenberg, Khorana, Holley Genetic code determined 1970 Temin and Baltimore Reverse transcriptase 1972 Cohen, Boyer, Berg Recombinant DNA technology 1975 Southern Transfer of DNA fragments from sizing gel to nitrocellulose (Southern blot) 1977 Sanger, Maxim, Gilbert DNA sequencing methods 1982 — GenBank database established C A T G A C 5' 3' Event 1869 G G Investigator G G C Year 3' Hydrogen-bonded pairs Figure 15-2. Schematic representation of a DNA molecule forming a double helix. DNA is made of four types of nucleotides, which are linked covalently into a DNA strand. A DNA molecule is composed of two DNA strands held together by hydrogen bonds between the pair bases. The arrowheads at the ends of the DNA strands indicate the polarities of the two strands, which run antiparallel to each other in the DNA molecule. The diagram at the bottom left of the figure shows the DNA molecule straightened out. In reality, the DNA molecule is twisted into a double helix, of which each turn of DNA is made up of 10.4 nucleotide pairs, as shown on the right. (Republished with permission of Garland Publishing, Inc. from Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell, 5th ed. New York: Garland Science; 2008. Permission conveyed through Copyright Clearance Center, Inc.) assortment. These two principles established the existence of paired elementary units of heredity and defined the statistical laws that govern them.5 DNA was isolated in 1869, and a number of important observations of the inherited basis of certain diseases were made in the early part of the twentieth century. Although today it appears easy to understand how DNA replicates, before the 1950s, the idea of DNA as the primary genetic material was not appreciated. The modern era of molecular biology began in 1944 with the demonstration that DNA was the substance that carried genetic information. The first experimental evidence that DNA was genetic material came from simple transformation experiments conducted in the 1940s using Streptococcus pneumoniae. One strain of the bacteria could be converted into another by incubating it with DNA from the other, 1985 Mullis Polymerase chain reaction 1986 — Automated DNA sequencing 1989 Collins Cystic fibrosis gene identified by positional cloning and linkage analysis 1990 — Human Genome Project initiated 1997 Roslin Institute Mammalian cloning (Dolly) 2001 IHGSC and Celera Genomics Draft versions of human genome sequence published 2003 — Human Genome Project completed IHGSC = International Human Genome Sequencing Consortium. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 445 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY Sugar phosphate just as the treatment of the DNA with deoxyribonuclease would inactivate the transforming activity of the DNA. Similarly, in the early 1950s, before the discovery of the double-helical structure of DNA, the entry of viral DNA and not the protein into the host bacterium was believed to be necessary to initiate infection by the bacterial virus or bacteriophage. Key historical events concerning genetics are outlined in Table 15-1. 446 DNA is a template for its own duplication Template S strand 3' 5' PART I Parent DNA double helix (shown flat): S strand 5' BASIC CONSIDERATIONS 3' G T A A C G G T C A C A T G C C A G T T 3' 3' G T A A C G G T C A C A T T G C C A G T 5' New S strand 5' S strand New S strand 3' 5' 3' G T A A C G G T C A C A T G C C A G T T 5' Template S strand For cells to pass on the genetic material (DNA) to each progeny, the amount of DNA must be doubled. Watson and Crick recognized that the complementary base-pair structure of DNA implied the existence of a template-like mechanism for the copying of genetic material. 1 The transfer of DNA material from the mother cell to daughter cells takes place during somatic cell division (also called mitosis). Before a cell divides, DNA must be precisely duplicated. During replication, the two strands of DNA separate, and each strand creates a new complementary strand by precise base-pair matching (Fig. 15-3). The two, new, double-stranded DNAs carry the same genetic information, which can then be passed on to two daughter cells. Proofreading mechanisms ensure that the replication process occurs in a highly accurate manner. The fidelity of DNA replication is absolutely crucial to maintaining the integrity of the genome from generation to generation. However, mistakes can still occur during this process, resulting in mutations, which may lead to a change of the DNA’s encoded protein and, consequently, a change of the cell’s behavior. The reliable dependence of many features of modern organisms on subtle changes in genome is linked to Mendelian inheritance and also contributes to the processes of Darwinian evolution. In addition, massive changes, so-called genetic instability, can occur in the genome of somatic cells such as cancer cells. Nucleus RNA transcript Nuclear envelope RNA processing Gene Regulation Living cells have the necessary machinery to enzymatically transcribe DNA into RNA and translate the mRNA into protein. This machinery accomplishes the two major steps required for gene expression in all organisms: transcription and translation (Fig. 15-4). However, gene regulation is far more complex, particularly in eukaryotic organisms. For example, many gene transcripts must be spliced to remove the intervening sequences. The sequences that are spliced off are called introns, which appear to be useless, but in fact may carry some regulatory information. The sequences that are joined together, and are eventually translated into protein, are called exons. Additional regulation of gene expression includes modification of mRNA, control of mRNA stability, and its nuclear export into cytoplasm (where it is assembled into ribosomes for translation). After mRNA is translated into protein, the levels and functions of the proteins can be further regulated posttranslationally. However, the following sections will mainly focus on gene regulation at transcriptional and translational levels. Transcription. Transcription is the enzymatic process of RNA synthesis from DNA.6 In bacteria, a single RNA polymerase carries out all RNA synthesis, including that of mRNA, rRNA, and tRNA. Transcription often is coupled with translation in such a way that an mRNA molecule is completely accessible to Cytoplasm DNA Transcription Figure 15-3. DNA replication. As the nucleotide A only pairs with T, and G with C, each strand of DNA can determine the nucleotide sequence in its complementary strand. In this way, double-helical DNA can be copied precisely. (Republished with permission of Garland Publishing, Inc. from Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell, 5th ed. New York: Garland Science; 2008. Permission conveyed through Copyright Clearance Center, Inc.) mRNA mRNA turnover Protein turnover RNA degradation Protein degradation mRNA Translation Protein Posttranslational modification Active protein RNA transport Transcriptional control Posttranscriptional control Translational control Posttranslational control Figure 15-4. Four major steps in the control of eukaryotic gene expression. Transcriptional and posttranscriptional control determine the level of messenger RNA (mRNA) that is available to make a protein, while translational and posttranslational control determine the final outcome of functional proteins. Note that posttranscriptional and posttranslational controls consist of several steps. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Eukaryotic gene transcription also involves the recognition and binding of RNA polymerase to the promoter DNA. However, the interaction between the polymerase and DNA is far more complex in eukaryotes than in prokaryotes. Because the majority of studies have been focused on the regulation and functions of proteins, this chapter primarily focuses on how protein-encoding mRNA is made by RNA polymerase II. Translation. DNA directs the synthesis of RNA; RNA in turn directs the synthesis of proteins. Proteins are variable-length polypeptide polymers composed of various combinations of 20 different amino acids and are the working molecules of the cell. The process of decoding information on mRNA to synthesize proteins is called translation (see Fig. 15-1). Translation takes place in ribosomes composed of rRNA and ribosomal proteins. The numerous discoveries made during the 1950s made it easy to understand how DNA replication and transcription involve base-pairing between DNA and DNA or DNA and RNA. However, at that time, it was still impossible to comprehend how mRNA transfers the information to the protein-synthesizing machinery. The genetic information on mRNA is composed of arranged sequences of four bases that are transferred to the linear arrangement of 20 amino acids on a protein. Amino acids are characterized by a central carbon unit linked to four side chains: an amino group (–NH2), a carboxy group (–COOH), a hydrogen, and a variable (–R) group. The amino acid chain is assembled via peptide bonds between the amino group of one amino acid and the carboxy group of the next. Because of this decoding, the information carried on mRNA relies on tRNA. Translation involves all three RNAs. The precise transfer of information from mRNA to protein is governed by genetic code, the set of rules by which codons are translated into an amino acid (Table 15-2). A codon, a triplet of three bases, codes for one amino acid. In this case, random combinations of the four bases form 4 × 4 × 4, or 64 codes. Because 64 codes are more than enough for 20 amino acids, most amino acids are coded by more than one codon. The start codon is AUG, which also corresponds to methionine; therefore, almost all proteins begin with this amino acid. The sequence of nucleotide triplets that follows the start codon signal is termed the reading frame. The codons on mRNA are sequentially recognized by tRNA adaptor proteins. Specific enzymes termed aminoacyl-tRNA synthetases link a specific amino acid to a specific tRNA. The translation of mRNA to protein requires the ribosomal complex to move stepwise along the mRNA until the initiator methionine sequence is identified. In concert with various protein initiator factors, the methionyl-tRNA is positioned on the mRNA and protein synthesis begins. Each new amino acid is added sequentially by the appropriate tRNA in conjunction with proteins called elongation factors. Protein synthesis proceeds in the amino-tocarboxy-terminus direction. The biologic versatility of proteins is astounding. Among many other functions, proteins serve as enzymes that catalyze critical biochemical reactions, carry signals to and from the extracellular environment, and mediate diverse signaling and regulatory functions in the intracellular environment. They also transport ions and various small molecules across plasma membranes. Proteins make up the key structural components of cells and the extracellular matrix and are responsible for cell motility. The unique functional properties of proteins are largely determined by their structure (Fig. 15-5). Regulation of Gene Expression. The human organism is made up of a myriad of different cell types that, despite their vastly VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 447 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY ribosomes, and bacterial protein synthesis begins on an mRNA molecule even while it is still being synthesized. Therefore, a discussion of gene regulation with a look at the simpler prokaryotic system precedes that of the more complex transcription and posttranscriptional regulation of eukaryotic genes. Transcription in Bacteria Initiation of transcription in prokaryotes begins with the recognition of DNA sequences by RNA polymerase. First, the bacterial RNA polymerase catalyzes RNA synthesis through loose binding to any region in the double-stranded DNA and then through specific binding to the promoter region with the assistance of accessory proteins called σ factors (sigma factors). A promoter region is the DNA region upstream of the transcription initiation site. RNA polymerase binds tightly at the promoter sites and causes the double-stranded DNA structure to unwind. Consequently, few nucleotides can be base-paired with the DNA template to begin transcription. Once transcription begins, the σ factor is released. The growing RNA chain may begin to peel off as the chain elongates. This occurs in such a way that there are always about 10 to 12 nucleotides of the growing RNA chains that are basepaired with the DNA template. The bacterial promoter contains a region of about 40 bases that include two conserved elements called –35 region and –10 region. The numbering system begins at the initiation site, which is designated +1 position, and counts backward (in negative numbers) on the promoter and forward on the transcribed region. Although both regions on different promoters are not the same sequences, they are fairly conserved and very similar. This conservation provides the accurate and rapid initiation of transcription for most bacterial genes. It is also common in bacteria that one promoter serves to transcribe a series of clustered genes, called an operon. A single transcribed mRNA contains a series of coding regions, each of which is later independently translated. In this way, the protein products are synthesized in a coordinated manner. Most of the time, these proteins are involved in the same metabolic pathway, thus demonstrating that the control by one operon is an efficient system. After initiation of transcription, the polymerase moves along the DNA to elongate the chain of RNA, although at a certain point, it will stop. Each step of RNA synthesis, including initiation, elongation, and termination, will require the integral functions of RNA polymerase as well as the interactions of the polymerase with regulatory proteins. Transcription in Eukaryotes Transcription mechanisms in eukaryotes differ from those in prokaryotes. The unique features of eukaryotic transcription are as follows: (a) Three separate RNA polymerases are involved in eukaryotes: RNA polymerase I transcribes the precursor of 5.8S, 18S, and 28S rRNAs; RNA polymerase II synthesizes the precursors of mRNA as well as microRNA; and RNA polymerase III makes tRNAs and 5S rRNAs. (b) In eukaryotes, the initial transcript is often the precursor to final mRNAs, tRNAs, and rRNAs. The precursor is then modified and/or processed into its final functional form. RNA splicing is one type of processing to remove the noncoding introns (the region between coding exons) on an mRNA. (c) In contrast to bacterial DNA, eukaryotic DNA often is packaged with histone and nonhistone proteins into chromatins. Transcription will only occur when the chromatin structure changes in such a way that DNA is accessible to the polymerase. (d) RNA is made in the nucleus and transported into cytoplasm, where translation occurs. Therefore, unlike bacteria, eukaryotes undergo uncoupled transcription and translation. 448 Table 15-2 The genetic code PART I Second Base in Codon U First Base U in Codon BASIC CONSIDERATIONS C A G C A G UUU Phe [F] UCU Ser [S] UAU Tyr [Y] UGU Cys [C] U UUC Phe [F] UCC Ser [S] UAC Tyr [Y] UGC Cys [C] C UUA Leu [L] UCA Ser [S] UAA STOP — UGA STOP — A UUG Leu [L] UCG Ser [S] UAG STOP — UGG Trp [W] G CUU Leu [L] CCU Pro [P] CAU His [H] CGU Arg [R] U CUC Leu [L] CCC Pro [P] CAC His [H] CGC Arg [R] C CUA Leu [L] CCA Pro [P] CAA Gln [Q] CGA Arg [R] A CUG Leu [L] CCG Pro [P] CAG Gln [Q] CGG Arg [R] G AUU Ile [I] ACU Thr [T] AAU Asn [N] AGU Ser [S] U AUC Ile [I] ACC Thr [T] AAC Asn [N] AGC Ser [S] C AUA Ile [I] ACA Thr [T] AAA Lys [K] AGA Arg [R] A AUG Met [M] ACG Thr [T] AAG Lys [K] AGG Arg [R] G GUU Val [V] GCU Ala [A] GAU Asp [D] GGU Gly [G] U GUC Val [V] GCC Ala [A] GAC Asp [D] GGC Gly [G] C GUA Val [V] GCA Ala [A] GAA Glu [E] GGA Gly [G] A GUG Val [V] GCG Ala [A] GAG Glu [E] GGG Gly [G] G Third Base in Codon A = adenine; C = cytosine; G = guanine; U = uracil; Ala = alanine; Arg = arginine; Asn = asparagine; Asp = aspartic acid; Cys = cysteine; Glu = glutamic acid; Gln = glutamine; Gly = glycine; His = histidine; Ile = isoleucine; Leu = leucine; Lys = lysine; Met = methionine; Phe = phenylalanine; Pro = proline; Ser = serine; Thr = threonine; Trp = tryptophan; Tyr = tyrosine; Val = valine. Letter in [ ] indicates single letter code for amino acid. Unfolded inactive protein Folded inactive protein Posttranslational modification (e.g., phosphorylation) P Cofactor binding Binding protein Mature inactive protein Figure 15-5. Maturation of a functional protein. Although the linear amino acid sequence of a protein often is shown, the function of a protein also is controlled by its correctly folded three-dimensional structure. In addition, many proteins also have covalent posttranslational modifications such as phosphorylation or noncovalent binding to a small molecule or a protein. different characteristics, contain the same genetic material. This cellular diversity is controlled by the genome and accomplished by tight regulation of gene expression. This leads to the synthesis and accumulation of different complements of RNA and, ultimately, to the proteins found in different cell types. For example, muscle and bone express different genes or the same genes at different times. Moreover, the choice of which genes are expressed in a given cell at a given time depends on signals received from its environment. There are multiple levels at which gene expression can be controlled along the pathway from DNA to RNA to protein (see Fig. 15-4). Transcriptional control refers to the mechanism for regulating when and how often a gene is transcribed. Splicing of the primary RNA transcript (RNA processing control) and selection of completed mRNAs for nuclear export (RNA transport control) represent additional potential regulatory steps. The mRNAs in the cytoplasm can be selectively translated by ribosomes (translational control) or selectively stabilized or degraded (mRNA degradation control). Finally, the resulting proteins can undergo selective activation, inactivation, or compartmentalization (protein activity control). Because a large number of genes are regulated at the transcriptional level, regulation of gene transcripts (i.e., mRNA) often is referred to as gene regulation in a narrow definition. Each of the steps during transcription is properly regulated in eukaryotic cells. Because genes are differentially regulated from one another, one gene can be differentially regulated in different cell types or at different developmental stages. Therefore, gene regulation at the level of transcription is largely context VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ TF Pol II Holoenzyme TBP TFBS TATA Figure 15-6. Transcriptional control by RNA polymerase. DNA is packaged into a chromatin structure. TATA = the common sequence on the promoter recognized by TBP and polymerase II holoenzyme; TBP = TATA-binding protein and associated factors; TF = hypothetical transcription factor; TFBS = transcription factor binding site; ball-shaped structures = nucleosomes. Coactivator or corepressor is a factor linking the TF with the Pol II complex. dependent. However, there is a common scheme that applies to transcription at the molecular level (Fig. 15-6). Each gene promoter possesses unique sequences called TATA boxes that can be recognized and bound by a large complex containing RNA polymerase II, forming the basal transcription machinery. Usually located upstream of the TATA box (but sometimes longer distances) are a number of regulatory sequences referred to as enhancers that are recognized by regulatory proteins called transcription factors. These transcription factors specifically bind to the enhancers, often in response to environmental or developmental cues, and cooperate with each other and with basal transcription factors to initiate transcription. Regulatory sequences that negatively regulate the initiation of transcription also are present on the promoter DNA. The transcription factors that bind to these sites are called repressors, in contrast to the activators that activate transcription. The molecular interactions between transcription factors and promoter DNA, as well as between the cooperative transcription factors, are highly regulated and context-dependent. Specifically, the recruitment of transcription factors to the promoter DNA occurs in response to physiologic signals. A number of structural motifs in these DNA-binding transcription factors facilitate this recognition and interaction. These include the helix-turn-helix, the homeodomain motif, the zinc finger, the leucine zipper, and the helixloop-helix motifs. Human Genome Genome is a collective term for all genes present in one organism. The human genome contains DNA sequences of 3 billion base pairs, carried by 23 pairs of chromosomes. The human genome has an estimated 25,000 to 30,000 genes, and overall, it is 99.9% identical in all people.7,8 Approximately 3 million locations where single-base DNA differences exist have been identified and termed single nucleotide polymorphisms. Single nucleotide polymorphisms may be critical determinants of human variation in disease susceptibility and responses to environmental factors. The completion of the human genome sequence in 2003 represented another great milestone in modern science. The Human Genome Project created the field of genomics, which is the study of genetic material in detail (see Fig. 15-1). The medical field is building on the knowledge, resources, and technologies emanating from the human genome to further the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 449 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY Coactivator or Corepressor understanding of the relationship of the genes and their mutations to human health and disease. This expansion of genomics into human health applications resulted in the field of genomic medicine. The emergence of genomics as a science will transform the practice of medicine and surgery in this century. This 3 breakthrough has allowed scientists the opportunity to gain remarkable insights into the lives of humans. Ultimately, the goal is to use this information to develop new ways to treat, cure, or even prevent the thousands of diseases that afflict humankind. In the twenty-first century, work will begin to incorporate the information embedded in the human genome sequence into surgical practices. By doing so, the genomic information can be used for diagnosing and predicting disease and disease susceptibility. Diagnostic tests can be designed to detect errant genes in patients suspected of having particular diseases or of being at risk for developing them. Furthermore, exploration into the function of each human gene is now possible, which will shed light on how faulty genes play a role in disease causation. This knowledge also makes possible the development of a new generation of therapeutics based on genes. Drug design is being revolutionized as researchers create new classes of medicines based on a reasoned approach to the use of information on gene sequence and protein structure function rather than the traditional trial-and-error method. Drugs targeted to specific sites in the body promise to have fewer side effects than many of today’s medicines. Finally, other applications of genomics will involve the transfer of genes to replace defective versions or the use of gene therapy to enhance normal functions such as immunity. Proteomics refers to the study of the structure and expression of proteins as well as the interactions among proteins encoded by a human genome (see Fig. 15-1).9 A number of Internet-based repositories for protein sequences exist, including Swiss-Prot (http://www.expasy.ch). These databases allow comparisons of newly identified proteins with previously characterized sequences to allow prediction of similarities, identification of splice variants, and prediction of membrane topology and posttranslational modifications. Tools for proteomic profiling include two-dimensional gel electrophoresis, time-of-flight mass spectrometry, matrix-assisted laser desorption/ionization, and protein microarrays. Structural proteomics aims to describe the three-dimensional structure of proteins that is critical to understanding function. Functional genomics seeks to assign a biochemical, physiologic, cell biologic, and/or developmental function to each predicted gene. An ever-increasing arsenal of approaches, including transgenic animals, RNA interference (RNAi), and various systematic mutational strategies, will allow dissection of functions associated with newly discovered genes. Although the potential of this field of study is vast, it is in its early stages. It is anticipated that a genomic and proteomic approach to human disease will lead to a new understanding of pathogenesis that will aid in the development of effective strategies for early diagnosis and treatment.10 For example, identification of altered protein expression in organs, cells, subcellular structures, or protein complexes may lead to development of new biomarkers for disease detection. Moreover, improved understanding of how protein structure determines function will allow rational identification of therapeutic targets, and thereby not only accelerate drug development, but also lead to new strategies to evaluate therapeutic efficacy and potential toxicity.9 450 Cell Cycle and Apoptosis PART I BASIC CONSIDERATIONS Every organism is composed of many different cell types at different developmental stages. Some cell types continue to grow, while some cells stop growing after a developmental stage or resume growth after a break. For example, embryonic stem cells grow continuously, while nerve cells and striated muscle cells stop dividing after maturation. Cell cycle is the process for every cell including DNA replication and protein synthesis, DNA segregation in half, and package DNA and protein in two newly formed cells to enable passage of identical genetic information from one parental cell to two daughter cells. Thus, the cell cycle is the fundamental mechanism to maintain tissue homeostasis. A cell cycle comprises four periods: G1 (first gap phase before DNA synthesis), S (synthesis phase when DNA replication occurs), G2 (the gap phase before mitosis), and M (mitosis, the phase when two daughter cells with identical DNA are generated) (Fig. 15-7). After a full cycle, the daughter cells enter G1 again, and when they receive appropriate signals, undergo another cycle, and so on. The machinery that drives cell cycle progression is made up of a group of enzymes called cyclin-dependent kinases (CDKs). Cyclin expression fluctuates during the cell cycle, and cyclins are essential for CDK activities and form complexes with CDK. The cyclin A/CDK1 and cyclin B/CDK1 drive the progression for the M phase, while cyclin A/CDK2 is the primary S phase complex. Early G1 cyclin D/CDK4/6 or late G1 cyclin E/CDK2 controls the G1-S transition. There also are negative regulators for CDK termed CDK inhibitors, which inhibit the assembly or activity of the cyclinCDK complex. Expression of cyclins and CDK inhibitors often is regulated by developmental and environmental factors. The cell cycle is connected with signal transduction pathways as well as gene expression. Although the S and M phases rarely are subjected to changes imposed by extracellular signals, the G1 and G2 phases are the primary periods when cells decide B/CDK1 Mitosis M G2 Signal Transduction Pathways G1 S A/CDK1 DNA replication A/CDK2 whether or not to move on to the next phase. During the G1 phase, cells receive green- or red-light signals, S phase entry or G1 arrest, respectively. Growing cells proliferate only when supplied with appropriate mitogenic growth factors. Cells become committed to entry of the cell cycle only toward the end of G1. Mitogenic signals stimulate the activity of early G1 CDKs (e.g., cyclin D/ CDK4) that inhibit the activity of pRb protein and activate the transcription factor called E2F to induce the expression of batteries of genes essential for G1-S progression. Meanwhile, cells also receive antiproliferative signals such as those from tumor suppressors. These antiproliferative signals also act in the G1 phase to stop cells’ progress into the S phase by inducing CKI production. For example, when DNA is damaged, cells will repair the damage before entering the S phase. Therefore, G1 contains one of the most important checkpoints for cell cycle progression. If the analogy is made that CDK is to a cell as an engine is to a car, then cyclins and CKI are the gas pedal and brake, respectively. Accelerated proliferation or improper cell cycle progression with damaged DNA would be disastrous. Genetic gain-of-function mutations in oncogenes (that often promote expression or activity of the cyclin/CDK complex) or loss-of-function mutations in tumor suppressor (that stimulate production of CKI) are causal factors for malignant transformation. In addition to cell cycle control, cells use genetically programmed mechanisms to kill cells. This cellular process, called apoptosis or programmed cell death, is essential for the maintenance of tissue homeostasis (Fig. 15-8). Normal tissues undergo proper apoptosis to remove unwanted cells, those that have completed their jobs or have been damaged or improperly proliferated. Apoptosis can be activated by many physiologic stimuli such as death receptor signals (e.g., Fas or cytokine tumor necrosis factor), growth factor deprivation, DNA damage, and stress signals. Two major pathways control the biochemical mechanisms governing apoptosis: the death receptor and mitochondrial. However, recent advances in apoptosis research suggest an interconnection of the two pathways. What is central to the apoptotic machinery is the activation of a cascade of proteinases called caspases. Similarly to CDK in the cell cycle, activities and expression of caspases are well controlled by positive and negative regulators. The complex machinery of apoptosis must be tightly controlled. Perturbations of this process can cause neoplastic transformation or other diseases. D/CDK4 D/CDK6 E/CDK2 Figure 15-7. The cell cycle and its control system. M is the mitosis phase, when the nucleus and the cytoplasm divide; S is the phase when DNA is duplicated; G1 is the gap between M and S; G2 is the gap between S and M. A complex of cyclin and cyclindependent kinase (CDK) controls specific events of each phase. Without cyclin, CDK is inactive. Different cyclin/CDK complexes are shown around the cell cycle. A, B, D, and E stand for cyclin A, cyclin B, cyclin D, and cyclin E, respectively. Gene expression in a genome is controlled in a temporal and spatial manner, at least in part by signaling pathways.11 A signaling pathway generally begins at the cell surface and, after a signaling relay by a cascade of intracellular effectors, ends up in the nucleus (Fig. 15-9). All cells have the ability to sense changes in their external environment. The bioactive substances to which cells can respond are many and include proteins, short peptides, amino acids, nucleotides/nucleosides, steroids, retinoids, fatty acids, and dissolved gases. Some of these substances are lipophilic and thereby can cross the plasma membrane by diffusion to bind to a specific target protein within the cytoplasm (intracellular receptor). Other substances bind directly with a transmembrane protein (cell-surface receptor). Binding of ligand to receptor initiates a series of biochemical reactions (signal transduction) typically involving protein-protein interactions and the transfer of high-energy phosphate groups, leading to various cellular end responses. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 451 Death signal (e.g., TNF or Fas) Mitochondrion Death receptor signaling pathway Cytochrome c release Activation of caspase cascade Apoptotic target cell Nucleus Normal target cell Ligand (e.g., growth factor) Ligand (e.g., hormone) Cell-surface receptor Plasma membrane Signaling cascade Intracellular receptor Nucleus Gene expression Figure 15-9. Cell-surface and intracellular receptor pathways. Extracellular signaling pathway: Most growth factors and other hydrophilic signaling molecules are unable to move across the plasma membrane and directly activate cell-surface receptors such as G-protein–coupled receptors and enzyme-linked receptors. The receptor serves as the receiver, and in turn activates the downstream signals in the cell. Intracellular signaling pathway: Hormones or other diffusible molecules enter the cell and bind to the intracellular receptor in the cytoplasm or in the nucleus. Either extracellular or intracellular signals often reach the nucleus to control gene expression. Figure 15-8. A simplified view of the apoptosis pathways. Extracellular death receptor pathways include the activation of Fas and tumor necrosis factor (TNF) receptors, and consequent activation of the caspase pathway. Intracellular death pathway indicates the release of cytochrome c from mitochondria, which also triggers the activation of the caspase cascade. During apoptosis, cells undergo DNA fragmentation and nuclear and cell membrane breakdown, and are eventually digested by other cells. Control and specificity through simple protein-protein interactions—referred to as adhesive interactions—is a common feature of signal transduction pathways in cells.12 Signaling also involves catalytic activities of signaling molecules, such as protein kinases/phosphatases, that modify the structures of key signaling proteins. Upon binding and/or modification by upstream signaling molecules, downstream effectors undergo a conformational (allosteric) change and, consequently, a change in function. The signal that originates at the cell surface and is relayed by the cytoplasmic proteins often ultimately reaches the transcriptional apparatus in the nucleus. It alters the DNA binding and activities of transcription factors that directly turn genes on or off in response to the stimuli. Abnormal alterations in signaling activities and capacities in otherwise normal cells can lead to diseases such as cancer. Advances in biology in the last two decades have dramatically expanded the view on how cells are wired with signaling pathways. In a given cell, many signaling pathways operate simultaneously and crosstalk with one another. A cell generally may react to a hormonal signal in a variety of ways: (a) by changing its metabolite or protein, (b) by generating an electric current, or (c) by contracting. Cells continually are subject to multiple input signals that simultaneously and sequentially activate multiple receptor- and non–receptor-mediated signal transduction pathways, which form a signaling network. Although the regulators responsible for cell behavior are rapidly identified as a result of genomic and proteomic techniques, the specific functions of the individual proteins, how they assemble, and the networks that control cellular behavior remain to be defined. An increased understanding of cell regulatory pathways—and how they are disrupted in disease—will likely reveal common themes based on protein interaction domains that direct associations of proteins with other polypeptides, phospholipids, nucleic acids, and other regulatory molecules. Advances in the understanding of signaling networks will require methods of investigation that move beyond traditional “linear” approaches into VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 15 MOLECULAR AND GENOMIC SURGERY Plasma membrane Death receptor 452 PART I BASIC CONSIDERATIONS medical informatics and computational biology. The bewildering biocomplexity of such networks mandates multidisciplinary and transdisciplinary research collaboration. The vast amount of information that is rapidly emerging from genomic and proteomic data mining will require the development of new modeling methodologies within the emerging disciplines of medical mathematics and physics. Signaling pathways often are grouped according to the properties of signaling receptors. Many hydrophobic signaling molecules are able to diffuse across plasma membranes and directly reach specific cytoplasmic targets. Steroid hormones, thyroid hormones, retinoids, and vitamin D are examples that exert their activity upon binding to structurally related receptor proteins that are members of the nuclear hormone receptor superfamily. Ligand binding induces a conformational change that enhances transcriptional activity of these receptors. Most extracellular signaling molecules interact with transmembrane protein receptors that couple ligand binding to intracellular signals, leading to biologic actions. There are three major classes of cell-surface receptors: transmitter-gated ion channels, seven-transmembrane G-protein–­coupled receptors (GPCRs), and enzyme-linked receptors. The superfamily of GPCRs is one of the largest families of proteins, representing over 800 genes of the human genome. Members of this superfamily share a characteristic seven-transmembrane configuration. The ligands for these receptors are diverse and include hormones, chemokines, neurotransmitters, proteinases, inflammatory mediators, and even sensory signals such as odorants and photons. Most GPCRs signal through heterotrimeric G proteins, which are guaninenucleotide regulatory complexes. Thus the receptor serves as the receiver, the G protein serves as the transducer, and the enzyme serves as the effector arm. Enzyme-linked receptors possess an extracellular ligand-recognition domain and a cytosolic domain that either has intrinsic enzymatic activity or directly links with an enzyme. Structurally, these receptors usually have only one transmembrane-spanning domain. Of at least five forms of enzyme-linked receptors classified by the nature of the enzyme activity to which they are coupled, the growth factor receptors such as tyrosine kinase receptor or serine/threonine kinase receptors mediate diverse cellular events including cell growth, differentiation, metabolism, and survival/apoptosis. Dysregulation (particularly mutations) of these receptors is thought to underlie conditions of abnormal cellular proliferation in the context of cancer. The following sections will further review two examples of growth factor signaling pathways and their connection with human diseases. Insulin Pathway and Diabetes.13 The discovery of insulin in the early 1920s is one of the most dramatic events in the treatment of human disease. Insulin is a peptide hormone that is secreted by the β-cell of the pancreas. Insulin is required for the growth and metabolism of most mammalian cells, which contain cell-surface insulin receptors (InsR). Insulin binding to InsR activates the kinase activity of InsR. InsR then adds phosphoryl groups, a process referred to as phosphorylation, and subsequently activates its immediate intracellular effector, called insulin receptor substrate (IRS). IRS plays a central role in coordinating the signaling of insulin by activating distinct signaling pathways, the PI3K-Akt pathway and MAPK pathway, both of which possess multiple protein kinases that can control transcription, protein synthesis, and glycolysis (Fig. 15-10). Insulin receptor (InsR) Insulin Adaptor IRS MAPK cascade Lipid & glucose metabolism Plasma membrane PI3K Cell survival Nucleus Gene expression Figure 15-10. Insulin-signaling pathway. Insulin is a peptide growth factor that binds to and activates the heterotetrameric receptor complex (InsR). InsR possesses protein tyrosine kinase activity and is able to phosphorylate the downstream insulin receptor substrate (IRS). Phosphorylated IRS serves as a scaffold and controls the activation of multiple downstream pathways for gene expression, cell survival, and glucose metabolism. Inactivation of the insulin pathway can lead to type 2 diabetes. The primary physiologic role of insulin is in glucose homeostasis, which is accomplished through the stimulation of glucose uptake into insulin-sensitive tissues such as fat and skeletal muscle. Defects in insulin synthesis/secretion and/ or responsiveness are major causal factors in diabetes, one of the leading causes of death and disability in the United States, affecting an estimated 16 million Americans. Type 2 diabetes accounts for about 90% of all cases of diabetes. Clustering of type 2 diabetes in certain families and ethnic populations points to a strong genetic background for the disease. More than 90% of affected individuals have insulin resistance, which develops when the body is no longer able to respond correctly to insulin circulating in the blood. Although relatively little is known about the biochemical basis of this metabolic disorder, it is clear that the insulin-signaling pathways malfunction in this disease. It is also known that genetic mutations in the InsR or IRS cause type 2 diabetes, although which one is not certain. The m ­ ajority of type 2 diabetes cases may result from defects in downstreamsignaling components in the insulin-signaling pathway. Type 2 diabetes also is associated with declining β-cell function, resulting in reduced insulin secretion; these pathways are under intense study. A full understanding of the basis of insulin resistance is crucial for the development of new therapies for type 2 diabetes. Furthermore, apart from type 2 diabetes, insulin resistance is a central feature of several other common human disorders, including atherosclerosis and coronary artery disease, hypertension, and obesity. Transforming Growth Factor-β (TGF-β) Pathway and C­ ancers.14 Growth factor signaling controls cell growth, differentiation, and apoptosis. Although insulin and many mitogenic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ TGF β Plasma membrane SMAD Nucleus Gene expression Antiproliferation Figure 15-11. TGF-β signaling pathway. The TGF-β family has at least 29 members encoded in the human genome. They are also peptide growth factors. Each member binds to a heterotetrameric complex consisting of a distinct set of type I and type II receptors. TGF-β receptors are protein serine/threonine kinases and can phosphorylate the downstream substrates called SMAD proteins. Phosphorylated SMADs are directly transported into the nucleus, where they bind to the DNA and regulate gene expression that is responsible for inhibition of cell proliferation. Inactivation of the TGF-β pathway through genetic mutations in the TGF-β receptors or SMADs is frequent in human cancer, leading to the uncontrolled proliferation of cancer cells. growth factors promote cell proliferation, some growth factors and hormones inhibit cell proliferation. TGF-β is one of them. The balance between mitogens and TGF-β plays an important role in controlling the proper pace of cell cycle progression. The growth inhibition function of TGF-β signaling in epithelial cells plays a major role in maintaining tissue homeostasis. The TGF-β superfamily comprises a large number of structurally related growth and differentiation factors that act through a receptor complex at the cell surface (Fig. 15-11). The complex consists of transmembrane serine/threonine kinases. The receptor signals through activation of heterotrimeric complexes of intracellular effectors called SMADs (which are contracted from homologous Caenorhabditis elegans Sma and Drosophila Mad, two evolutionarily conserved genes for TGF-β signaling). Upon phosphorylation by the receptors, SMAD complexes translocate into the nucleus, where they bind to gene promoters and cooperate with specific transcription factors to regulate the expression of genes that control cell proliferation and differentiation. For example, TGF-β strongly induces the transcription of a gene called p15INK4B (a type of CKI) and, at the same time, reduces the expression of many oncogenes such as c-Myc. The outcome of the altered gene expression leads to the inhibition of cell cycle progression. Meanwhile, the strength and duration of TGF-β signaling is fine-tuned by a variety of positive or negative modulators, including protein phosphatases. Therefore, controlled activation of TGF-β signaling is an intrinsic mechanism for cells to ensure controlled proliferation. Gene Therapy and Molecular Drugs in Cancer Modern advances in the use of molecular biology to manipulate genomes have greatly contributed to the understanding of the molecular basis for how cells live, die, or differentiate. Given the fact that human diseases arise from improper changes in the genome, the continuous understanding of how the genome functions will make it possible to tailor medicine on an individual basis. Although significant hurdles remain, the course toward therapeutic application of molecular biology already has been mapped out by many proof-of-principle studies in the literature. In this section, cancer is used as an example to elaborate some therapeutic applications of molecular biology. Modern molecular medicine includes gene therapy and molecular drugs that target genes or gene products that wire human cells. Cancer is a complex disease, involving uncontrolled growth and spread of tumor cells (Fig. 15-12). Cancer development depends on the acquisition and selection of specific characteristics that set the tumor cell apart from normal somatic cells. Cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis. Many lines of evidence indicate that tumorigenesis in humans is a multistep process and that these steps reflect genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives. The genomes of tumor cells are invariably altered at multiple sites, having suffered disruption through lesions as subtle as point mutations and as obvious as changes in chromosome complement. A succession of genetic changes, each conferring one or another type of growth advantage, leads to the progressive conversion of normal human cells into cancer cells. Cancer research in the past 20 years has generated a rich and complex body of knowledge, revealing cancer to be a disease involving dynamic changes in the genome. The causes of cancer include genetic predisposition, environmental influences, infectious agents, and aging. These transform normal cells into cancerous ones by derailing a wide spectrum of regulatory pathways including signal transduction pathways, cell VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 453 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY TGF β receptor Resistance to TGF-β’s anticancer action is one hallmark of human cancer cells. TGF-β receptors and SMADs are identified as tumor suppressors. The TGF-β signaling circuit can be disrupted in a variety of ways and in different types of human tumors. Some lose TGF-β responsiveness through downregulation or mutations of their TGF-β receptors. The cytoplasmic SMAD4 protein, which transduces signals from ligand-activated TGF-β receptors to downstream targets, may be eliminated through mutation of its encoding gene. The locus encoding cell cycle inhibitor p15INK4B may be deleted. Alternatively, the immediate downstream target of its actions, cyclindependent kinase 4 (CDK4), may become unresponsive to the inhibitory actions of p15INK4B because of mutations that block p15INK4B binding. The resulting cyclin D/CDK4 complexes constitutively inactivate tumor suppressor pRb by hyperphosphorylation. Finally, functional pRb, the end target of this pathway, may be lost through mutation of its gene. For example, in pancreatic and colorectal cancers, 100% of cells derived from these cancers carry genetic defects in the TGF-β signaling pathway. Therefore, the antiproliferative pathway converging onto pRb and the cell division cycle is, in one way or another, disrupted in a majority of human cancer cells. Besides cancer, dysregulation of TGF-β signaling also has been associated with other human diseases such as Marfan’s syndrome and thoracic aortic aneurysm. 454 Mutant epithelial cell PART I Cell with two mutations BASIC CONSIDERATIONS Cell with multiple mutations Normal epithelial cell Cell proliferation Cell proliferation Uncontrolled cell proliferation Tumor cells break loose and enter bloodstream Blood vessel Tumor cells escape from blood vessel and proliferate to form metastatic tumors Figure 15-12. Tumor clonal evolution and metastasis. A tumor develops from mutant cells with multiple genetic mutations. Through repeated alterations in the genome, mutant epithelial cells are able to develop into a cluster of cells (called a tumor clone) that proliferates in an uncontrollable fashion. Further changes in the tumor cells can transform the tumor cells into a population of cells that can enter the blood vessels and repopulate in a new location. cycle machinery, or apoptotic pathways.15,16 The early notion that cancer was caused by mutations in genes critical for the control of cell growth implied that genome stability is important for preventing oncogenesis. There are two classes of cancer genes in which alteration has been identified in human and animal cancer cells: oncogenes, with dominant gain-of-function ­mutations, and tumor suppressor genes, with recessive loss-­offunction mutations. In normal cells, oncogenes promote cell growth by activating cell cycle progression, whereas tumor suppressors counteract oncogenes’ functions. Therefore, the balance between oncogenes and tumor suppressors maintains a well-controlled state of cell growth. During the development of most types of human cancer, cancer cells can break away from primary tumor masses, invade adjacent tissues, and hence travel to distant sites where they form new colonies. This spreading process of tumor cells, called metastasis, is the cause of 90% of human cancer deaths. Metastatic cancer cells that enter the bloodstream can reach virtually all tissues of the body. Bones are one of the most common places for these cells to settle and start growing again. Bone metastasis is one of the most frequent causes of pain in people with cancer. It also can cause bones to break and create other symptoms and problems for patients. The progression in the knowledge of cancer biology has been accelerating in recent years. All of the scientific knowledge acquired through hard work and discovery has made it possible for cancer treatment and prevention. As a result of explosive new discoveries, some modern treatments were developed. The success of these therapies, together with traditional treatments such as surgical procedures, is further underscored by the fact that in 2002 the cancer rate was reduced in the United States. Current approaches to the treatment of cancer involve killing cancer cells with toxic chemicals, radiation, or surgery. Alternatively, several new biologic- and gene-based therapies are aimed at enhancing the body’s natural defenses against invading cancers. Understanding the biology of cancer cells has led to the development of designer therapies for cancer prevention and treatment. Gene therapy, immune system modulation, genetically engineered antibodies, and molecularly designed chemical drugs are all promising fronts in the war against cancer. Immunotherapy. The growth of the body is controlled by many natural signals through complex signaling pathways. Some of these natural agents have been used in cancer treatment and have been proven effective for fighting several cancers through the clinical trial process. These naturally occurring biologic agents, such as interferons, interleukins, and other cytokines, can now be produced in the laboratory. These agents, as well as the synthetic agents that mimic the natural signals, are given to patients to influence the natural immune response agents either by directly altering the cancer cell growth or by acting indirectly to help healthy cells control the cancer. One of the most exciting applications of immunotherapy has come from the identification of certain tumor targets called antigens and the aiming of an antibody at these targets. This was first used as a means of localizing tumors in the body for diagnosis and was more recently used to attack cancer cells. Trastuzumab (Herceptin) is an example of such a drug.17 Trastuzumab is a monoclonal antibody that neutralizes the mitogenic activity of cell-surface growth factor receptor HER-2, which is overexpressed in approximately 25% of breast cancers. HER-2–overexpressing tumors tend to grow faster and generally are more likely to recur than tumors that do not overproduce HER-2. Trastuzumab is designed to attack cancer cells that overexpress HER-2 by slowing or preventing the growth of these cells, resulting in increased survival of HER-2–positive breast cancer patients. Another significant example is the administration of interleukin-2 (IL-2) to patients with metastatic melanoma or kidney cancer, which has been VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Chemotherapy. The primary function of anticancer chemicals is to block different steps involved in cell growth and replication. These chemicals often block a critical chemical reaction in a signal transduction pathway or during DNA replication or gene expression. For example, STI571, also known as Gleevec, is one of the first molecularly targeted drugs based on the changes that cancer causes in cells.18 STI571 offers promise for the treatment of chronic myeloid leukemia (CML) and may soon surpass interferon-γ as the standard treatment for the disease. In CML, STI571 is targeted at the Bcr-Abl kinase, an activated oncogene product in CML (Fig. 15-13). Bcr-Abl is an overly activated ­protein kinase resulting from a specific genetic abnormality generated by chromosomal translocation that is found in the cells of patients with CML. STI571-mediated inhibition of Bcr-Abl kinase activity not only prevents cell growth of Bcr-Abl–­transformed leukemic cells, but also induces apoptosis. Clinically, the drug quickly corrects the blood cell abnormalities caused by the leukemia in a majority of patients, achieving a complete disappearance of the leukemic blood cells and the return of normal blood cells. ­Additionally, the drug appears to have some effect on other ­cancers including certain brain tumors and gastrointestinal (GI) stromal tumors, a very rare type of stomach cancer. Gene Therapy. Gene therapy is an experimental treatment that involves genetically altering a patient’s own tumor cells or lymphocytes (cells of the immune system, some of which can attack cancer cells). For years, the concept of gene therapy has held promise as a new, potentially potent weapon to attack cancer. Although a rapid progression in the understanding of Bcr-Abl kinase Bcr-Abl kinase ATP the molecular and clinical aspects of gene therapy has been witnessed in the past decade, gene therapy treatment has not yet been shown to be superior to standard treatments in humans. Several problems must be resolved to transform it into a clinically relevant form of therapy. The major issues that limit its translation to the clinic are improving the selectivity of tumor targeting, improving the delivery to the tumor, and the enhancement of the transduction rate of the cells of interest. In most gene therapy trials for malignant diseases, tumors can be accessed and directly injected (in situ gene therapy). The in situ gene therapy also offers a better distribution of the vector virus throughout the tumor. Finally, a combination of gene therapy strategies will be more effective than the use of a single gene therapy system. An important aspect of effective gene therapy involves the choice of appropriate genes for manipulation. Genes that promote the production of messenger chemicals or other immune-active substances can be transferred into the patient’s cells. These include genes that inhibit cell cycle progression, induce apoptosis, enhance host immunity against cancer cells, block the ability of cancer cells to metastasize, and cause tumor cells to undergo suicide. Recent development of RNAi technology, which uses a loss-of-function approach to block gene functions, ensures a new wave of hopes for gene therapy. Nonetheless, gene therapy is still experimental and is being studied in clinical trials for many different types of cancer. The mapping of genes responsible for human cancer is likely to provide new targets for gene therapy in the future. The preliminary results of gene therapy for cancer are encouraging, and as advancements are made in the understanding of the molecular biology of human cancer, the future of this rapidly developing field holds great potential for treating cancer. It is noteworthy that the use of multiple therapeutic methods has proven more powerful than a single method. The use of chemotherapy after surgery to destroy the few remaining cancerous cells in the body is called adjuvant therapy. Adjuvant therapy was first tested and found to be effective in breast cancer. It was later adopted for use in other cancers. A major discovery in chemotherapy is the advantage of multiple chemotherapeutic agents (known as combination or cocktail chemotherapy) over single agents. Some types of fast-growing leukemias and lymphomas (tumors involving the cells of the bone marrow and lymph nodes) responded extremely well to combination chemotherapy, and clinical trials led to gradual improvement of the drug combinations used. Many of these tumors can be cured today by combination chemotherapy. As Bcr-Abl kinase STI571 PO4 Tyr Tyr Tyr Substrate Substrate Substrate Inactive (In the absence of ATP) Overly active Blocked activity Uncontrolled cell proliferation Blocked cell proliferation VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 15-13. Mechanism of STI571 as a molecular drug. Bcr-Abl is an overly activated oncogene product resulting from a specific genetic abnormality generated by chromosomal translocation that is found in cells of patients with chronic myeloid leukemia. Bcr-Abl is an activated protein kinase and thus requires adenosine triphosphate (ATP) to phosphorylate substrates, which in turn promote cell proliferation. STI571 is a small molecule that competes with the ATPbinding site and thus blocks the transfer of phosphoryl group to substrate. PO4 = phosphate; Tyr = tyrosine. 455 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY shown to mediate the durable regression of metastatic cancer. IL-2, a cytokine produced by human helper T lymphocytes, has a wide range of immune regulatory effects, including the expansion of lymphocytes following activation by a specific antigen. Although IL-2 has no direct impact on cancer cells, the impact of IL-2 on cancers in vivo derives from its ability to expand lymphocytes with antitumor activity. The expanded lymphocyte pool enables recognition of the antigen on cancer cells. Thus, the molecular identification of cancer antigens has opened new possibilities for the development of effective immunotherapies for patients with cancer. Clinical studies using immunization with peptides derived from cancer antigens have shown that high levels of lymphocytes with antitumor activity can be produced in cancer-bearing patients. Highly avid antitumor lymphocytes can be isolated from immunized patients and grown in vitro for use in cell-transfer therapies. 456 PART I cancer cells carry multiple genetic defects, the use of combination chemotherapy, immunotherapy, and gene therapies may be more effective in treating cancers. using early embryos to generate ES cells, but also ensures a potentially limitless source of patient-specific stem cells for tissue engineering and regenerative medicine. Stem Cell Research The Atomic Theory of Disease22 BASIC CONSIDERATIONS Stem cell biology represents a cutting-edge scientific research field with potential clinical applications.19 It may have an enormous impact on human health by offering hope for curing human diseases such as diabetes mellitus, Parkinson’s disease, neurologic degeneration, and congenital heart disease. Stem cells are endowed with two remarkable properties (Fig. 15-14). First, stem cells can proliferate in an undifferentiated but pluripotent state and, as a result, can self-renew. Second, they have the ability to differentiate into many specialized cell types. There are two groups of stem cells: embryonic stem (ES) cells and adult stem cells. Human ES cells are derived from early preimplantation embryos called blastocysts (5 days postfertilization) and are capable of generating all differentiated germ layers in the body—ectoderm, mesoderm, and endoderm—and therefore are considered pluripotent. Adult stem cells are present in and can be isolated from adult tissues. They often are tissue specific and only can generate the cell types comprising a particular tissue in the body; therefore, they are considered multipotent. However, in some cases, they can transdifferentiate into cell types found in other tissues, called transdifferentiation. For example, hematopoietic stem cells are adult stem cells. They reside in bone marrow and are capable of generating all cell types of the blood and immune system. Stem cells can be grown in culture and be induced to differentiate into a particular cell type, either in vitro or in vivo. With the recent and continually increasing improvement in culturing stem cells, scientists are beginning to understand the molecular mechanisms of stem cell self-renewal and differentiation in response to environmental cues. It is believed that discovery of the signals that control self-renewal vs. differentiation will be extremely important for the therapeutic use of stem cells in treating disease. It is possible that success in the study of the changes in signal transduction pathways in stem cells will lead to the development of therapies to replace diseased or damaged cells in the body using stem cell derivatives. Recently, stem cell research has been transformed by the discovery from the Shinya Yamanaka group and the James Thomsen group, who have found that a simple genetic manipulation can reprogram adult differentiated cells back into pluripotent stem cells.20,21 This exciting discovery not only bypasses the ethical issues of The staggering advances in anatomy, physiology, and molecular biology over the past centuries have led us to our current state in which the atom is now the anatomy of the twenty-first century. As 99% of the body is composed of six elements ­(oxygen, carbon, hydrogen, nitrogen, calcium, and phosphorus), the next great advance in medicine will be bridging the subatomic, molecular, and genomic levels by forming an atomic theory of disease, which states that alterations in the composition of s­ ubatomic particles are the root cause of disease. The atomic theory of disease would include genetic alterations at the atomic/subatomic level that are akin to single nucleotide polymorphisms (SNPs), in which alleles for a gene differ on the exact nucleotide in a single location, which can change the ultimate protein structure. This can lead to subtle changes in function or dramatic results that cause pathology. We hypothesize that on a subatomic level, there could potentially be polymorphisms as well, in which there are subtle changes in the sea of subatomic particles. Isotopes, discovered 100 years ago, would fall into this category of subatomic polymorphism, as they differ in the number of neutrons present in the atom. Differences in other particles may not change the mass of the atom, but may alter some of the characteristics of the atom. A known example of a change in the subatomic milieu of an element leading to a disease process is that of methemoglobinemia, a disorder characterized by an overabundance of methemoglobin. Methemoglobin contains an oxidized form of iron (carrying an extra electron), as opposed to the reduced form in normal hemoglobin. This results in a shift in the oxygenhemoglobin dissociation curve to the left, causing hypoxia. Methemoglobinemia can be congenital, due to a defect in an enzyme that normally reduces methemoglobin back to hemoglobin, or acquired, caused by breakdown products of drugs that can oxidize hemoglobin. Although there is less than 1% of methemoglobin normally present in human tissues, affecting local blood flow and inflammation through its effects on nitric oxide and heme, large quantities can lead to respiratory failure and death. TECHNOLOGIES OF MOLECULAR AND CELL BIOLOGY DNA Cloning Differentiation Stem cell Terminally differentiated cell Self-renewal Figure 15-14. Stem cells. A stem cell is capable of self-renewal (unlimited cell cycle) and differentiation (becoming nondividing cells with specialized functions). Differentiating stem cells often undergo additional cell divisions before they become fully mature cells that carry out specific tissue functions. Since the advent of recombinant DNA technology three decades ago, hundreds of thousands of genes have been identified. Recombinant DNA technology is the technology that uses advanced enzymatic and microbiologic techniques to manipulate DNA.23 Pure pieces of any DNA can be inserted into bacteriophage DNA or other carrier DNA such as plasmids to produce recombinant DNA in bacteria. In this way, DNA can be reconstructed, amplified, and used to manipulate the functions of individual cells or even organisms. This technology, often referred to as DNA cloning, is the basis of all other DNA analysis methods. It is only with the awesome power of recombinant DNA technology that the completion of the Human Genome Project was possible. It also has led to the identification of the entire gene complements of organisms such as viruses, bacteria, worms, flies, and plants. Molecular cloning refers to the process of cloning a DNA fragment of interest into a DNA vector that ultimately VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Digest with restriction enzyme Insert DNA of interest Ligation E. coli containing recombinant plasmid Recombinant plasmid Introduce into E. coli E. coli containing recombinant plasmid Propagation Figure 15-15. Generation of recombinant DNA. The vector is a circular DNA molecule that is capable of replicating in Escherichia coli cells. Insert DNA (often your favorite gene) is ligated to the vector after ends of both DNA are properly treated with restriction enzymes. Ligated DNA (i.e., the recombinant plasmid DNA) is then transformed into E. coli cells, where it replicates to produce recombinant progenies. E. coli cells carrying the recombinant plasmid can be propagated to yield large quantities of plasmid DNA. is delivered into bacterial or mammalian cells or tissues24,25 (Fig. 15-15). This represents a very basic technique that is widely used in almost all areas of biomedical research. DNA vectors often are called plasmids, which are extrachromosomal molecules of DNA that vary in size and can replicate and be transmitted from bacterial cell to cell. Plasmids can be propagated either in the cytoplasm or after insertion, as part of the bacterial chromosome in Escherichia coli. The process of molecular cloning involves several steps of manipulation of DNA. First, the vector plasmid DNA is cleaved with a restriction enzyme to create compatible ends with the foreign DNA fragment to be cloned. The vector and the DNA fragment are then joined in vitro by a DNA ligase. Alternatively, DNA cloning can be simply done through the so-called Gateway Technology that allows for the rapid and efficient transfer of DNA fragments between different cloning vectors while maintaining reading frame and orientation, without the use of restriction endonucleases and DNA ligase. The technology, which is based on the site-specific recombination system of bacteriophage l, is simple, fast, robust, and automatable and thus compatible for high-throughput DNA cloning. Finally, the ligation product or the Gateway reaction product is introduced into competent host bacteria; this procedure is called transformation, which can be done by either calcium/ heat shock or electroporation. Precautions must be taken in every step of cloning to generate the desired DNA construct. The vector must be correctly prepared to maximize the creation of recombinants; for example, it must be enzymatically treated to prevent self-ligation. Host bacteria must be made sufficiently competent to permit the entry of recombinant plasmids into cells. The selection of desired recombinant plasmid-bearing E. coli normally is achieved by the property of drug resistance conferred by the plasmid vectors. The plasmids encoding markers provide specific resistance to (i.e., the ability to grow in the presence of) antibiotics such as ampicillin, kanamycin, and tetracycline. The foreign component in the plasmid vector can be a mammalian expression cassette, which can direct expression of foreign genes in mammalian cells. The resulting plasmid vector can be amplified in E. coli to prepare large quantities of DNA for its subsequent applications such as transfection, gene therapy, transgenics, and knockout mice. chemiluminescently labeled probe (Fig. 15-16).26 Southern blotting is named after E. M. Southern, who in 1975 first described the technique of DNA analysis. It enables reliable and efficient analysis of size-fractionated DNA fragments in an immobilized membrane support. Southern blotting is composed of several steps. It normally begins with the digestion of the DNA samples with appropriate restriction enzymes, which will discriminate wild-type and mutant DNA by size and the separation of DNA samples in an agarose gel by electrophoresis with appropriate DNA size markers, called the DNA ladder. The DNA gel is stained with a dye, usually ethidium DNA is digested with restriction enzymes. DNA fragments are denatured and separated by gel electrophoresis. DNA fragments are transferred to a membrane filter. Radioactive probe The filter is hybridized with a radioactive DNA probe. DNA fragment that is hybridized to the radioactive DNA is detected by autoradiography. Detection of Nucleic Acids and Proteins Southern Blot Hybridization. Southern blotting refers to the technique of transferring DNA fragments from an electrophoresis gel to a membrane support and the subsequent analysis of the fragments by hybridization with a radioactively or Figure 15-16. Southern blotting. Restriction enzymatic fragments of DNA are separated by agarose gel electrophoresis, transferred to a membrane filter, and then hybridized to a radioactive probe. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 15 MOLECULAR AND GENOMIC SURGERY Vector 457 458 PART I BASIC CONSIDERATIONS bromide, and photographed with a ruler laid alongside the gel so that band positions can later be identified on the membrane. The DNA gel then is treated so the DNA fragments are denatured (i.e., strand separation). The DNA then is transferred onto a nitrocellulose membrane by capillary diffusion or under electricity. After immobilization, the DNA can be subjected to hybridization analysis, enabling bands with sequence similarity to a radioactively or chemiluminescently labeled probe to be identified. The development of Southern transfer and the associated hybridization techniques made it possible for the first time to obtain information about the physical organization of single and multicopy sequences in complex genomes. The later application of Southern blotting hybridization to the study of restriction fragment length polymorphisms opened up new possibilities such as genetic fingerprinting and prenatal diagnosis of genetic diseases. DNA fragment by PCR reaction are affected by the proper setting of the reaction parameters (e.g., enzyme, primer, and Mg2+ concentration, as well as the temperature cycling profile). Modifying various PCR parameters to optimize the specificity of amplification yields more homogenous products, even in rare template reactions. The emergence of the PCR technique has dramatically altered the approach to both fundamental and applied biologic problems. The capability of amplifying a specific DNA fragment from a gene or the whole genome greatly advances the study of the gene and its function. It is simple, yet robust, speedy, and most of all, flexible. As a recombinant DNA tool, it underlies almost all of molecular biology. This revolutionary technique enabled the modern methods for the isolation of genes, construction of a DNA vector, introduction of alterations into DNA, and quantitation of gene expression, making it a fundamental cornerstone of genetic and molecular analysis. Northern Blot Hybridization. Northern blotting refers to the Immunoblotting and Immunoprecipitation. Analyses of technique of size fractionation of RNA in a gel and the transferring of an RNA sample to a solid support (membrane) in such a manner that the relative positions of the RNA molecules are maintained. The resulting membrane then is hybridized with a labeled probe complementary to the mRNA of interest. Signals generated from detection of the membrane can be used to determine the size and abundance of the target RNA. In principle, Northern blot hybridization is similar to Southern blot hybridization (and hence its name), with the exception that RNA, not DNA, is on the membrane. Although reverse-transcriptase PCR has been used in many applications (described in the next section, Polymerase Chain Reaction), Northern analysis is the only method that provides information regarding mRNA size and has remained a standard method for detection and quantitation of mRNA. The process of Northern hybridization involves several steps, as does Southern hybridization, including electrophoresis of RNA samples in an agarose-formaldehyde gel, transfer to a membrane support, and hybridization to a radioactively labeled DNA probe. Data from hybridization allow quantification of steady-state mRNA levels and, at the same time, provide information related to the presence, size, and integrity of discrete mRNA species. Thus, Northern blot analysis, also termed RNA gel blot analysis, commonly is used in molecular biology studies relating to gene expression. Polymerase Chain Reaction. PCR is an in vitro method for the polymerase-directed amplification of specific DNA sequences using two oligonucleotide primers that hybridize to opposite strands and flank the region of interest in the target DNA (Fig. 15-17).27 One cycle of PCR reaction involves template denaturation, primer annealing, and the extension of the annealed primers by DNA polymerase. Because the primer extension products synthesized in one cycle can serve as a template in the next, the number of target DNA copies nearly doubles at each cycle. Thus, a repeated series of cycles result in the exponential accumulation of a specific fragment in which the termini are sharply defined by the 5′ ends of the primers. The introduction of the thermostable DNA polymerase (e.g., Taq polymerase) transforms the PCR into a simple and robust reaction. The reaction components (e.g., template, primers, Taq polymerase, 2′-deoxynucleoside 5′-triphosphates, and buffer) could all be assembled and the amplification reaction carried out by simply cycling the temperatures within the reaction tube. The specificity and yield in amplifying a particular proteins are primarily carried out by antibody-directed immunologic techniques. For example, Western blotting, also called immunoblotting, is performed to detect protein levels in a population of cells or tissues, whereas immunoprecipitation is used to concentrate proteins from a larger pool. Using specific antibodies, microscopic analysis called immunofluorescence and immunohistochemistry is possible for the subcellular localization and expression of proteins in cells or tissues, respectively. Immunoblotting refers to the process of identifying a protein from a mixture of proteins (Fig. 15-18). It consists of five steps: (a) sample preparation; (b) electrophoresis (separation of a protein mixture by sodium dodecyl sulfate-polyacrylamide gel electrophoresis); (c) transfer (the electrophoretic transfer of proteins from gel onto membrane support [e.g., nitrocellulose, nylon, or polyvinylidene difluoride]); (d) staining (the subsequent immunodetection of target proteins with specific antibody); and (e) development (colorimetric, chemiluminescent, and recently fluorescent visualization of the antibody-­recognized protein). Thus, immunoblotting combines the resolution of gel electrophoresis with the specificity of immunochemical detection. Immunoblotting is a powerful tool used to determine a number of important characteristics of proteins. For example, immunoblotting analysis will determine the presence and the quantity of a protein in a given cellular condition and its relative molecular weight. Immunoblotting also can be used to determine whether posttranslational modification such as phosphorylation has occurred on a protein. Importantly, through immunoblotting analysis, a comparison of the protein levels and modification states in normal vs. diseased tissues is possible. Immunoprecipitation, another widely used immunochemical technique, is a method that uses antibody to enrich a protein of interest and any other proteins that are associated with it (Fig. 15-19). The principle of the technique lies in the property of a strong and specific affinity between antibodies and their antigens to locate and pull down target proteins in solution. Once the antibody-antigen (target protein) complexes are formed in the solution, they are collected and purified using small agarose beads with covalently attached protein A or protein G. Both protein A and protein G specifically interact with the antibodies, thus forming a large immobilized complex of antibody-antigen bound to beads. The purified protein can then be analyzed by a number of biochemical methods. When immunoprecipitation is combined with immunoblotting, it can VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 459 5' Hybridization of primers +DNA polymerase +dATP +dGTP +dCTP +dTTP DNA from synthesis primers 5' Step 1 Step 2 Step 3 First cycle A Separate DNA strands and annual primer Separate DNA strands and add primer DNA synthesis Separate DNA strands and annual primer DNA synthesis DNA synthesis Etc. DNA oligonucleotide primers Region of double-stranded DNA to be amplified First cycle Producing two double-stranded DNA molecules B Second cycle Producing four double-stranded DNA molecules Third cycle Producing eight double-stranded DNA molecules Figure 15-17. Amplification of DNA using the polymerase chain reaction (PCR) technique. Knowledge of the DNA sequence to be amplified is used to design two synthetic DNA oligonucleotides, each complementary to the sequence on one strand of the DNA double helix at opposite ends of the region to be amplified. These oligonucleotides serve as primers for in vitro DNA synthesis, which is performed by a DNA polymerase, and they determine the segment of the DNA that is amplified. A. PCR starts with a double-stranded DNA, and each cycle of the reaction begins with a brief heat treatment to separate the two strands (Step 1). After strand separation, cooling of the DNA in the presence of a large excess of the two primer DNA oligonucleotides allows these primers to hybridize to complementary sequences in the two DNA strands (Step 2). This mixture is then incubated with DNA polymerase and the four deoxyribonucleoside triphosphates so that DNA is synthesized, starting from the two primers (Step 3). The entire cycle is then begun again by a heat treatment to separate the newly synthesized DNA strands. B. As the procedure is performed over and over again, the newly synthesized fragments serve as templates in their turn, and, within a few cycles, the predominant DNA is identical to the sequence bracketed by and including the two primers in the original template. Of the DNA put into the original reaction, only the sequence bracketed by the two primers is amplified because there are no primers attached anywhere else. In the example illustrated in B, three cycles of reaction produce 16 DNA chains, eight of which (boxed in brown) are the same length as and correspond exactly to one or the other strand of the original bracketed sequence shown at the far left; the other strands contain extra DNA downstream of the original sequence, which is replicated in the first few cycles. After three more cycles, 240 of the 256 DNA chains correspond exactly to the original bracketed sequence, and after several more cycles, essentially all of the DNA strands have this unique length. (Republished with permission of Garland Publishing, Inc. from Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell, 5th ed. New York: Garland Science; 2008. Permission conveyed through Copyright Clearance Center, Inc.) be used for the sensitive detection of proteins in low concentrations, which would otherwise be difficult to detect. Moreover, combined immunoprecipitation and immunoblotting analysis is very efficient in analyzing the protein-protein interactions or determining the posttranslational modifications of proteins. In addition, immunoprecipitated proteins can be used as preparative steps for assays such as intrinsic or associated enzymatic activities. The success of immunoprecipitation is influenced by two major factors: (a) the abundance of the protein in the original preparation and (b) the specificity and affinity of the antibody for this protein. Recently, immunoprecipitation is even used to enrich modified DNA (for example, 5-methylcytosine) for bisulfite sequencing. Besides proteins of interest, specific antibodies can also be raised against specially modified DNA. Like the protein immunoprecipitation, modified DNA can be pulled down, taking advantage of the specificity and affinity of antibody to antigen. DNA Microarray. Now that the human genome sequence is completed, the primary focus of biologists is rapidly shifting toward gaining an understanding of how genes function. One of the interesting findings about the human genome is that there are only approximately 25,000 to 30,000 protein-encoding genes. However, it is known that genes and their products function in a complicated and yet orchestrated fashion and that the surprisingly small number of genes from the genome sequence is sufficient to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 15 MOLECULAR AND GENOMIC SURGERY Double-stranded DNA Heat to separate strands 460 • Sample preparation Cell tissue lysates 1 2 3 4 5 6 PART I • Gel electrophoresis Separation of proteins BASIC CONSIDERATIONS • Western transfer Transfer of proteins to membrane • Immunostaining Block membrane 1°/2° antibody staining 1 2 3 4 5 6 • Development Colorimetric/chemiluminescence detection Figure 15-18. Immunoblotting. Proteins are prepared from cells or tissues, separated according to size by sodium dodecyl sulfatepolyacrylamide gel electrophoresis, and transferred to a membrane filter. Detection of a protein of interest can be done by sequential incubation with a primary antibody directed against the protein, and then with an enzyme-conjugated secondary antibody that recognizes the primary antibody. Visualization of the protein is carried out by using colorimetric or luminescent substrates for the conjugated enzyme. make a human being. Nonetheless, with the tens of thousands of genes present in the genome, traditional methods in molecular biology, which generally work on a one-gene-in-one-experiment basis, cannot generate the whole picture of genome function. In the past several years, a new technology called DNA microarray has attracted tremendous interest among biologists as well as clinicians. This technology promises to monitor the whole genome on a single chip so researchers can have a better picture of the interactions among thousands of genes simultaneously. DNA microarray, also called gene chip, DNA chip, and gene array, refers to large sets of probes of known sequences orderly arranged on a small chip, enabling many hybridization reactions to be carried out in parallel in a small device (Fig. 15-20).28 Like Southern and Northern hybridization, the underlying principle of this technology is the remarkable ability of nucleic acids to form a duplex between two strands with complementary base sequences. DNA microarray provides a medium for matching known and unknown DNA samples based on base-pairing rules and automating the process of identifying the unknowns. Microarrays require specialized robotics and imaging equipment that spot the samples on a glass or nylon substrate, carry out the hybridization, and analyze the data generated. DNA microarrays containing different sets of genes from a variety of organisms are now commercially available, allowing biologists to simply purchase the chips and perform hybridization and data collection. The massive scale of microarray experiments requires the aid of computers. They are used during the capturing of the image of the hybridized target, the conversion of the image into usable measures of the extent of hybridization, and the interpretation of the extent of hybridization into a meaningful measure of the amount of the complementary sequence in the target. Some data-analysis packages are available commercially or can be found in the core facility of certain institutions. DNA microarray technology has produced many significant results in quite different areas of application. There are two major application forms for the technology: identification of sequence (gene/gene mutation) in multiple regions of a genome and determination of expression level (abundance) of large numbers of genes simultaneously. For example, analysis of genomic DNA detects amplifications and deletions found in human tumors. Differential gene expression analysis also has uncovered networks of genes differentially present in cancers that cannot be distinguished by conventional means. Significantly, recent advancements in next-generation sequencing (e.g., Solexa and 454 technology) have demonstrated the precision and speed to analyze gene expression in any genome. Next-Generation Sequencing.29,30 The recombinant DNA technology greatly impacts the completion of the Human Genome Project due to the invention of shotgun sequencing, which includes breaking the genome DNA into small pieces and randomly cloning those pieces into DNA vectors that are easily sequenced. Based on the overlapping sequence of each clone, computer analysis can be programmed to map and align the DNA sequence that will ultimately cover the whole human genome. Based on shotgun sequencing, as the sequencing technologies advance, next-generation sequencing has become one of the most powerful tools to analyze DNA mutation, to identify epigenetic modification, and to profile gene expression or ncRNA expression.31 The next-generation sequencing process usually includes library construction, sequencing, and data analysis. Take the Illumina next-generation sequencing as an example: DNA are shared or digested into small pieces and then used to generate a DNA library with adapters on both ends of each DNA piece. Then, the DNA library is diluted and loaded on a chamber of a slide, called a lane, for cluster amplification. Cycled fluorescent deoxyribonucleotide triphosphates (dNTPs) are then added to the chamber to enable DNA polymerization, resulting in different fluorescent emission representing different dNTP reading on different clusters, into a microscope. The fluorescent VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 461 Your favorite protein (YFP) Wash SDS-PAGE Enriched YFP & YBPs YFP-binding proteins (YBPs) Junk proteins Anti-YFP conjugated to beads Cell #1 Figure 15-19. Immunoprecipitation. Proteins prepared from cells or tissues can be enriched using an antibody directed against them. The antibody is first conjugated to agarose beads and then incubated with protein mixture. Due to the specific high-affinity interaction between antibody and its antigen (the protein), the antigen-antibody complex can be collected on beads by centrifugation. The immunoprecipitated protein can then be analyzed by immunoblotting. Alternatively, if proteins are radiolabeled in cells or tissues, detection of immunoprecipitated proteins can be achieved by simple sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography. Cell #2 mRNA mRNA cDNA cDNA DNA microarray DNA microarray data Figure 15-20. DNA microarrays. DNA microarrays, also referred to as gene chips, have arrayed oligonucleotides or complementary DNAs (cDNAs) corresponding to tens or hundreds of distinct genes. DNA microarray is used to comparatively analyze gene expression in different cells or tissues. Messenger RNAs (mRNAs) extracted from different sources are converted into cDNAs, which are then labeled with different fluorescent dyes. The two fluorescent cDNA probes are mixed and hybridized to the same DNA microarrays. The ratio of red to green fluorescence at each spot on the chip represents the relative expression of levels of that gene between two different cells. In the example shown in the figure, cDNA from cell #1 is labeled with red fluorescence and that from cell #2 is labeled with green fluorescence. On the microarray, red spots demonstrate that the gene in the cell sample #1 is expressed at a higher level than the corresponding gene in cell sample #2. The green spots indicate that the gene in the cell sample #2 is expressed at a higher level than the corresponding gene in the cell sample #1. Yellow spots represent equal expression of the gene in both cell samples. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 15 MOLECULAR AND GENOMIC SURGERY Anti-YFP beads 462 PART I BASIC CONSIDERATIONS signal is transformed into sequencing data that will be aligned and mapped to a standard genome database. The advantages of next-generation sequencing include the following: no necessity of DNA cloning; fast and cost-effective; and a huge amount of data to give a good depth and accuracy of the sequence. Based on the applications, the most common next-­ generation sequencing technologies for whole-genome sequencing are whole-genome DNA sequencing, whole-genome bisulfite sequencing (BS-seq), RNA sequencing (RNA-seq), and chromatin immunoprecipitation (ChIP) sequencing ­(ChIP-seq). Whole-genome DNA sequencing is purely to sequence the DNA sequence of a genome without any preprocessing of the DNA, reflecting any deletions, replications, and mutations within the genomic DNA. BS-seq is commonly used to identify DNA methylation on the genome (5-methylcytosine [5mC]). The process always involves a bisulfite treatment of DNA before library construction, during which the unmethylated cytosine will be transformed to a uracil, resulting in reading as a thymine in data output, whereas 5mC is protected and remains as cytosine in data output. Thus, 5mC and cytosine are distinguished by this way. RNA-seq is usually performed to analyze transcription for the same purpose as performing a microarray. However, RNA-seq is more accurate and provides more information such as splicing variants than traditional microarray. Usually, cDNA that is reversely transcribed from extracted RNA is used to generate libraries. Depending on the needs, mRNA and ncRNA can be enriched in different protocols for RNA extraction. ChIP-seq is always used to map the location of a DNA-binding protein in the genome. Prior to library construction, ChIP is performed to enrich DNA bound by the protein of interest (POI). First, POI and DNA are cross-linked before sonication. Then, a specific antibody is used to pull down POI and attached DNA fragments. After the protein and DNA are reverse cross-linked, DNA will be purified to make the ChIP-seq library. By using next-generation sequencing technology, any potential mutations in a patient will be scrutinized as well as any defects in epigenetic modification, which will greatly facilitate the diagnosis of patients and personalization of medicine in a fast and economic way. Tissue sample Cell isolation Cell Manipulations Cell Culture. Cell culture has become one of the most powerful tools in biomedical laboratories, as cultured cells are being used in a diversity of biologic fields ranging from biochemistry to molecular and cellular biology.32 Through their ability to be maintained in vitro, cells can be manipulated by the introduction of genes of interest (cell transfection) and be transferred into in vivo biologic receivers (cell transplantation) to study the biologic effect of the interested genes (Fig. 15-21). In the common laboratory settings, cells are cultured either as a monolayer (in which cells grow as one layer on culture dishes) or in suspension. It is important to know the wealth of information concerning cell culturing before attempting the procedure. For example, conditions of culture will depend on the cell types to be cultured (e.g., origins of the cells such as epithelial or fibroblasts, or primary vs. immortalized/transformed cells). It is also necessary to use cell type-specific culture medium that varies in combination of growth factors and serum concentrations. If primary cells are derived from human patients or animals, some commercial resources have a variety of culture media available for testing. Generally, cells are manipulated in a sterile hood, and the working surfaces are wiped with 70% to 80% ethyl alcohol solution. Cultured cells are usually maintained in a humidified carbon dioxide incubator at 37°C (98.6°F) and need to be examined daily under an inverted microscope to check for possible contamination and confluency (the area cells occupy on the dish). As a general rule, cells should be fed with fresh medium every 2 to 3 days and split when they reach confluency. Depending on the growth rate of cells, the actual time and number of plates required to split cells in two varies from cell line to cell line. Splitting a monolayer requires the detachment of cells from plates by using a trypsin or collagenase treatment, of which concentration and time period vary depending on cell lines. If cultured cells grow continuously in suspension, they are split or subcultured by dilution. Because cell lines may change their properties when cultured, it is not possible to maintain cell lines in culture indefinitely. Therefore, it is essential to store cells at various time Primary culture Propagation A Production of recombinant proteins Analysis of gene function B Transfection with DNA VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 15-21. Cell culture and transfection. A. Primary cells can be isolated from tissues and cultured in medium for a limited period of time. After genetic manipulations to overcome the cell aging process, primary cells can be immortalized into cell lines for long-term culture. B. DNA can be introduced into cells to produce recombinant gene products or to analyze the biologic functions of the gene. Cell Transfection. Cells are cultured for two reasons: to maintain and to manipulate them (see Fig. 15-21). The transfer of foreign macromolecules, such as nucleic acid, into living cells provides an efficient method for studying a variety of cellular processes and functions at the molecular level. DNA transfection has become an important tool for studying the regulation and function of genes. The cDNA to be expressed should be in a plasmid vector, behind an appropriate promoter working in mammalian cells (e.g., the constitutively active cytomegalovirus promoter or inducible promoter). Depending on the cell type, many ways of introducing DNA into mammalian cells have been developed. Commonly used approaches include calcium phosphate, electroporation, liposome-mediated transfection, the nonliposomal formulation, and the use of viral vectors. These methods have shown variable success when attempting to transfect a wide variety of cells. Transfection can be performed in the presence or absence of serum. It is suggested to test the transfection efficiency of cell lines of interest by comparing transfection with several different approaches. For a detailed transfection protocol, it is best to follow the manufacturer’s instructions for the particular reagent. General considerations for a successful transfection depend on several parameters, such as the quality and quantity of DNA and cell culture (type of cell and growth phase). To minimize variations in both of these in transfection experiments, it is best to use cells that are healthy, proliferate well, and are plated at a constant density. Depending on the transfection method, DNA expression can be transient or stable. Using calcium phosphate and liposome-mediated transfection, after DNA is introduced into the cells, it is normally maintained epitopically in cells and will be diluted while host cells undergo cell division. Therefore, functional assays should be performed 24 to 72 hours after transfection, also termed transient transfection. In many applications, it is important to study the long-term effects of DNA in cells by stable transfection. Thus, electroporation and viral vector are often used in these situations to enable integration of ectopic DNA into the host genome. Stable cell clones can be selected when plasmids carry an antibiotic-resistant marker. In the presence of antibiotics, only those cells that continuously carry the antibiotic-resistant marker (after generations of cell division) can survive. One application of stable transfection is the generation of transgenic or knockout mouse models, in which the transgene has to be integrated in the mouse genome in the ES cells, followed by microinjection of those transgenic ES cells into blastocysts to generate chimera mice. Stable cells also can be transplanted into host organs to test the effect of transgenic cells in vivo. Genetic Manipulations Understanding how genes control the growth and differentiation of the mammalian organism has been the most challenging topic of modern research. It is essential for us to understand how genetic mutations and chemicals lead to the pathologic condition of human bodies. The knowledge and ability to change the genetic program will inevitably make a great impact on society and have far-reaching effects on how we think of ourselves. The mouse has become firmly established as the primary experimental model for studying how genes control mammalian development. Genetically altered mice are powerful tools to study the function and regulation of genes as well as modeling human diseases.33 The gene function can be studied by 4 creating mutant mice through homologous recombination (gene knockout). A gene of interest (GOI) also can be introduced into the mouse (transgenic mouse) to study its effect on development or diseases. Because mouse models do not precisely represent human biology, genetic manipulations of human somatic or ES cells provide a great means for the understanding of the molecular networks in human cells in addition to mouse models. In all cases, the gene to be manipulated must first be cloned. Gene cloning has been made easy by recombinant DNA technology and the availability of human and mouse genomes (see the Human Genome section). The following section briefly describes the technologies and the principles behind how to combine both mouse genetics and human cell culture in exploring gene function and disease mechanisms. Transgenic Mice. During the past 20 years, DNA cloning and other techniques have allowed the introduction of new genetic material into the mouse germline. As early as 1980, the first genetic material was successfully introduced into the mouse germline by using pronuclear microinjection of DNA (Fig. 15-22). These animals, called transgenic, contain foreign DNA within their genomes. In simple terms, a transgenic mouse is created by the microinjection of ectopic DNA into the one-celled mouse embryo to induce integration, allowing the efficient introduction of cloned genes into the following developing mouse somatic tissues, as well as into the germline. DNA Pronucleus Transgenic mouse DNA microinjected into pronucleus of fertilized egg Foster mother carrying microinjected DNA VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 15-22. Transgenic mouse technology. DNA is microinjected into a pronucleus of a fertilized egg, which is then transplanted into a foster mother. The microinjected egg develops offspring mice. Incorporation of the injected DNA into offspring is indicated by the different coat color of offspring mice. 463 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY passages for future use. The common procedure to use is cryopreservation. The solution for cryopreservation is usually fetal calf serum containing 10% dimethyl sulfoxide or glycerol, stored in liquid nitrogen (−196°C [−320.8°F]) for years of preservation. However, the viability and health of cells when thawed will decrease over time even in liquid nitrogen. 464 PART I BASIC CONSIDERATIONS Designs of a Transgene The transgenic technique has proven to be extremely important for basic investigations of gene regulation, creation of animal models of human disease, and genetic engineering of livestock. The design of a transgene construct is a simple task. Like constructs used in cell transfection, a simple transgene construct consists of a protein-encoding gene and a promoter that precedes it. The most common applications for the use of transgenic mice are similar to those in the cell culture system: (a) to study the functions of proteins encoded by the transgene, (b) to analyze the tissue-specific and developmentalstage–specific activity of a gene promoter, and (c) to generate reporter lines to facilitate biomedical studies. Examples of the first application include overexpression of oncogenes, growth factors, hormones, and other key regulatory genes, as well as genes of viral origins. Overexpression of the transgene normally represents gain-of-function mutations. The tissue distribution or expression of a transgene is determined primarily by cis-acting promoter enhancer elements within or in the immediate vicinity of the genes themselves. Thus, controlled expression of the transgene can be made possible by using an inducible or tissue-specific promoter. Furthermore, transgenic mice carrying dominant negative mutations of a regulatory gene also have been generated. For example, a truncated growth factor receptor that can bind to the ligand, but loses its catalytic activity when expressed in mice, can block the growth factor binding to the endogenous protein. In this way, the transgenic mice exhibit a loss of function of phenotype, possibly resembling the knockout of the endogenous gene. The second application of the transgenic expression is to analyze the gene promoter of interest. The gene promoter of interest normally is fused to a reporter gene that encodes β-galactosidase (also called LacZ), luciferase, or green fluorescence protein. Chemical staining of LacZ activity or detection of chemiluminescence/fluorescence can easily visualize the expression of the reporter gene. The third application originates from the second: when the activity of the promoter is known, a fluorescent reporter gene (such as GFP) will be driven by the tissue-specific promoter, therefore labeling a particular type of cells at a particular stage. This application is generally used to isolate a special cell type expressing the GFP reporter by fluorescence-activated cell sorting (FACS), as well as lineagetracing experiments. Production of Transgenic Mice The success of generating transgenic mice is largely dependent on the proper quality and concentration of the DNA supplied for microinjection. For DNA to be microinjected into mouse embryos, it should be linearized by restriction digestion to increase the chance of proper transgene integration. Concentration of DNA should be accurately determined. Mice that develop from injected eggs often are termed founder mice. Genotyping of Transgenic Mice The screening of founder mice and the transgenic lines derived from the founders is accomplished by determining the integration of the injected gene into the genome. This normally is achieved by performing PCR or Southern blot analysis with a small amount of DNA extracted from the mouse tail. Once a given founder mouse is identified to be transgenic, it will be mated to begin establishing a transgenic line. Usually, for a given gene, more than one transgenic line is generated to assure that the phenotype is due to transgene but not to the interruption of the gene where the transgene integrates into. Analysis of Phenotype of Transgenic Mice Phenotypes of transgenic mice are dictated by both the expression pattern and biologic functions of the transgene. Depending on the promoter and the transgene, phenotypes can be predictable or unpredictable. Elucidation of the functions of the transgeneencoded protein in vitro often offers some clue to what the protein might function to do in vivo. When a constitutively active promoter is used to drive the expression of transgenes, mice should express the gene in every tissue; however, this mouse model may not allow the identification and study of the earliest events in disease pathogenesis. Ideally, the use of tissuespecific or inducible promoter allows one to determine if the pathogenic protein leads to a reversible or irreversible disease process in a cell-autonomous manner. For example, rat insulin promoter can target transgene expression exclusively in the β-cells of pancreatic islets. The phenotype of insulin promotermediated transgenic mice is projected to affect the function of human β-cells. Gene Knockout in Mice. The first recorded knockout mouse was created by Mario R. Capecchi, Sir Martin J. Evans, and Oliver Smithies in 1989. They were awarded the 2007 Nobel Prize in Physiology or Medicine. The isolation and genetic manipulation of mouse ES cells represent one of the most important milestones for modern genetic technologies.34 Several unique properties of ES cells, such as the pluripotency to differentiate into all germ layers in an embryo, including the germline, make them an efficient vehicle to introduce genetic alterations in mice. An important breakthrough from this idea is to generate gene-targeted mutation in mice, first by introducing the targeting vector into the ES cells, allowing selection for successful homologous recombination in a dish, then introducing the selected ES clone into the blastocysts, and finally recovering animals bearing the mutant allele from the germline (Fig. 15-23). This not only makes mouse genetics a powerful approach for addressing important gene functions, but also identifies the mouse as a great system to model human disease. Targeting Vector The basic concept in building a target vector to knock out a gene is to use two segments of homologous sequence to a GOI that flank a part of the gene essential for functions (e.g., the coding region). In the targeting vector, a positive selectable marker (e.g., the neo gene) is placed between the homology arms. Upon the homologous recombination between the arms of the vector and the corresponding genomic regions of the GOI in ES cells, the positive selectable marker will replace the essential segment of the target gene, thus creating a null allele. In addition, a negative selectable marker also can be used alone or in combination with the positive selectable marker, but must be placed outside of the homologous arms to enrich for homologous recombination. To create a conditional knockout (i.e., gene knockout in a spatiotemporal fashion), sitespecific recombinases such as the popular cre-loxP system are used. If the consensus loxP sequences that are recognized by cre recombinases are properly designed into targeting loci, controlled expression of the recombinase as a transgene can result in the site-specific recombination at the right time and in the right place (i.e., cell type or tissue). This method, often referred as conditional knockout, is markedly useful to prevent developmental compensations and to introduce null mutations in the adult mouse that would otherwise be lethal. Overall, this creloxP system allows for spatial and temporal control over transgene expression and takes advantage of inducers with minimal pleiotropic effects. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ A B Isolated early embryo Introduce a DNA fragment containing altered gene into many cells Inject ES cells into early embryo Let each cell grow to form a colony Early embryo partly formed from ES cells Introduce early embryo into pseudopregnant mouse Test for the rare colony in which the DNA fragment has replaced one copy of the normal gene Birth Somatic cells of offspring tested for presence of altered gene, and selected mice bred to test for gene in germline cells ES cells with one copy of target gene replaced by mutant gene Transgenic mouse with one copy of target gene replaced by altered gene in germline Figure 15-23. Knockout mouse technology. Summary of the procedures used for making gene replacements in mice. In the first step (A), an altered version of the gene is introduced into cultured embryonic stem (ES) cells. Only a few rare ES cells will have their corresponding normal genes replaced by the altered gene through a homologous recombination event. Although the procedure is often laborious, these rare cells can be identified and cultured to produce many descendants, each of which carries an altered gene in place of one of its two normal corresponding genes. In the next step of the procedure (B), these altered ES cells are injected into a very early mouse embryo; the cells are incorporated into the growing embryo, and a mouse produced by such an embryo will contain some somatic cells that carry the altered gene. Some of these mice also will contain germline cells that contain the altered gene. When bred with a normal mouse, some of the progeny of these mice will contain the altered gene in all of their cells. If two such mice are in turn bred (not shown), some of the progeny will contain two altered genes (one on each chromosome) in all of their cells. If the original gene alteration completely inactivates the function of the gene, these mice are known as knockout mice. When such mice are missing genes that function during development, they often die with specific defects long before they reach adulthood. These defects are carefully analyzed to help decipher the normal function of the missing gene. (Republished with permission of Garland Publishing, Inc. from Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell, 5th ed. New York: Garland Science; 2008. Permission conveyed through Copyright Clearance Center, Inc.) Introduction of the Targeting Vector into ES Cells ES cell lines can be obtained from other investigators or commercial sources or established from blastocyst-stage embryos. To maintain ES cells at their full developmental potential, optimal growth conditions should be provided in culture. If culture conditions are inappropriate or inadequate, ES cells may acquire genetic lesions or alter their gene expression patterns, and consequently decrease their pluripotency. Excellent protocols are available in public domains or in mouse facilities in most ­institutions. To alter the genome of ES cells, the targeting vector DNA then is transfected into ES cells. Electroporation is the most widely used and the most efficient transfection method for ES cells. Similar procedures for stable cell transfection are used for VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 465 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY Female mouse ES cells growing In tissue culture Altered version of target gene constructed by genetic engineering Mate and wait 3 days 466 PART I BASIC CONSIDERATIONS selecting ES cells that carry the targeting vector. High-quality, targeting-vector DNA free of contaminating chemicals is first linearized and then electroporated into ES cells. Stable ES cells are selected in the presence of a positive selectable antibiotic drug. After a certain period of time and depending on the type of antibiotics, all sensitive cells die and the resistant cells grow into individual colonies of the appropriate size for subcloning by picking. It is extremely important to minimize the time during which ES cells are in culture between selection and injection into blastocysts. Before injecting the ES cells, DNA is prepared from ES colonies to screen for positive ES cells that exhibit the correct integration or homologous recombination of the targeting vector. Positive ES colonies are then expanded and used for creation of chimeras. Creation of the Chimera A chimeric organism is one in which cells originate from more than one embryo source. Here, chimeric mice are denoted as those that contain some tissues from the ES cells with an altered genome. When these ES cells give rise to the lineage of the germ layer, the germ cells carrying the altered genome can be passed on to the offspring, thus creating the germline transmission from ES cells. There are two methods for introducing ES cells into preimplantation-stage embryos: injection and aggregation. The injection of embryonic cells directly into the cavity of blastocysts is one of the fundamental methods for generating chimeras, but aggregation chimeras also have become an important alternative for transmitting the ES cell genome into mice. Since every tissue type of a chimera should contain cells from different origins, the mixture of recognizable markers (e.g., coat color) that are specific for each the donor mouse and ES cells can be used to identify chimeric mice. However, most experimenters probably use existing mouse core facilities already established in some institutions, or contract a commercial vendor for the creation of a chimera. Genotyping and Phenotyping of Knockout Animals The next step is to analyze whether germline transmission of targeted mutation occurs in mice. DNA from a small amount of tissue from offspring of the chimera is extracted and subjected to genomic PCR or Southern blot DNA hybridization. Positive mice (i.e., those with properly integrated targeting vector into the genome) will be used for the propagation of more knockout mice for phenotype analysis. When the knockout genes are crucial for early embryogenesis, mice often die in utero, an occurrence called embryonic lethality. When this happens, only the phenotype of the homozygous (both alleles ablated) knockout mouse embryos and the phenotype of the heterozygous (only one allele ablated) adult mice can be studied. Because most are interested in the phenotype of adult mice, in particular when using mice as disease models, it is recommended to create the conditional knockout using the creloxP system so that the GOI can be knocked out at will. To date, more than 5000 genes have been disrupted by homologous recombination and transmitted through the germline. The phenotypic studies of these mice provide ample information on the functions of these genes in growth and differentiation of organisms and during development of human diseases. RNA Interference. Although gene ablation in animal models provides an important means to understand the in vivo functions of GOI, animal models may not adequately represent human biology. Alternatively, gene targeting can be used to knock out genes in human cells, including human ES cells. Gene ­targeting in human ES cells by homologous recombination has been extremely low efficiency, although there are more new t­echniques emerging aimed at increasing the targeting efficiency. A number of recent advances have made gene targeting in somatic cells as easy as in murine ES cells.33 However, gene targeting (knocking out both alleles) in somatic cells is a timeconsuming process. Development of RNAi technology in the past few years has provided a more promising approach to understanding the biologic functions of human genes in human cells.35 RNAi is an ancient natural mechanism by which small, double-stranded RNA (dsRNA) acts as a guide for an enzyme complex that destroys complementary RNA and downregulates gene expression in a sequence-specific manner. Although the mechanism by which dsRNA suppresses gene expression is not entirely understood, experimental data provide important insights. In nonmammalian systems such as Drosophila, it appears that longer dsRNA is processed into 21–23 nt dsRNA (called small interfering RNA or siRNA) by an enzyme called Dicer containing RNase III motifs. The siRNA apparently then acts as a guide sequence within a multicomponent nuclease complex to target complementary mRNA for degradation. Because long dsRNA induces a potent antiviral response pathway in mammalian cells, short siRNAs are used to perform gene silencing experiments in mammalian cells (Fig. 15-24). For siRNA studies in mammalian cells, researchers have used two 21-mer RNAs with 19 complementary nucleotides and 3′ terminal noncomplementary dimers of thymidine or uridine. The antisense siRNA strand is fully complementary to the mRNA target sequence. Target sequences for an siRNA are identified visually or by software. The target 19 nucleotides should be compared to an appropriate genome database to eliminate any sequences with significant homology to other genes. Those sequences that appear to be specific to the GOI are the potential siRNA target sites. A few of these target sites are selected for siRNA design. The antisense siRNA strand is the reverse complement of the target sequence. The sense strand of the siRNA is the same sequence as the target mRNA sequence. A deoxythymidine dimer is routinely incorporated at the 3′ end of the sense strand siRNA, although it is unknown whether this noncomplementary dinucleotide is important for the activity of siRNAs. There are two ways to introduce siRNA to knock down gene expression in human cells: 1. RNA transfection: siRNA can be made chemically or using an in vitro transcription method. Like DNA oligos, chemically synthesized siRNA oligos can be commercially ordered. However, synthetic siRNA is expensive, and several siRNAs may have to be tried before a particular gene is successfully silenced. In vitro transcription provides a more economic approach. Both short and long RNA can be synthesized using bacteriophage RNA polymerase T7, T3, or SP6. In the case of long dsRNAs, RNase such as recombinant Dicers will be used to process the long dsRNA into a mixture of 21–23 nt siRNA. siRNA oligos or mixtures can be transfected into a few characterized cell lines such as HeLa (human cervical carcinoma) and 293T cells (human kidney carcinoma). Transfection of siRNA directly into primary cells may be difficult. 2. DNA transfection: Expression vectors for expressing siRNA have been made using RNA polymerase III promoters such as U6 and H1. These promoters precisely transcribe a hairpin structure of dsRNA, which will be processed into siRNA in VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Pol III 467 TTTTT UU Dicer siRNA UU UU AAAAAA m7G m7G UU AAAAAA mRNA targeted by siRNA mRNA RISC AAAAAA m7G mRNA cleaved and degraded Figure 15-24. RNA interference in mammalian cells. Small interfering RNA (siRNA) can be produced from a polymerase III–driven expression vector. Such a vector first synthesizes a 19–29 nt double-stranded (ds)RNA stem and a loop (labeled as shRNA in the figure), and then the RNase complex called Dicer processes the hairpin RNA into a small dsRNA (labeled as siRNA in the figure). siRNA can be chemically synthesized and directly introduced into the target cell. In the cell, through RNA-induced silencing complex (RISC), siRNA recognizes and degrades target messenger RNAs (mRNAs). the cell (see Fig. 15-24). Therefore, properly designed DNA oligos corresponding to the desired siRNA will be inserted downstream of the U6 or H1 promoter. There are two advantages of the siRNA expression vectors over siRNA oligos. First, it is easier to transfect DNA into cells. Second, stable populations of cells can be generated that maintain the long-term silencing of target genes. Furthermore, the siRNA expression cassette can be incorporated into a retroviral or adenoviral vector to provide a wide spectrum of applications in gene therapy. There has been a fast and fruitful development of RNAi tools for in vitro and in vivo use in mammals. These novel approaches, together with future developments, will be crucial to put RNAi technology to use for effective disease therapy or to exert the awesome power of mammalian genetics. Therefore, the applications of RNAi to human health are enormous. siRNA can be applied as a new tool for sequence-specific regulation of gene expression in functional genomics and biomedical studies. With the availability of the human genome sequences, RNAi approaches hold tremendous promise for unleashing the dormant potential of sequenced genomes. Practical applications of RNAi will possibly result in new therapeutic interventions. In 2002, the concept of using siRNA in battling infectious diseases and carcinogenesis was proven effective. These include notable successes in blocking replication of viruses, such as HIV, hepatitis B virus, and hepatitis C virus, in cultured cells using siRNA targeted at the viral genome or the human gene encoding viral receptors. RNAi has been shown to antagonize the effects of hepatitis C virus in mouse models. In cancers, silencing of oncogenes such as c-Myc or Ras can slow down the proliferation rate of cancer cells. Finally, siRNA also has potential applications for some dominant genetic disorders. The twenty-first century, already heralded as the “century of the gene,” carries great promise for alleviating suffering from disease and improving human health. On the whole, completion of the human genome blueprint, the promise of gene therapy and molecular therapies, and the existence of stem cells have captured the imagination of the public and the biomedical community. Aside from their potential in curing human diseases, these emerging technologies also have provoked many political, economic, religious, and ethical discussions. As more is discerned about the technologic scientific advances, more attention must also be paid to concerns for their inherent risks and social implications. It is important for surgeons to play a leadership role in the emergence of personalized medicine and surgery, as surgeons have access to the diseased tissues. Surgeons should be establishing collaborations with the genomic and molecular scientists to develop genomic biobanks in order to study the genome and molecular signaling of the disease tissues that will help with an understanding of the underlying cause of an individual’s disease and ultimately lead to effective, targeted therapies. Surgeons must take this enormous opportunity to collaborate with basic and clinical scientists to develop the field of personalized genomic medicine and 5 surgery this century. Bifunctional RNAi Technology.36 Over the last 20 years, the field has worked to define oncogene and nononcogene addiction, discriminate between driver and passenger genes, and appreciate the complexity of complex, robust, network interactions. These insights have led to a preliminary understanding of therapeutically relevant sensitivity and resistance pathway signal patterns requiring multiple target modulation. However, this knowledge has not been effectively or reproducibly clinically translated. Clinical response is usually far greater when a combination of single-target molecular therapy is administered. However, it must also be realized that targeting two or more pathways may also increase the toxicity profile, particularly if target specificity is limited. When attempted, off-target toxicity has been demonstrated with combination small-molecule therapy. In contrast, multitargeting bifunctional short hairpin (bi-shRNA) DNA vectors are designed to limit off-target effect given the high specificity for the genes they are designed to target. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 15 MOLECULAR AND GENOMIC SURGERY shRNA 468 PART I BASIC CONSIDERATIONS Exogenously applied hairpin constructs can be designed to be incorporated into cleavage-dependent RISC or ­cleavage-independent RISC complexes, or both. The concept of a bifunctional shRNA37 is to increase knockdown efficiency without loss of sequence specificity by engaging both siRNA and miRNA-like (i.e., common biogenic pathway but complementary to target sequence) RISCs, thereby concurrently activating nucleolytic (Ago2-RISC) and nonnucleolytic (Ago1, 3, 4 ± Ago2-RISC) processes.38 Each bi-shRNA contains both a matched stem sequence to promote Ago2-mediated passenger strand cleavage and a second partial mismatched stem sequence for cleavage-independent passenger strand departure. Thus, functionality of the effectors is set by programmed passenger strand guided RISC loading rather than Ago subset distribution in the cancer cell. Both component Ago2 and Ago [1, 2, 4 ± 3] RNAi moieties are fully complementary to the mRNA target sequence. Preliminary data indicate reduced “off-target effects” by shRNA compared with target-identical siRNAs. More than two mismatches in sequences within the target region drastically reduce knockdown effect to undetectable levels (unpublished results). The design process involves in silico scanning of the entire human mRNA RefSeq database to avoid any potential sequence-related “off-target effects.” Published data also indicate persistent susceptibility to shRNA-mediated gene knockdown despite recent evidence of reduced Dicer expression in human cancer cells.39 The first clinical experience with the bi-shRNA platform involved the ex vivo knockdown of furin, a Ca2+-dependent, nonredundant proprotein convertase that is essential for proteolytic maturational processing of immunosuppressive TGF-β isoforms (β1 and β2). An autologous whole-cell cancer vaccine, FANG™ (furin-knockdown and GMCSF-augmented),40 was produced based on a dual function immunosensitization principle of augmenting tumor antigen expression, presentation, and processing via granulocyte-macrophage colony-­ stimulating factor (GMCSF) cytokine transgene expression and attenuating secretory immunosuppressive TGF-β. Harvested, autologous cancer cells are transfected with the GMCSF/bishRNAfurin (FANG) expression plasmid via electroporation. A phase I clinical trial (BB-IND 14205) involving 52 cancer patients was recently completed. Results demonstrated better than 90% knockdown of the bi-shRNA target, furin, and better than 90% knockdown of furin-regulated proteins TGF-β1 and TGF-β2, thereby confirming the mechanistic expectation of this novel RNAi platform. Moreover, predicted extensive GMCSF expression verified our ability to successfully construct multi-cassette vectors with good manufacturing practice techniques fulfilling Food and Drug Administration requirements for clinical testing. Twenty-seven patients received one or more vaccine dose, and 23 patients achieved stable disease as their best response. No toxic effect was identified. Median survival of the FANG™treated patients from time of procurement was 554 days and has not been reached from time of treatment. Expected survival of similar patients is historically less than 1 year. Sequential enzyme-linked immunosorbent spot (ELISPOT) analysis revealed a dramatic and significant increase in immune response from baseline to month 4 in half of the FANG™-treated patients. Comparison of survival between ELISPOT-positive and ELISPOT-negative patients demonstrated a statistically significant increase in survival from time of procurement (P = .045) and time of treatment (P = .025). These phase I study results demonstrated mechanism, safety, and effectiveness of the bi-shRNA technology and clinical functionality of a multitargeting (dual) DNA expression vector. Further utilization of bi-shRNAi technology is under way clinically (targeting STMN1, a microtubule modulation critical to cancer program) and preclinically targeting PDX141 (an oncogene-like transcription factor for pancreatic embryogenesis using nonviral nanoparticle delivery mechanisms).42 Personalized Genomic Medicine and Surgery43 Genes determine our susceptibility to diseases and direct our body’s response to medicine. Because an individual’s genes differ from those of another, the determination of each individual’s genome has the potential to improve the predication, prevention, and treatment of disease. Sequencing of individual genomes holds the key to realize this revolution called personalized genomic medicine and surgery. Next-generation sequencing, such as Illumina sequencing and 454 pyrosequencing technology, is promising to reduce the time and cost so that genome sequencing can be affordable within healthcare systems. The goal of personalized genomic medicine and surgery is to identify the gene variations in each individual and to target the specific gene variations causing the disease by choosing personalized treatments that effectively work in association with the individual’s genomic profile. The importance of surgeons in this transformational field of biomedical science is that surgeons have access to the diseased tissues on a daily basis. Surgeons should partner with the genomic scientists to develop genomic biobanks in order to study the genome of the disease tissues. These discovery studies are rapidly leading to the uncovering of mutations and SNPs that are the underlying cause of an individual’s disease and ultimately lead to targeted therapies. Although personalized genomic medicine and surgery holds the potential to revolutionize the practice of modern medicine, there currently exists a gap between our ability to sequence any given individual’s genome and how clinicians can apply this information to guide care. There is a rapidly growing list of single genes that are currently guiding care, and these genes are listed as type 1 personalized genes. Examples of these genes are BRCA1, 6 RET proto-oncogene, and CHD1 mutation, which guide potential use of mastectomy, thyroidectomy, and gastrectomy, respectively; however, the great challenge before the scientific and medical community this century is to learn to use the entire genome to guide personalized care. REFERENCES Entries highlighted in bright blue are key references. 1. Watson JD, Crick FH. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature. 1953;171:737. 2. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th ed. New York: Garland Science; 2002. 3. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931-945. 4. ENCODE Project Consortium, Birney E, Stamatoyannopoulos JA, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447(7146):799-816. 5. Mendel G. Versuche über Planzen-Hybriden. Verhandlungen des naturforschenden Vereines, Abhandlungen. Brünn: 4, 3, 1866. 6. Carey M, Smale ST. Transcriptional Regulation in Eukaryotes. New York: Cold Spring Harbor Laboratory Press; 2000. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 27. Mullis K, Faloona F, Scharf S, et al. Specific enzymatic amplification of DNA in vitro: the polymerase chain reaction. Cold Spring Harb Symp Quant Biol. 1986;51(0): 263-273. 28. Bowtell D, Sambrook J. DNA Microarrays: A Molecular Cloning Manual. 1st ed. New York: Cold Spring Harbor Laboratory Press; 2002. 29. Caruccio N. Preparation of next-generation sequencing libraries using Nextera™ technology: simultaneous DNA fragmentation and adaptor tagging by in vitro transposition. Methods Mol Biol. 2011;733:241-255. 30. Pettersson E, Lundeberg J, Ahmadian A. Generations of sequencing technologies. Genomics. 2009;93(2):105-111. 31. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399-405. 32. Bonifacino JS, Dasso M, Harford JB, et al. Current Protocols in Cell Biology. New York: John Wiley & Sons; 2003. 33. Nagy A. Manipulating the Mouse Embryo: A Laboratory Manual. 3rd ed. New York: Cold Spring Harbor Laboratory Press; 2002. 34. Evans M. Discovering pluripotency: 30 years of mouse embryonic stem cells. Nat Rev Mol Cell Biol. 2011;12(10):680-686. 35. Steitz JA. In:Hannon GH, ed. RNAi: A Guide to Gene Silencing. Cold Spring Harbor Laboratory Press. RNA. 2004;10(3):350. 36. Rao DD, Senzer N, Wang Z, et al. Bifunctional short hairpin RNA (bi-shRNA): design and pathway to clinical application. Methods Mol Biol. 2013;942:259-278. 37. Rao DD, Maples PB, Senzer N, et al. Enhanced target gene knockdown by a bifunctional shRNA: a novel approach of RNA interference. Cancer Gene Ther. 2010;17(11):780-791. 38. MacRae IJ, Zhou K, Li F, et al. Structural basis for doublestranded RNA processing by dicer. Science. 2006;311(5758): 195-198. 39. Senzer N, Rao D, Nemunaitis J. Letter to the editor: does dicer expression affect shRNA processing? Gene Regul Syst Bio. 2009;3:103-104. 40. Senzer N, Barve M, Kuhn J, et al. Phase I trial of “bishRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer. Mol Ther. 2012;20(3):679-686. 41. Liu SH, Patel S, Gingras MC, et al. PDX-1: demonstration of oncogenic properties in pancreatic cancer. Cancer. 2011; 117(4):723-733. 42. Templeton NS, Lasic DD, Frederik PM, et al. Improved DNA: liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol. 1997;15(7):647-652. 43. Nemunaitis J, Rao DD, Liu SH, Brunicardi FC. Personalized cancer approach: using RNA interference technology. World J Surg. 2011;35(8):1700-1714. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 469 CHAPTER 15 MOLECULAR AND GENOMIC SURGERY 7. Wolfsberg TG, Wetterstrand KA, Guyer MS, et al. A user’s guide to the human genome. Nat Genet. 2002;32(Suppl):1-79. 8. U.S. Department of Energy. Genomics and its impact on science and society: the human genome project and beyond. Published online by Human Genome Management Information System (HGMIS). Available at: http://web.ornl.gov/sci/techresources/ Human_Genome/publicat/primer2001/primer11.pdf. 9. Simpson RJ. Proteins and Proteomics. New York: CSHL Press; 2003. 10. Hanash S. Disease proteomics. Nature. 2003;422(6928): 226-232. 11. Ptashne M, Gann A. Genes & Signals. New York: CSHL Press; 2002. 12. Pawson T, Nash P. Assembly of cell regulatory systems through protein interaction domains. Science. 2003;300(5618):445-452. 13. Lizcano JM, Alessi DR. The insulin signalling pathway. Curr Biol. 2002;12(7):R236-R238. 14. Feng X-H, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21: 659-693. 15. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70. 16. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. 17. McNeil C. Herceptin raises its sights beyond advanced breast cancer. J Natl Cancer Inst. 1998;90:882. 18. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of BcrAbl positive cells. Nat Med. 1996;2:561. 19. Kiessling AA, Anderson SC. Human Embryonic Stem Cells: An Introduction to the Science and Therapeutic Potential. Boston: Jones & Bartlett Pub; 2003. 20. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-872. 21. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917-1920. 22. Orcutt S. Subatomic medicine and the atomic theory of disease. Transl Med. 2012;2:2. 23. Cohen SN, Chang AC, Boyer HW, Helling RB. Construction of biologically functional bacterial plasmids in vitro. Proc Natl Acad Sci USA. 1973;70(11):3240-3244. 24. Green MR, Sambrook J. Molecular Cloning: A Laboratory Manual. 4th ed. New York: Cold Spring Harbor Laboratory Press; 2012. 25. Ausubel FM, Brent R, Kingston RE, et al. Current Protocols in Molecular Biology. 3rd ed. New York: John Wiley & Sons; 1995. 26. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975; 98:503. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Part Specific Considerations VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ II This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 16 chapter Introduction Anatomy and Histology 473 473 Background / 473 Epidermis / 473 Epidermal Components / 473 Dermis / 475 Hypodermis (Subcutaneous Fat, Panniculus Adiposus) / 476 Inflammatory Conditions Radiation-Induced Injuries / 477 Trauma-Induced Injuries / 478 Caustic Injury / 479 Sajid A. Khan, Jonathan Bank, David H. Song, and Eugene A. Choi Thermal Injury / 480 Pressure Injury / 482 Bioengineered Skin Substitutes 482 Bacterial Infections of the Skin and Subcutaneous Tissue 483 Uncomplicated Skin Infections / 483 Complicated Skin Infections / 483 Actinomycosis / 484 476 Hidradenitis Suppurativa / 476 Pyoderma Gangrenosum / 476 Toxic Epidermal Necrolysis and Steven-Johnson Syndrome / 477 Injuries The Skin and Subcutaneous Tissue Viral Infections with Surgical Implications 477 Benign Tumors 485 Hemangioma / 485 Nevi / 485 Cystic Lesions / 486 INTRODUCTION Malignant Tumors 486 Basal Cell Carcinoma / 486 Squamous Cell Carcinoma / 487 Melanoma / 488 Merkel Cell Carcinoma / 492 Kaposi’s Sarcoma / 492 Dermatofibrosarcoma Protuberans / 492 Malignant Fibrous Histiocytoma (Undifferentiated Pleomorphic Sarcoma and Myxofibrosarcoma) / 493 Angiosarcoma / 493 Extramammary Paget’s Disease / 493 Conclusion 493 Epidermis The skin is a complex organ encompassing the body’s surface and continuous with the mucous membranes. Accounting for approximately 15% of total body weight, it is the largest organ in the human body. Enabled by an array of tissue and cell types, intact skin protects the body from external insults. However, the skin is also the source of a myriad of pathologies that include inflammatory disorders, mechanical and thermal injuries, infectious diseases, and benign and malignant tumors. The intricacies of this organ and associated pathologies are reasons the skin and subcutaneous tissue remain of great interest and require the attention of various surgical disciplines that include plastic ­surgery, dermatology, general surgery, and surgical oncology. ANATOMY AND HISTOLOGY Background 485 Human Papillomavirus Infections / 485 Cutaneous Manifestations of Human Immunodeficiency Virus / 485 Keratosis / 486 Soft Tissue Tumors / 486 Neural Tumors / 486 Components of epithelial, connective, vascular, muscular, and nervous tissue are organized into three histologic layers (epidermis, dermis, and hypodermis), which vary in consistency between various body parts (Fig. 16-1). The thickness of each layer, distribution of dermal appendages, density and type of nerve endings, and melanocyte distribution are just some of the variables that differ by location and purpose. The epidermis and its appendages are of ectodermal origin, whereas the dermis and hypodermis are of mesodermal origin.1 The epidermis consists of stratified epithelium that undergoes continuous regeneration. Ninety to ninety-five percent of these epithelial cells are ectodermally derived keratinocytes. 1 During their differentiation, keratinocytes form flattened, anucleate cells that are ­ultimately shed from the skin surface. This process results in the formation of distinct cell layers (from deep to superficial): ­stratum basale (single cell layer), stratum spinosum (5 to 15 cells thick), stratum granulare (1 to 3 cells), and stratum corneum (5 to 10 cells), which is further subdivided into a deep, compact stratum compactum layer and a more superficial, loose stratum disjunctum layer. In the palmoplantar region, an additional layer, the stratum lucidum, can be seen between strata granulare and corneum (see Fig. 16-1). Transit time (keratinization) is approximately 30 days. Epidermal thickness differs between skin regions, ranging from 50 μm on the eyelids to 1 mm on the soles. Interventions such as tissue expansion result in thickening of the epidermis (and thinning of the dermis). Epidermal Components Keratinocytes. Basal layer keratinocytes are columnar or cubical cells with a basophilic cytoplasm and large nucleus, and they are aligned with an underlying basement membrane and anchored by hemidesmosomes. Melanosomes are positioned over the nucleus. The cytoplasm includes bundles of filaments comprised of keratin polypeptides; these insert into the desmosomes and contribute to the formation of the ­cytoskeleton, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 474 Key Points 1 2 3 PART II 4 The epidermis consists of continually regenerating stratified epithelium, and 90% of cells are comprised of ectodermally derived keratinocytes. Dermal fibers are predominantly made of type I and III collagen in a 4:1 ratio. They are responsible for the mechanical resistance of skin. Staphylococcus aureus is the most common isolate of all skin infections. Impetigo, cellulitis, erysipelas, folliculitis, furuncles, and simple abscesses are examples of uncomplicated infections, whereas deep-tissue infections, extensive cellulitis, necrotizing fasciitis, and myonecrosis are examples of complicated infections. Hemangiomas arise from benign proliferation of endothelial cells surrounding blood-filled cavities. They most commonly 5 6 7 conferring mechanical resistance to the epidermis as a whole. Other types of intercellular junctions (including gap and adherens junctions) are present as well. Proliferation occurs at this cell layer. Spinosum layer keratinocytes are polygonal, with an eosinophilic cytoplasm. Ultrastructurally, they contain coarse bundles of tonofilaments, cytoplasmic protein found in epithelial cells. Granular layer keratinocytes are flattened cells, lying parallel to the skin surface, with a diameter of 25 μm; they contain keratohyalin granules and keratin and lamellar bodies. The latter are involved in the process of desquamation and in the formation of a lipid pericellular coat that acts as a penetration barrier against foreign (hydrophilic) substances. Corneum layer keratinocytes are highly flattened, hexagonal, eosinophilic cells, containing mainly keratin matrix, that are eventually shed from the skin surface and contribute to the skin’s barrier function. The superficial part of eccrine sweat glands and hair follicles are considered part of the epidermis as well. The epithelial cells comprising these units have separate Sweat pore biologic properties with regard to regeneration, differentiation, and response to various stimuli. Five to ten percent of epidermal cells are nonkeratinocytes, including primarily Langerhans cells, melanocytes, and Merkel cells. Langerhans Cells. These are mobile, dendritic, antigenpresenting cells present in all stratified epithelia that originate from bone marrow precursors. These cells are capable of uptaking exogenous antigens (by use of Birbeck granules), processing them and presenting them to T cells; they represent 3% to 6% of all cells in the epidermis.2 Melanocytes. Originating from the neural crest, these cells migrate into the epidermis where they produce melanin, the main natural pigment of the skin. They are distributed regularly among basal keratinocytes, at a ratio of 1 melanocyte for every 4 to 10 keratinocytes. Their density reaches 500 to 2000 cells per mm2 of cutaneous surface, with regional variations (maximal density on genital skin). Dermal papilla Sensory nerve ending for touch Hair shaft Stratum corneum Pigment ligament Stratum germinativum Stratum spinosum Stratum basale Arrector pili muscle Sebaceous gland Hair follicle Papilla of hair Nerve fiber Epidermis Dermis Subcutis (hypodermis) Blood and lymph vessels 474 present after birth, rapidly grow during the first year of life, and gradually involute in most cases. Basal cell carcinoma represents the most common tumor diagnosed in the United States, and the nodular variant is the most common subtype. Squamous cell carcinoma is the second most common skin cancer, and primary treatment modalities are surgical excision and Moh’s microsurgery. Cautery and ablation, cryotherapy, drug therapy, and radiation therapy are alternative treatments. Tumor thickness, ulceration, and mitotic rate are the most important prognostic indicators of survival in melanoma. If a sentinel node contains metastatic cancer, prognosis is determined by the number of positive nodes, the primary tumor thickness, mitotic rate and ulceration, and the age of the patient. Vein Artery Sweat gland Pacinian corpuscle Figure 16-1. Schematic representation of the skin and its appendages. Note that the root of the hair follicle may extend beneath the dermis into the subcutis. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Merkel Cells. Merkel cells display both neuroendocrine and epithelial features. They function as mechanoreceptors and synapse with dermal sensory axons in the basal layer of the epidermis and the epithelial sheath of hair follicles. Lymphocytes. The normal human epidermis contains a small percentage (<1%) of lymphocytes, present mainly in the basal layer. They express predominantly a T-memory/effector ­phenotype.3 Toker Cells. These are cells with a clear cytoplasm and are located within the nipple epidermis in 10% of both males and females. Their role in normal skin and pathology remains poorly understood, but they may be precursors of Paget’s cell carcinoma.4 Epidermal Appendages. These are specialized epithelial structures, connected to the surface epidermis but located mainly within the dermis and hypodermis. Appendages serve functions that include lubrication, sensation, contractility, and heat loss. Sweat Glands. Sweat glands are tubular exocrine glands, consisting of a secretory coil and an excretory duct. Eccrine sweat glands are the main sweat glands in humans, playing a vital role in the process of thermoregulation. They are present almost everywhere on the skin (except mucous membranes), with a maximal density over the palms, soles, axillae, and forehead. Apocrine sweat glands are less abundant in humans and are derived embryologically from the germ cells that produce the pilosebaceous follicle and are, therefore, structurally associated with it. These glands are found in the axillary, anogenital, and nipple regions. They consist of a secretory coil that is larger and more irregular in shape than that of eccrine glands. A third type of sweat gland was more recently described in the axillary region. The so-called “apoeccrine” glands are atrichial glands, opening directly to the skin surface, but their secretory coil is similar to that of apocrine glands and they present during puberty.5 Pilosebaceous Follicles. These structures are derived from the epithelial germ layer and lie obliquely in the dermis, with their deepest part reaching the hypodermis. They are present throughout the integument, excluding the glabrous skin (palms, soles) and portions of the genitalia. Their size and morphology are variable (terminal, vellus, lanugo, and intermediary hair). Their growth is cyclic and proceeds through three distinct phases of uneven duration (anagen, catagen, and telogen) during which their histology varies considerably. Nails. The nails overlie the dorsal aspect of the distal phalanges of the fingers and toes. They consist of three parts: (a) the root, covered by the proximal nail fold, continuous with the lateral nail folds; (b) the nail plate, comprised of hard keratin; and (c) the free edge, overlying the hyponychium, a thickened epidermis. The nail lies on the nail bed, a richly vascular ­connective tissue containing numerous arteriovenous shunts. The proximal part of the nail bed is continuous with the nail matrix, responsible for nail growth and adhesion. 475 Dermis Architecture. The dermis is a compressible, elastic connective tissue that supports and protects the epidermis, dermal appendages, and neurovascular plexuses. It consists of cells, fibrous molecules, and a ground substance. It turns over continuously, regulated by mechanisms controlling the synthesis and degradation of its protein components. The thickness of the dermis varies considerably with the anatomic location (being much thicker on the back, palms, and soles than on the eyelids). The papillary (superficial) dermis forms conic upward projections (dermal papillae) alternating with epidermal rete ridges, thus increasing the surface of contact between the dermis and epidermis and allowing for better adhesion between these layers. It contains several cell types (fibroblasts, dermal dendrocytes, and mast cells), vessels, and nerve endings. It is made of collagen fibers arranged in loose bundles and thin elastic fibers stretching perpendicularly to the dermal-epidermal junction. In the distal extremities, dermal papillae contain tactile corpuscles, specialized nerve endings acting as mechanoreceptors. The reticular (deep) dermis is made of coarser collagen bundles, tending to lie parallel to the skin surface. The elastic network is also thicker in this layer. The reticular dermis contains the deep part of cutaneous appendages and vascular and nerve plexuses. Dermal Fibers. The majority (>90%) of dermal fibers are collagen, predominantly types I and III, which are responsible for the mechanical resistance of the skin. Collagen 2 accounts for 98% of the total mass of dry dermis. Collagen fibers are arranged in bundles that are loose in the papillary dermis and become thicker in the deep dermis. Other collagens found in the dermis include type IV collagen (at the dermo-epidermal junction and in the basement membranes of cutaneous appendages, vessels, muscles, and nerves) and type VII collagen (anchoring fibers of the dermo-epidermal junction). Elastic fibers are responsible for the retractile properties of the skin due to their ability to stretch to twice their resting length and return to their baseline shape after the deforming force is relieved. In the papillary dermis, they are thin; they become thicker in the reticular dermis, where they tend to run horizontally. By electron microscopy, elastic fibers show variations depending on age and the area studied (sun-exposed or not). They have irregular contours and are made of a central amorphous matrix composed of elastin, an insoluble protein. This core is surrounded by a varying number of microfibrils made of fibrillin. Reticulin fibers consist biochemically of an assembly of thin collagen fibers (types I and III) and fibronectin. Cells. Fibroblasts are the fundamental cells of the dermis and all connective tissues that synthesize all types of fibers and the ground substance. They appear as spindle-shaped or stellate cells, containing a well-developed rough endoplasmic reticulum. Myofibroblasts are cells derived from fibroblasts, namely during the process of wound healing; they contain myofilaments, visible by electron microscopy, and express (smooth) muscle actin and more rarely desmin.6 Dermal dendrocytes represent a heterogeneous population of mesenchymal dendritic cells, recognizable mainly by immunohistochemistry. They are present around capillaries of the papillary dermis, around sweat gland coils, and within the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE Melanin is produced through the enzymatic activity of tyrosinase on the substrate tyrosine and is then stored in melanosomes; these are transported along the dendritic processes of melanocytes and are eventually transferred to adjacent keratinocytes where they form an umbrella-like cap over the nucleus, protecting it from the effects of ultraviolet (UV) light. Melanocytes express the bcl-2 oncoprotein, S100 protein, and vimentin. Ethnic variations in pigmentation are due to differences in activity of melanocytes and distribution of melanosomes within the epidermis and not differences in the number of melanocytes. 476 connective tissue septa of the hypodermis. Dermal dendrocytes complement the immunologically functional cells of the epidermis. Mast cells are mononuclear cells of bone marrow origin, sparsely distributed in the perivascular and periadnexal dermis. Cutaneous Vasculature. Excluding the epidermis, which is a UNIT II PART SPECIFIC CONSIDERATIONS nonvascular tissue, the skin possesses a rich vascular network that largely exceeds the skin metabolic requirements. This network plays a role in thermoregulation, wound healing, immune reactions, and blood pressure control. Cutaneous vessels belong to the arterial, venous, or lymphatic system; they originate from perforating arteries arising from underlying vessels of the muscles and form two distinct horizontal plexuses that communicate via vessels traversing the dermis vertically. The deep plexus lies close to the dermal-hypodermal junction and provides nutritional arteries to sweat glands and hair follicles. The superficial plexus, derived from terminal arterioles, lies at the interface between the papillary and reticular dermis and provides a vascular loop to every dermal papilla toward the surface (except in the nail bed). This consists of an ascending precapillary arteriole, arterial and venous capillaries forming a hairpin turn, and a descending postcapillary venule (these account for the majority of vessels in the papillary dermis).7 Cutaneous Enervation. The skin contains a rich and complex enervation, consisting of an afferent and an efferent limb. The afferent limb is responsible for the perception of eternal stimuli (touch, pressure, vibration, pain, temperature, itch) via a network of sensory myelinated and nonmyelinated fibers, free terminal nerve endings, and tactile corpuscles. The efferent limb is supported by nonmyelinated fibers of the sympathetic system that regulate vasomotricity, sweat secretion, and piloerection. Hypodermis (Subcutaneous Fat, Panniculus Adiposus) Fatty tissue is the deepest part of the skin, separating it from the underlying muscle fascia or the periosteum. It plays an important role in thermoregulation, insulation, storage of energy, and protection from mechanical injuries. The main cells of the hypodermis are the adipocytes— large, rounded cells with a lipid-laden cytoplasm (triglycerides, fatty acids) compressing the nucleus against the cell membrane. Adipocytes are arranged in primary and secondary lobules, the morphology of which varies according to gender and body region. These lobules are separated by connective tissue septa containing cells (fibroblasts, dendrocytes, mast cells), the deepest part of sweat glands, and vessels and nerves contributing to the formation of the corresponding dermal plexuses. INFLAMMATORY CONDITIONS Hidradenitis Suppurativa Hidradenitis suppurativa is a chronic inflammatory disease presenting as painful subcutaneous nodules. Patients experience appreciable physical, psychological, and economical hardship and decreased quality of life when compared to patients who suffer from other chronic dermatologic disease such as psoriasis and alopecia.8 It is characterized by multiple abscesses, internetworking sinus tracts, foul-smelling exudate from draining sinuses, inflammation in the dermis, both atrophic and hypertrophic scars, ulceration, and infection, which may extend deep into the fascia. The diagnosis is made clinically without the need for imaging or laboratory tests. Affected sites are axillary, i­nguinal, perineal, mammary, and inframammary areas corresponding to a “milk-line” distribution. The current pathophysiologic mechanism is that there is follicular occlusion, and not an apocrine disorder as previously believed. Hyperandrogenism does not have a proven role in the disease; poor hygiene, smoking, alcohol consumption, and bacterial involvement are thought to exacerbate rather than initiate the disease process. Treatment varies depending on disease severity and extent. The majority of patients with early-stage disease (abscesses without significant scarring) respond to topical or systemic antibiotics (clindamycin is first-line therapy). Antiandrogens have an equivocal role in therapy. Application of various anti-inflammatory agents has been successful in limited accounts and with questionable long-term efficacy. With the goal of ablating hair follicles, radiation therapy, radiofrequency ablation, and carbon dioxide (CO2) laser ablation have been employed, again with less than satisfactory long-term results.9-12 Refractory cases respond best to wide surgical debridement of the affected sites. Recurrence rates tend to be higher in the inframammary and inguino-perineal regions, reaching up to 50%. Primary wound closure after debridement bears a high risk of recurrence and is therefore discouraged. Locoregional flaps, split-thickness skin grafting, and healing by secondary intention are other alternatives. Skin grafting has a faster healing rate compared with secondary wound closure. However, the cost of having a painful donor site and limb immobilization led most patients in one reported study to prefer secondary healing.13 Topical antimicrobial creams should be used during the healing process. Pyoderma Gangrenosum Pyoderma gangrenosum (PG) is a relatively uncommon noninfectious neutrophilic dermatosis. This disease is commonly associated with inflammatory bowel disease, rheumatoid arthritis, hematologic malignancies, and monoclonal gammopathies. Clinically, the condition is characterized by the presence of sterile pustules, which progress and ulcerate to variable depths and dimensions. The lower extremities are the most commonly affected site, although all other parts of the skin can be involved. Extracutaneous manifestations include the upper airway, eye, genitalia mucosa, lungs, spleen, and muscle. Secondary infection is common. PG is more common in women and peaks in the third to sixth decades of life. Lesion borders are purplish in color with erythematous edges. Five clinical types are identified: ulcerative, pustular, bullous, vegetative, and peristomal. Treatment of this condition is centered on treatment of the inciting disease (i.e., management of Crohn’s disease) and often includes systemic steroids or calcineurin inhibitors. Treatment of PG combines systemic, topical, and surgical modalities. Systemic therapy is instituted in widespread and progressing cases and revolves around anti-inflammatory medications. Calcineurin inhibitors (inhibitors of T-cell activation) and corticosteroids are the mainstay of therapy. Other immunomodulators include sulfa drugs (dapsone), clofazimine, thalidomide, colchicine, azathioprine, cyclophosphamide, and mycophenolate mofetil. Patients with Crohn’s disease and PG treated with infliximab (tumor necrosis factor [TNF]-α inhibitor) and etanercept (TNF-α antagonist) had a marked improvement in their PG.14,15 Once ulcers develop, topical antimicrobials should be used to decrease the likelihood of secondary infections. Wound care should be geared toward debridement of purulent exudate VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ and devitalized tissue, while maintaining a moist environment to facilitate healing. Topical calcineurin inhibitors have been shown to be useful in peristomal PG.16 Surgical debridement should be used concomitantly with systemic therapy, as the surgical insult may trigger further PG. Wound closure can usually be achieved with split-thickness skin grafting and temporary coverage with allografts or bioengineered skin substitutes. Toxic Epidermal Necrolysis and StevenJohnson Syndrome INJURIES Radiation-Induced Injuries Figure 16-2. Blisters on the forearm of a patient several days after exposure to vancomycin. Note the clear antishear dressing and the dark silver-impregnated antimicrobial dressing (Acticoat™). Radiation-induced injuries can be the result of environmental exposure, industrial/occupational applications, and medical etiologies. Surgeons must be aware of the role radiation plays in oncologic multidisciplinary care. In addition to radiation treatment for cancers such as lymphoma and head and neck squamous cell carcinomas, radiotherapy plays a role in the adjuvant setting either before or after surgical resection in diseases such as rectal, esophageal, and cervical cancers. Although the newer modalities and principles of radiation oncology have allowed for more precise administration of this therapy with theoretically fewer side VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 477 CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE These inflammatory diseases represent a spectrum of an autoimmune reaction to stimuli such as drugs that result in structural defects in the epidermal-dermal junction. The cutaneous manifestations of toxic epidermal necrolysis syndrome (TENS) follow a prodromal period reminiscent of an upper respiratory tract infection.17 A symmetrical macular eruption follows starting from the face and trunk and spreading to the extremities. Typically, a Nikolsky sign develops in which lateral pressure causes the epidermis to detach from the basal layer. The macular eruption evolves into blisters, causing an extensive superficial partial-thickness skin injury with exposed dermis (Fig. 16-2). The process progresses for 7 to 10 days; re-epithelialization occurs over 1 to 3 weeks. Mucosal and ocular surfaces may be involved in a similar fashion. Immunosuppressed patients are at higher risk. TENS historically was considered to be the extreme of a spectrum, with erythema multiforme and Stevens-Johnson syndrome (SJS) being less extensive forms of disease. Currently, erythema multiforme is thought to be a separate entity, related to herpetic and Mycoplasma pneumoniae infection. TENS involves more than 30% total body surface area; between 10% and 30% is considered the SJS-TEN overlap syndrome. Prognosis is related to the extent of disease and related primarily to secondary infection and other intensive care unit (ICU)-associated morbidity. With modern-day burn and ICU care, the mortality has declined significantly.17 The mildest form of the disease is SJS, which clinically presents as second-degree burns appearing as erythema and blisters/bullae of the oropharynx, anoderm, and torso. Less than 10% of total body surface area is involved with this disease. TENS is driven by the same dermo-epidermal structural defects but consists of greater than 30% total body surface area. In addition to the aforementioned, it affects the mouth, esophagus, small bowel, and colon, resulting in sloughing of mucosa that may present as gastrointestinal bleeding and intestinal malabsorption.18 It also affects the eyes, genitalia, and other mucosal surfaces. The drugs most commonly associated with TENS-SJS include aromatic anticonvulsants, sulfonamides, allopurinol, oxicams (nonsteroidal anti-inflammatory drugs), and nevirapine. The pathophysiology of TENS is not completely understood; current theories involve apoptosis due to Fas-mediated mechanisms (a soluble or a membrane-bound protein that causes apoptosis upon activation), granulysin (a proapoptotic protein that permits cell-mediated cytotoxicity), and reactive oxygen species. There appears to be a genetic component, and genetic testing before carbamazepine treatment is recommended in people of Han Chinese ancestry to exclude carriers of HLAB1502.19 The two principles of TENS management include early withdrawal of the offending drug and supportive care (i.e., pain control, intravenous fluid, electrolyte repletion, prevention of skin infections, enteral feeds, and possible respiratory support) in a burn unit. Despite drug withdrawal, noxious metabolites may persist. Wound care differs between centers and focuses on debridement of devitalized tissue and coverage with nonadherent dressings. Temporary skin coverage is sometimes needed until re-epithelialization is allowed to progress, reducing the probability of skin infections and dehydration. Coverage can be achieved with biologic dressing (allograft skin), biosynthetic dressings (Biobrane), and antimicrobial dressings (antibiotic or silver-impregnated such as Acticoat). A Wood’s lamp examination every 1 hour should be performed to look for corneal sloughing. It should be noted that these diseases should be distinguished from staphylococcal scalded skin syndrome, which clinically appears similar but is a result of exotoxins produced after staphylococcal infections of nasopharynx or otitis media. Systemic treatment with steroids has fallen out of favor due to increased sepsis rates, prolonged admission, and potentially higher mortality rates. Intravenous immunoglobulin (IVIG) is thought to be a treatment given the presence of antiFas antibodies within IVIG. The antagonistic antibodies inhibit Fas-mediated cell apoptosis.20 However, a high variability exists between batches with this regard. There are mixed reports of IVIG treatment efficacy. A 2007 meta-analysis of nine IVIG trials concluded that high-dose IVIG does, in fact, improve survival.21 Other treatment protocols include plasmapheresis aimed at decreasing cytokine and drug load, cyclosporine, cyclophosphamide, and anti–TNF-α antibodies.17 478 UNIT II PART SPECIFIC CONSIDERATIONS effects, there still are complications and clinical entities related to the skin (and deeper viscera) that the surgeon needs to be attuned to. The replicating basal keratinocytes, hair follicle stem cells, and melanocytes are the most radiosensitive components of the skin. Damage to basal keratinocytes and hair follicle cells causes an immediate burst of free radicals, irreversible double-stranded breaks in nuclear and mitochondrial DNA, and inflammation. The first dose of radiation destroys a percentage of basal keratinocytes, hindering the regenerative capacity of the epidermis; repeated exposures do not allow time for cells to repair. Acute skin changes are the result of injury to the basal epithelium in the radiated region. Within weeks, this manifests as erythema, edema, and alopecia. As the cells of the skin and subcutaneous tissue undergo repair, permanent hyperpigmentation is clinically apparent. Histologically, the epidermis appears thickened, but the functional integrity is compromised. Severe radiation injury results in complete loss of the epidermis with persistent edema and fibrinous exudate. Re-epithelialization from unaffected wound edges and from recuperating dermal adnexa begins within 10 to 14 days of exposure, provided other parameters are optimized (nutrition, infection, etc.). Chronic changes result from thrombosis and necrosis of capillaries, presenting months to years after the inciting event, ultimately leading to fibrosis and possible ulcers. Chronic skin changes include thinning, hypovascularization, telangiectasia of remaining vessels, ulceration, fibrosis with loss of elasticity, and increased susceptibility to trauma and infection. Chronic radiation skin injury includes delayed ulcers, fibrosis, and telangiectasias that present weeks to years after exposure. Treatment of minor radiation skin injury consists primarily of maintaining the integrity of remaining skin with moisturizers until recovery of skin adnexa. Management of severe radiation includes surgical excision of damaged tissues as well as control of the typically opiate-resistant pain. Environmental-induced injuries are from UV radiation and solar-induced skin toxicity and are the most common forms of radiation exposure skin injuries. Radiation reaching the surface of the earth contains infrared (700–2500 nm), visible (400– 700 nm), and invisible UV radiation (290–400 nm).22 UVC rays are filtered by the ozone layer of the atmosphere. UVB rays (290–320 nm) and UVA rays (320–400 nm) reach the earth’s surface and have cutaneous effects. UVB radiation reaches the earth in relatively low amounts but is highly energetic. UVA rays are lower in energy, but are more abundant, constituting approximately 95% of UV rays reaching the ground. Seasonal, temporal, geo-orbital, and environmental parameters affect solar irradiance. Seventy percent of UVB radiation that reaches the skin is absorbed by the stratum corneum, 20% reaches deeper in the epidermis, and only 10% penetrates the upper part of the dermis. UVA rays are more penetrant, with 20% to 30% reaching the deep dermis. The major chromophores are nucleic acids, aromatic amino acids, and melanin. Short-term solar radiation effects include erythema and pigmentation. UVB is more effective than UVA in causing a dermal inflammatory response resulting in erythema in a delayed phenomenon, peaking at 6 to 24 hours (dose and skin type dependent). Pigmentation occurs as a result of photooxidation of melanin by UVA. Partial fading occurs rapidly within 1 hour after the end of exposure. For higher UVA doses, a stable residual pigmentation is observed after the transient effect. Neomelanization is characterized by a visible brown pigmentation in UV-exposed skin, which represents an increase in epidermal melanin content. It becomes visible after about 72 hours. An acute erythemogenic dose of UVB is necessary to induce delayed pigmentation; UVA is less effective in tanning and in radiation protection. UVB pigmentation results in a homogeneous tan and UVA protection. However, melanization produced by cumulative UVA exposures appears to be longer lasting than that acquired with UVB exposures.22 Long-term effects of UV pigmentation can lead to irregular pigmentation and hyperpigmented areas, melasma, postinflammatory pigmentation, and actinic lentigines (sun spots). Radiation damage results from an increase in lysozyme activity, which inhibits the activity of collagenase and elastase and prevents the elastic fibers from proteolysis. The collagen fibril network is impaired and causes an accumulation of an amorphous, elastin-containing material. There is also a loss of collagen and a change in collagen composition (increase in collagen III to collagen I ratio). This structural disarrangement manifests as a loss of firmness and resilience of skin, leading to an older appearance to the skin. Trauma-Induced Injuries Mechanical Injury. Skin injuries may occur as a result of penetrating, blunt, and shear forces, or a combination of these. Clean lacerations may be closed primarily after irrigation, debridement, and exploration. Many surgeons will primarily close clean wounds if the injury is treated within 6 hours of the inciting event. However, there is no systematic evidence regarding the timing of closure23; practitioners are advised to use their judgment. Contaminated or infected wounds should be allowed to heal by secondary intention or delayed primary closure.24 Tangential abrasions should be approached similarly to burns injuries, with management dependent on the depth of the injury incurred. Superficial partial-thickness wounds may be left to heal spontaneously while providing topical antimicrobial prophylaxis or sterile biologic dressings. Deeper wounds may require split-thickness skin grafting to avoid prolonged need for dressing changes and hypertrophic scarring that might result from a prolonged healing period. Degloved skin may be used to provide coverage similar to a skin graft, or as a temporary dressing, provided the wound bed has been cleaned. Bite Wounds. Accounting for over 4.5 million injuries each year, with many more presumably unreported, seemingly innocuous punctures may lead to severe deep-tissue infections if unrecognized and not treated appropriately.25 Bite bacteriology is influenced by normal mouth flora, as well as the content of the offending animal’s food. Early presentation bite wounds yield polymicrobial cultures. Common aerobic bacterial genera include Pasteurella multocida, Streptococcus, Staphylococcus, Neisseria, and Corynebacterium; anaerobic organisms include Fusobacterium, Porphyromonas, Prevotella, Propionibacterium, Bacteroides, and Peptostreptococcus. Capnocytophaga canimorsus bacteria after a dog bite are rare. It appears that immunocompromised patients are most susceptible to this type of infection and its complications. Cultures from an infected bite wound that presents late usually will grow a single organism type. Bacterial load in dog bites is heavily dependent on the content and timing of the last meal and can range between 103 with a dry meal (biscuits) to 107 within 8 hours of a wet meat meal (Fig. 16-3).26 The bacterial spectrum found in cat bites is very similar to that of dog bites, with a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 479 B Figure 16-3. A. Dog bite to the face involving the lip and left oral commissure. B. Primary closure following debridement and irrigation. Closure was performed due to aesthetic and functional considerations. slightly higher prevalence of Pasteurella species. Rare infections acquired from cats have been with Francisella tularensis (tularemia) and Yersinia pestis (human plague). Bacteria colonizing human bites are those present on the skin or in the mouth. These include the gram-positive aerobic organisms Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus species, and anaerobes including Peptococcus species, Peptostreptococcus species, Bacteroides species, and Eikenella corrodens (facultative anaerobe). Antibiotic coverage must cover gram-positive and anaerobic organisms. A first-generation cephalosporin in combination with penicillin or ampicillin in combination with clavulanic acid provides adequate coverage. Clindamycin is an alternative, but additional coverage for Eikenella corrodens should be administered. Most wounds are amenable to standard wound care protocols. Irrigation (preferably with sterile saline solution) should be performed, although it will reduce surface bacteria only if done with nonpulsatile irrigation. To significantly reduce bacterial load and eliminate particulate debris in the wound, pressure irrigation should be performed. Eighty percent of wounds presenting to the emergency department have a bacterial load under 105, and superficial irrigation will suffice. Larger wounds with signs of infection will require pulse irrigation. Rapid quantitative cultures should be used to guide treatment in wounds with suspected infection. Human bites typically are characterized by higher bacteria load (>105). In select cases, bite wounds may be closed primarily, particularly in areas of aesthetic significance such as the face, where secondary intention healing will result in unsightly scarring. This approach should follow initial management as outlined earlier, along with close follow-up to permit early detection of infection. Rabies in domestic animals in the United States is rare, and the majority of cases are contracted from bat bites. In developing countries, dog bites remain the most common source of rabies. Management of this is beyond the scope of this chapter. Caustic Injury Between 2.4% and 10.7% of burns are due to chemical exposure27; however, approximately 30% of burn deaths are related to chemical burns. Damage from chemical burns is related to the concentration, duration, and quantity of acidic or alkaline solution. Acidic injuries typically cause a more superficial burn pattern due to eschar formation as a result of coagulation necrosis of the skin. This limits subsequent tissue penetration. Exothermic chemical reactions associated with acid burns may cause a combined thermal and chemical injury. Without treatment, this injury will result in erythema and ulcers through the subcutaneous tissue. Injuries related to basic fluids result from liquefactive necrosis starting with fat saponification and result in longer more sustained injuries causing a deeper pattern of injury (Fig. 16-4). Common examples are sodium hydroxide (drain decloggers, paint remover) and calcium hydroxide (cement). This permits further penetration of the unattached molecules, causing further tissue destruction. The treatment for both types of injuries is based on neutralization of the inciting solution and starts with running distilled water or saline over the affected skin for at least 30 minutes for acidic solutions and 2 hours for alkaline injuries. It should be noted that neutralizing agents do not offer a significant advantage over dilution with water, may delay treatment, and may worsen the injury due to the exothermic reaction that may occur. The clinician observes and treats based on the degree of presentation. Many cases are successfully managed conservatively with topical emollients and oral analgesics, and most cases result in edema, erythema, and induration. If signs of deep second-degree burns develop, local wound care may include debridement, Silvadene, and protective petroleum gauze. In severe cases, injury to the underlying vessels, bones, muscle, and tendon may occur, and these cases may be managed within 24 hours by liposuction through a small catheter and then saline injection. Surgery is indicated for tissue necrosis, uncontrolled pain, or deep-tissue damage. Antibiotics should not be administered unless signs of infection are­ present. Injuries that have specific additional treatments include hydrofluoride burns Hydrofluoride is found in air conditioning cleaners and petroleum refineries. Treatment of hydrofluoride burns should include topical or locally injected calcium ­gluconate to bind fluorine ions. Intra-arterial calcium gluconate can provide pain relief and preserves arteries from necrosis, whereas intravenous (IV) calcium repletes resorbed calcium stores. Topical calcium carbonate gel and quaternary VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE A 480 UNIT II PART SPECIFIC CONSIDERATIONS Figure 16-4. Self-inflicted alkali burn with cleaner fluid. a­ mmonium compounds detoxify fluoride ions. This mitigates the leaching of calcium and magnesium ions by the hydrofluoric acid from the affected tissues and prevents potentially severe hypocalcemia and hypomagnesemia that predispose to cardiac arrhythmias. IV fluid extravasation results in yet another type of chemical injury and occurs in 0.1% to 0.7% of all cytotoxic drug administrations (Fig. 16-5). The dorsum of the hand is the most common location of this type of injury, predisposing exposure of the extensor tendon. There is a higher risk in patients receiving chemotherapy, and the risk increases dramatically in the pediatric population (11%–58%). Doxorubicin is often the offending agent, and its effects are attributable to direct toxicity resulting in cellular death, perpetuated by release of doxorubicin from cell lysis and failed wound healing. Resultant tissue injury depends on several factors, including solution osmolality, tissue toxicity, vasoconstrictive properties, infusion pressure, and regional anatomic properties.28 Although most extravasations do not culminate in significant injuries, skin and subcutaneous damage is more likely in the critically ill and neonates. This is due, in part, to the type of infusions employed in these patients, the thin skin at the IV site (dorsum of hands and feet), fragility of veins, and the relatively poorly perfused tissue in these locations. Initial presentation may include erythema, blistering, and pain. The true extent of the injury may be beyond the apparent external margins, and this may take days to manifest completely (longer in the case of calcium carbonate infiltrations). Injury to deeper structures should be excluded. Treatment varies from conservative management with limb elevation to saline infiltration (for dilution) and aspiration with liposuction cannula.28 These methods have been shown to be effective only in the early period following extravasation. Cold or warm compresses should be avoided because they may add a thermal injury ­component to an area in which thermoregulatory mechanism are impeded due to vasoconstriction, pressure, and inflammation. Surgical intervention includes debridement of devitalized tissue and reconstruction with appropriate technique (i.e., skin substitutes, skin grafting, flaps, or secondary intention). Topical antimicrobial therapy is encouraged until surgery is possible. Thermal Injury Exposure of the skin to thermal extremes disrupts its primary function as a barrier to heat loss, evaporation, and microbial invasion. The depth and extent of injury are dependent on the duration and temperature of the exposure. The pathophysiology and management are discussed elsewhere in this book. Briefly, the epicenter of the injury undergoes a varying extent of necrosis (depending on the exposure), otherwise referred to as the zone of coagulation, which is surrounded by the zone of stasis, which has marginal perfusion and questionable viability.29 This is the area of tissue that is most amenable to salvage by appropriate resuscitative and wound management techniques, which would theoretically limit the extent of injury. The outermost area of skin shows characteristics similar to other inflamed tissues and has been designated the zone of hyperemia. The degree of burn corresponds to histologic layers of the affected dermis and correlates with management and prognosis pertaining to timeline of healing and magnitude of scarring (Fig. 16-6). Hypothermic skin injury (frostbite) can result from direct cellular damage or the secondary effects of microvascular VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 481 B C Figure 16-5. A. Potassium chloride intravenous infiltrate in a critically ill patient on multiple vasopressors. B. Following operative debridement to paratenon layer. C. Temporary coverage with Integra skin substitute. thrombosis and subsequent ischemia.30 Freezing of tissue leads to intracellular and extracellular ice formation, intracellular ice formation, cell dehydration and crenation, local electrolyte abnormalities, and disturbances in lipid-protein complexes. With rewarming, the ice melts and damaged cells take up water; affected capillaries leak fluid into the interstitium. S ­ ubsequently, this edema and concomitant inflammatory process result in epidermal blistering and microvasoconstriction, propagating further tissue injury. Treatment includes rapid rewarming to 40 to 42°C, analgesia, debridement of blisters, hydrotherapy, elevation, topical antimicrobials, topical antithromboxanes (aloe vera), and systemic antiprostaglandins (aspirin). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE A 482 UNIT II PART SPECIFIC CONSIDERATIONS A Figure 16-6. Scald burn of upper arm, back, and buttock. Pink areas are superficial partial-thickness burn, whereas whiter areas are deeper burns in the dermis. Pressure Injury Tissue pressures that exceed the pressure of the microcirculation (30 mmHg) result in tissue ischemia. Frequent or prolonged ischemic insults will ultimately result in tissue damage (Fig. 16-7). Areas of bony prominence are particularly prone to ischemia, the most common areas being ischial tuberosity (28%), trochanter (19%), sacrum (17%), and heel (9%). Tissue pressures can measure up to 300 mmHg in the ischial region during sitting and 150 mmHg over the sacrum while lying supine.31 Muscle is more susceptible than skin to ischemic insult due to its relatively high metabolic demand. Wounds are staged as follows: stage 1, nonblanching erythema over intact skin; stage 2, partial-thickness injury (epidermis or dermis)—blister or crater; stage 3, full-thickness injury extending down to, but not including, fascia and without undermining of adjacent tissue; and stage 4, full-thickness skin injury with destruction or necrosis of muscle, bone, tendon, or joint capsule. Management principles for pressure sores should include pressure relief (air mattresses and gel cushions for redistribution of pressure), systemic optimization (particularly nutritional support), and wound care.32,33 Goals of surgical intervention are drainage of fluid collections, wide debridement of devitalized and scarred tissue, excision of pseudobursa, ostectomy of involved bones, hemostasis, and tension-free closure of dead space with well-vascularized tissue (muscle, musculocutaneous, or fasciocutaneous flaps). Stage 2 and 3 ulcers may be left to heal secondarily after debridement. Subatmospheric pressure wound therapy devices (vacuum-assisted closure) play a role in B Figure 16-7. A. Pressure wound after removal of a poorly padded cast. Stage cannot be determined until debridement but is at least a grade 2 lesion. B. Decubitus ulcer of the sacral region, stage 4, to the tendinous and bone layers. wound management by removing excess interstitial fluid, promoting capillary circulation, decreasing bacterial colonization, increasing vascularity and granulation tissue formation, and contributing to wound size reduction.34 BIOENGINEERED SKIN SUBSTITUTES Recent work in surgical laboratories has provided surgeons with advancements in bioengineered skin substitutes. Different types of skin substitutes arise from xenograft, autologous, synthetic, and allogeneic sources.35 An example of a xenograft substitute is the porcine dermis Permacol (Tissue Sciences Laboratory), whereas the cultured keratinocyte Epicel (Genzyme Tissue VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ BACTERIAL INFECTIONS OF THE SKIN AND SUBCUTANEOUS TISSUE In 1998, the Food and Drug Administration (FDA) categorized infections of the skin and skin structures for the purpose of clinical trials. A revision of this categorization in 2010 excluded specific diagnoses such as bite wounds, decubitus ulcers, diabetic foot ulcers, perirectal abscesses, and necrotizing fasciitis. The general division into “uncomplicated” and “complicated” skin infections can be applied to help guide management.36 Staphylococcus aureus is the most common isolate (~44%).37 Other gram-positive bacteria such as Enterococcus species (9%), β-hemolytic streptococci (4%), and coagulasenegative staphylococci (3%) are less common. Gram-negative species, including Pseudomonas aeruginosa (11%), Escherichia coli (7.2%), and Enterobacter (5%), Klebsiella (4%), and Serratia (2%) species, among others, should be considered in complicated infections in patients with diabetes, neutro3 penia, and cirrhosis. Uncomplicated Skin Infections Disease processes included in this category are limited to the epidermis or its appendages and involve a surface area that is less than 75 cm2. Impetigo, cellulitis, erysipelas, folliculitis, furuncles, and simple abscesses are included in this category. Folliculitis is an infection of a hair follicle that may progress to a furuncle or a carbuncle (abscess with multiple draining sinuses). Folliculitis and furuncles resolve with adequate hygiene and warm soaks. Minor primary infections, or a secondarily infected lesion, should be treated with topical ointments such as 2% mupirocin to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA). For an uncomplicated furuncle or carbuncle (simple abscess), incision and drainage are sufficient, and antibiotics are not warranted. For nonpurulent, uncomplicated cellulitis β-hemolytic streptococci coverage is recommended (β-lactam such as cephalexin), with MRSA coverage to be added if no response is seen within 48 to 72 hours or in the presence of chills, fevers, expanding erythema, or uncontrolled pain. Dual coverage can be achieved with clindamycin, trimethoprimsulfamethoxazole, linezolid, or the combination of a tetracycline and a β-lactam. Purulent cellulitis that does not meet criteria for a complicated infection requires MRSA coverage. Need for empiric coverage for streptococci is unlikely. Clindamycin, trimethoprim-sulfamethoxazole, linezolid, and tetracyclines are options. The infections can be managed on an outpatient basis in the vast majority of cases. 483 Complicated Skin Infections Deep-tissue infections (below the dermis), extensive cellulitis, necrotizing fasciitis, and myonecrosis are considered complicated skin infections. A thorough history and exam should be performed to elicit information (e.g., history of trauma, diabetes mellitus, cirrhosis, neutropenia, bites, IV or subcutaneous drug abuse) as well as physical findings such as crepitus (gas-forming organism), fluctuance (abscess), purpura (sepsis in streptococcal infections), bullae (streptococci, Vibrio vulnificus), lymphangitis, and signs of a systemic inflammatory response. Aspirated fluid from suspected infected collection should be cultured. Swabs and aspirates in cellulitis have a low yield (10%), whereas tissues cultures may have a higher rate of organism recovery (20%–30%). The utility of computed tomography (CT) or magnetic resonance imaging (MRI) in diagnosing a deep infection is limited and should not delay surgical evaluation and debridement. Treatment of nonpurulent, complicated cellulitis can begin with a β-lactam, with MRSA coverage added if no response is observed. Empiric MRSA coverage is warranted in all other complicated skin and subcutaneous infections. Vancomycin is the mainstay of therapy, although it is inferior to β-lactams for methicillin-sensitive Staphylococcus aureus (MSSA) and has a relatively slow onset of efficacy in vitro. Linezolid, daptomycin, tigecycline, and telavancin are other FDA-approved alternatives for MRSA treatment. Clindamycin is also approved for S. aureus; however, resistance may develop, and diarrhea can occur in up to 20% (Clostridium difficile related). Necrotizing infections can manifest with bullae, skin necrosis, pain beyond the margins of erythema, crepitus, gas on imaging, hypotension, or other signs of systemic inflammatory response syndrome (SIRS). These signs are late findings and are frequently absent. Due to substantial morbidity and mortality associated with these infections, the index for suspicion should be high, and the threshold for surgical exploration should be low, particularly in a weakened host, such as diabetic patients, the malnourished, alcoholics, neutropenic or functionally neutropenic patients, cirrhotic patients, renal failure patients, and individuals with peripheral vascular disease. Common sites of origin are the genitalia, perineum (Fournier’s gangrene), and abdominal wall. Classification is based on the anatomic site, the involved tissue planes (e.g., adipose, fascia, muscle), the offending organisms, and the velocity of the infection. Involvement of the deep fascia (necrotizing ­fasciitis—deep to the adipose tissue, overlying the muscle) results in a rapidly progressing infection with bacteria spreading along low-resistance tissue planes (Fig. 16-8). Necrotizing myositis primarily involves the muscle but can spread to surrounding tissue as well. Three types of necrotizing infections can be distinguished based on the organisms involved. Type 1 is the most common, with a polymicrobial source including gram-positive cocci, gram-negative rods, and anaerobes (Bacteroides species, ­Clostridium perfringens and septicum), occurring in the perineum and trunk of the immunocompromised host. Occasionally an entry site can be identified (incisions, lines, or intestinal perforation), but in 20% to 50% of cases, a risk factor is not VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE Repair Corp) grafts represent an autologous substitute. Some examples of synthetic skin substitutes include Biobrane (UDL Laboratories) and Integra (Integra Life Science Corp). Biobrane is a silicon and nylon mesh layer bound with porcine collagen. Integra is a two-layered membrane composed of a silicon layer to maintain hydration and a porous bovine collagen and chondroitin sulfate layer that provides an environment for fibroblasts, macrophages, and capillaries to lay down a vascularized collagen matrix dermal layer. The more superficial silicon layer can be removed, and an autograft can subsequently be applied. AlloDerm (Life Cell) is an allogeneic substitute made of acellular dermal matrix derived from human skin tissue. It provides a matrix for revascularization, incorporating into host tissue, and provides additional strength. In contrast to Integra, it does not provide a dermal matrix to support a skin graft, and thus is not often used as a skin substitute. Several other skin substitutes are also available. UNIT II PART SPECIFIC CONSIDERATIONS where in meant? is a rare but fulminant subset resulting from a V. vulnificus infection of traumatized skin in sea divers. Laboratory findings are nonspecific. Leukocytosis, low calcium, and elevated lactate, creatine kinase, and creatinine may be seen. Advanced illness may bring on coagulopathy and acidemia. Blood cultures may or may not be positive. A retrospectively developed scoring system, called the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score, which includes C-reactive protein (CRP), white blood cell (WBC) count, hemoglobin, plasma sodium, creatinine, and glucose, can be of diagnostic assistance with a high sensitivity and specificity. Tissue samples will demonstrate necrosis, WBC count infiltration, thrombosis, angiitis, and microorganisms. Management of patients with suspected necrotizing infections should begin with proper patient triage to an ICU for initial evaluation, resuscitation, and treatment. If the diagnosis is clear, operative exploration and debridement should not be delayed. Broad-spectrum IV antibiotics should be started as soon as possible, with vancomycin (for MRSA) in addition to clindamycin or linezolid (to inhibit toxin synthesis) and gram-negative rod coverage (in the form of a third-generation cephalosporin or a quinolone). Surgery is the definitive treatment. Incisions should be made over the involved skin, parallel to neurovascular bundles, extending to and exposing the deep fascia to assess tissue viability. Necrotic tissue will appear dull, gray, and avascular and should be excised. Characteristic “murky dishwater”– like fluid may be encountered at the affected sites. Borders for debridement are where tissue planes cease to readily separate. Rapid quantitative tissue cultures (if available) and frozen section analysis may help guide the debridement. In Fournier’s gangrene, one should aim to preserve the anal sphincter as well as the testicles (blood supply is independent of the overlying tissue; usually not infected). Revision surgery should be planned (“second look”) within 24 to 48 hours. Adjuncts to surgery include topical antimicrobial creams, subatmospheric pressure wound dressings, and optimization of nutrition. Controversial topics are the role of hyperbaric oxygen (may inhibit infection by creating an oxidative burst, with anecdotally fewer debridements required and improved survival, but the availability is limited) and IVIG (may modulate the immune response to streptococcal superantigens). Wound closure is performed once bacteriologic, metabolic, and nutritional balances are obtained. Mortality ranges from 25% to 40% and is higher in truncal and perineal cases. 484 A Actinomycosis B Figure 16-8. A. Initial presentation of necrotizing soft issue infection in an obese, diabetic patient. B. Following operative debridement to muscle layer. identified. Type 2 is a less common, monomicrobial infection with β-hemolytic streptococci or staphylococci (MRSA rising in frequency to 40%). It can be associated with toxic shock and occur in a previously healthy host, typically on the trunk or extremities, with a history of trauma commonly elicited. Type 3 Actinomycosis should be considered in the differential diagnosis of any acute, subacute, or chronic cutaneous swelling of the head and neck. The cervicofacial form of Actinomycetes infection is the most common presentation, typically as an acute pyogenic infection in the submandibular or paramandibular area, but infection could be elsewhere in the mandibular and maxillary regions. The primary skin infection may spread to adjacent structures such as the scalp, orbit, ears, and other areas. Oral infection may spread to the hypopharynx, larynx, trachea, salivary glands, and sinuses. Actinomycosis can spread beyond boundaries of tissue planes and may also mimic chronic osteomyelitis. Treatment consists of a combination of penicillin therapy and surgical debridement. Debulking and debriding infected tissue arising from sinus tracts and abscess cavities inhibit actinomycosis growth in most cases. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ VIRAL INFECTIONS WITH SURGICAL IMPLICATIONS Human Papillomavirus Infections Cutaneous Manifestations of Human Immunodeficiency Virus Skin involvement may result from HIV infection itself or from opportunistic disorders secondary to immune suppression.41 Primary HIV may manifest as a generalized morbilliform rash. Kaposi’s sarcoma may precede the onset of immunosuppression. BENIGN TUMORS Hemangioma Hemangiomas result from benign proliferation of endothelial cells that surround blood-filled cavities. Their natural history most commonly is presentation soon after birth, rapid growth during the first year of life, and gradual involution in more than 90% of cases. Occasionally, their rapid growth directly interferes with the airway, gastrointestinal tract, or musculoskeletal function, and in these select cases, resection is indicated before tumor involution. These tumors may consume a large proportion of cardiac output, resulting in high-output cardiac failure, or may result in a consumptive coagulopathy. In both of these cases, resection is also indicated. Systemic prednisone and interferon-α can impede tumor progression. If these tumors persist into adolescence leaving a cosmetically undesirable telangiectasia, surgical resection may be considered. When surgical resection or debulking is considered, upfront selective embolization can help with planned resection. Finally, some vascular malformations, such as port wine stains of the trigeminal nerve distribution, may prompt the search for a systemic syndrome such as Sturge-Weber syndrome. 4 Nevi Overgrowth of melanocytic nevus cells may be found in the epidermis (junctional), partially in the dermis (compound), or completely within the dermis (dermal). They are most commonly acquired, and most involute after migration into the dermis. Congenital nevi are found in less than 1% of neonates, and when characterized as giant congenital nevi, they have up to a 5% chance of developing into a malignant melanoma.43,44 The treatment of choice is total excision, and at times, the large wound defect requires serial excisions and local tissue expanders. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 485 CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE Human papillomaviruses (HPV) are small DNA viruses of the papovavirus family. Over 100 different types have been described and can be classified as cutaneous or mucosal, depending on their tropism. The cutaneous types, HPV-1, -2 and -4, cause common warts, whereas HPV-5 and -8 are associated with epidermodysplasia verruciformis, an extremely rare autosomal recessive genetic disorder of the skin that entails a higher risk of malignant transformation. Mucosal types HPV-6 and -11 have a low malignant potential; lesions induced by HPV-16 and -18 have a higher malignancy potential. Regression of HPV lesions is frequently an immune-mediated, spontaneous event that is exemplified by the persistent and extensive manifestation of this virus in the immune-compromised patient. Cutaneous manifestations of HPV can vary. Common warts (verruca vulgaris) are caused by HPV-1, -2 and -4, with a prevalence of up to 33% in schoolchildren and 3.5% in adults; prevalence is higher in the immunosuppressed patient.38 The hands are the most commonly affected sites. Histologically, nonspecific findings of hyperkeratosis, papillomatosis, and acanthosis are found, as well as the hallmark koilocytes (clear halo around nucleus). Plantar warts occur on the soles of the feet, caused by HPV-1 and -4, commonly at pressure points, and are characterized by a keratotic plug surrounded by a hyperkeratotic ring, with black dots (thrombosed capillaries) on the surface. Plane warts occur on the face, dorsum of hands, and shins. They are caused by HPV-3 and -10 and tend to be multiple, flat-topped lesions with a smooth surface and light brown color. They regress spontaneously. Condyloma acuminatum manifests as multiple exophytic papillomatous lesions in the anogenital area. Sexually transmitted HPV-6 and -11 are responsible for 90% for genital wart cases, although other types have been implicated as well. Giant condyloma acuminatum of BuschkeLowenstein is a large exophytic, cauliflower-like tumor and is now thought to be a variant of verrucous carcinoma. Epidermodysplasia verruciformis is a form of primary genetic immunodeficiency, rendering patients susceptible to infections with HPV-5 and -8. Recently, a similar clinical picture has been described in human immunodeficiency virus (HIV) and transplant patients.39,40 Epidermodysplasia verruciformis presents clinically as multiple flat warts resembling seborrheic keratosis. There is a 30% to 50% risk of squamous cell carcinoma (SCC) transformation. First-line therapy for single or multiple warts includes topical preparations of salicylic acid, silver nitrate, and glutaraldehyde. If these fail, cryotherapy may be considered. Treatment of recalcitrant lesions includes a variety of therapeutic options aimed at physically destroying the lesions by electrodessication, cryoablation, and pulsed dye laser therapy. Additional modalities such as H2-antagonists and zinc sulfate may have a role in augmenting the immune response and reducing recurrence rates. During early stages of HIV infection, nonspecific skin changes occur, as well as common disorders with atypical clinical features, including recurrent varicella zoster, hyperkeratotic warts, and seborrheic dermatitis. Condylomata acuminata and verrucae appear early; however, their frequency and severity do not change with disease progression. Cutaneous manifestations during later stages commonly include chronic herpes simplex virus and cytomegalovirus infections and, to a lesser extent, molluscum contagiosum, which is typically treatable with imiquimod.41 Mycobacterial infections and mucocutaneous candidiasis also occur. Recurrent and persistent mucocutaneous candidiasis is common in patients with HIV infection. Bacterial infections such as impetigo and folliculitis may be more persistent and widespread. Malignant lesions such as Kaposi’s sarcoma occur in less than 5% of HIV-infected patients in the United States, although the worldwide prevalence in acquired immunodeficiency syndrome (AIDS) patients exceeds 30%. Other cutaneous cancers, particularly basal cell cancer, are becoming more common than Kaposi’s sarcoma in patients adhering to highly active antiretroviral therapy (HAART). Approximately 6% of HIV patients will develop a cutaneous malignancy over a 7.5-year period. With regard to general surgical considerations in HIV patients, contributing related morbidities such as malnutrition, decreased CD4 count, and presence of opportunistic infection may result in delayed and attenuated wound healing capacity.42 486 Cystic Lesions UNIT II PART SPECIFIC CONSIDERATIONS There are three types of cutaneous cysts: epidermal, dermoid, and trichilemmal.45 All of these benign entities are comprised of epidermis that grows toward the center of the cyst, resulting in central accumulation of keratin to form a cyst. All clinically appear as a white, creamy substance-containing subcutaneous, thin-walled nodule. Epidermal cysts are the most common cutaneous cyst and histologically characterized by mature epidermis complete with granular layer. Trichilemmal cysts are the second most common lesion; they tend to form on the scalp of females, have a distinct odor after rupture, histologically lack a granular layer, and have an outer layer resembling the root sheath of a hair follicle. Dermoid cysts are congenital, found between the forehead to nose tip, and contain squamous epithelium, eccrine glands, and pilosebaceous units, occasionally developing bone, tooth, or nerve tissue. The eyebrow is the most frequent site of presentation. These cysts are commonly asymptomatic but can become inflamed and infected, thus necessitating incision and drainage. After the acute phase subsides, the entire cyst should be removed to prevent recurrence. Keratosis Actinic Keratosis. Actinic keratosis is a commonly detected abnormal proliferation of intraepidermal keratinocytes primarily found in fair-skinned individuals. The general behavior of this premalignant lesion is regression, progression, or persistence, and their calculated 10-year potential to transform into SCC is between 6.1% and 10%. In fact, 60% to 65% of SCCs are believed to originate from these precursor lesions. Seborrheic Keratosis. These premalignant, light-brown lesions with velvet-like texture appear in the sun-exposed skin of older individuals. Histologically, the lesions are characterized by atypical-appearing keratinocytes, and their natural behavior typically is transformation into SCC that rarely metastasizes. Treatment options are excision, fluorouracil, cautery and destruction, and dermabrasion.46,47 Interestingly, sudden eruptions of multiple seborrheic keratosis may be associated with other malignancies. Soft Tissue Tumors Acrochordons represent hyperplastic cells of the epidermis attached to a fibrous connective tissue stalk. They appear on the trunk, eyelids, and axilla as pedunculated masses and are resected usually for cosmesis.48-50 Dermatofibromas are 1- to 2-cm, soft, solitary nodules consisting of predominantly nonencapsulated whorls of collagen laid down by fibroblasts located on the legs and trunks. These fibromas can be managed nonoperatively, but excision is the treatment of choice.48-50 In rare cases, basal cell carcinomas may develop within the dermatofibromas. Lipomas are the most common subcutaneous neoplasm and have no malignant potential.51 This soft and fleshy conglomeration of benign adipocytes can be appear almost anywhere on the body, but they are most often found on the trunk and commonly undergo rapid growth. Surgical excision can be considered for symptomatic or large lesions that compromise musculoskeletal function. Neural Tumors Benign cutaneous tumors that arise from the nerve sheath are collectively referred to as neural tumors. Dermal neurofibromas are benign neoplasms arising from nerve sheath that appear as fleshy and nontender sessile or pedunculated masses on the skin. They are most often associated with café-au-lait spots and Lisch nodules in neurofibromatosis type 1 (NF1) disease, also known as von Recklinghausen’s disease.49,50 Neurilemomas are discrete nodules consisting of Schwann cells of the peripheral nerve sheath, often causing pain along the distribution of the nerve, and are treated with simple resection. Granular cell tumors are derived from Schwann cells, infiltrate surrounding skeletal muscle, and are resected when symptomatic.49,50,52 MALIGNANT TUMORS Basal Cell Carcinoma Basal cell carcinoma (BCC) arises from the basal layer of nonkeratinocytes and represents the most common tumor diagnosed in the United States.53,54 Annually it accounts for 25% 5 of all diagnosed cancers and 75% of skin cancers.55 The primary risk factor for disease development is sun exposure (UVB rays more than UVA rays) particularly during adolescence; however, other factors include immune suppression (i.e., organ transplant recipients, HIV), chemical exposure, and ionizing radiation exposure. BCC can also be a feature of inherited conditions such as xeroderma pigmentosa, unilateral basal cell nevus syndrome, and nevoid BCC syndrome.55 The natural behavior of BCC is one of local invasion rather than distant metastasis. Untreated BCC can result in significant morbidity. Thirty percent of cases are found on the nose, and bleeding, ulceration, and itching are often part of the clinical presentation. The most common form of BCC (60%) is the nodular variant, characterized by raised, pearly pink papules and occasionally a depressed tumor center with raised borders giving the classic “rodent ulcer” appearance. This variant tends to develop in sun-exposed areas of individuals over the age of 60. Superficial BCC accounts for 15% of BCC, is diagnosed at a mean age of 57 years, and typically appears on the trunk as a pink or erythematous plaque with a thin pearly border. The infiltrative form appears on the head and neck in the late 60s with similar clinical appearance to the nodular variant. An important variant to keep in mind is the pigmented variant of nodular BCC because this may be difficult to differentiate from nodular melanoma. Other important subtypes include the morpheaform variant, accounting for 3% of cases and characterized by indistinct borders with a yellow hue, and fibroepithelioma of Pinkus. Histologic subtypes of BCC include nodular and micronodular (50%), superficial (15%), and infiltrative. Treatment options include Moh’s microsurgery, excisional surgery, and cautery and destruction. Moh’s microsurgery provides histologic confirmation of excision and maximal conservation of tissue, which is important to keep in mind in cosmetically sensitive areas such as facial lesions. It has also been shown to be cost-effective and associated with low recurrence rates (1%).56,57 It is the treatment of choice for morpheaform, poorly delineated, recurrent, and infiltrative BCC, particularly facial lesions. Alternative treatment is excisional surgery with 4-mm margins with extension into subcutaneous tissue, which provides definitive treatment of nonmorpheaform lesions <2 cm in diameter. A common approach used by dermatologists is cautery and destruction, although it should be kept in mind that the results are operator and institution dependent as shown by a study showing inferior results for individuals having the procedure performed at academic training institutions as opposed to experienced private practitioners (local cure 81% VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Squamous Cell Carcinoma SCC is the second most common skin cancer, accounting for approximately 100,000 cases each year and generally 6 afflicting individuals of lighter skin color. The primary risk factor and driving force for the development of this common cancer is UV exposure; however, other risks include environmental factors such as chemical agents, physical agents (ionizing radiation), psoralen and UVA (PUVA), HPV-16 and -18 infections (immunosuppression), and smoking. Chronic nonhealing wounds, burn scars, and chronic dermatosis are other risk factors, and many darker skin individuals who develop SCC often have a history of one these risk factors (Fig. 16-9). Heritable conditions such as xeroderma pigmentosum, epidermolysis bullosa, and oculocutaneous albinism are predisposing risk factors. SCC has in situ variants (including Bowen’s disease and erythroplasia of Queyrat in situ lesions of the penis) and invasive variants. In situ disease presents as well-delineated pink Figure 16-9. Squamous cell carcinoma forming in a chronic wound. papules or plaques, and invasive disease presents as slightly pink or skin-colored, raised plaques. Bleeding of the lesion with minimal trauma is not uncommon, and pain is rare. Most in situ cases grow slowly over time and do not progress to invasive disease, except for Bowen’s disease and erythroplasia of Queyrat where the risk of malignant transformation is 3% to 5% and 10%, respectively.65 The natural history of invasive disease depends on location and inherent tumor characteristics. For example, lesions associated with chronic inflammation and located at mucocutaneous junctions may metastasize in 10% to 30% of cases, whereas lesions arising in sun-exposed areas without adverse risk factors are less likely to spread and have a better prognosis.64 Clinical risk factors for recurrence include presentation with neurologic symptoms, immunosuppression, tumor with poorly defined borders, and tumor that arises at a site of prior radiation. Perineural involvement increases the incidence of local recurrence and lymph node metastasis and has a poorer survival. Other histologic features indicative of aggressive disease include poor differentiation, thickness greater than 4 mm, and adenoid, adenosquamous, and desmoplastic subtypes.54 Treatment modalities for SCC include cautery and ablation, cryotherapy, drug therapy including imiquimod, surgical excision, Moh’s microsurgery, and radiation therapy. However, cautery and ablation carry the risk of leaving residual tumor behind; in a study of 291 patients with primary in situ lesions treated with cautery and ablation, all but two patients recurred.66 This modality is not recommended in dense hair-bearing regions and for tumors extending into subcutaneous tissue. Surgical excision is the treatment of choice, when feasible. For lesions less than 2 cm in diameter, wide excision with a 4-mm margin for low-grade lesions and a 6-mm margin for high-grade lesions is sufficient. Factors rendering tumors high risk are size >2 cm in diameter and involvement of subcutaneous tissue. Moh’s microsurgery is indicated for lesions at sites where cosmesis or function preservation is critical, for poorly differentiated tumors, for invasive lesions, and for verrucous carcinomas. Lower recurrence rates are seen with this modality with primary lesions of the ear or lip, recurrent lesions, primaries with perineural invasion, lesions with diameters >2 cm, and poorly differentiated lesions.64,67 It has also found use in nail bed lesions and in those arising in a background of osteomyelitis. When patients are poor surgical candidates, radiation therapy can play a role in primary modality treatment. It may also act as an adjunct to surgical treatment in cases of lip carcinoma with 30% to 50% involvement, microscopic positive margins, perineural histology, underlying tissue invasion, and multiple recurrences.55,68 The role of lymph node dissection in the setting of SCC is evolving. Regional palpable nodes should be removed along with susceptible regional lymph node basins in patients with SCC in the setting of chronic wounds. Management of lymph node disease involves surgical resection and/or radiation therapy. Patients with parotid disease commonly benefit from a superficial or total parotidectomy (with facial nerve preservation) and adjuvant radiotherapy (60 Gy in 30 fractions). Isolated cervical lymph node involvement without adverse features is managed with follow-up surveillance for patients, which involves skin and regional lymph node examination every 1 to 3 months for the first year after treatment, every 2 to 4 months for the ensuing year, every 4 to 6 months for the next 3 years, and then every 6 to 12 months for the rest of life.54 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 487 CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE vs. 94%).58 This option should only be considered in patients who are not candidates for the more extensive surgical options and for lesions not located in mid-face. Poor surgical candidates and patients without recurrent or morpheaform lesions may be treated with radiation therapy. Radiation also may be used in cases of questionable resection margins or microscopic positive margins after surgery. The practitioner must be aware of the potential consequences of radiation therapy, including poor cosmetic outcomes and future cancer risk. Six to 12 weeks of imiquimod, an FDA-approved drug and immune modifier, is an option for small-diameter (<2 cm), superficial BCC of the neck, trunk, or extremities, with reported histologic clearance rates of 42% to 76%.59-63 Topical fluorouracil is another FDA-approved treatment for superficial BCC, and one study of 31 tumors treated daily for 11 weeks showed a 90% histologic clearance rate. Lastly, topical photodynamic therapy has shown some benefit in treatment as well. It is critical for each patient to have routine annual followup that includes full-body skin examinations. Sixty-six percent of recurrences develop within 3 years, and with a few exceptions occurring decades after initial treatment, the remaining recur within 5 years of initial treatment.57,64 A second primary BCC may develop after treatment and, in 40% of cases, presents within the first 3 years after treatment. 488 Melanoma Background. In 2013, an estimated 76,690 individuals were UNIT II PART SPECIFIC CONSIDERATIONS diagnosed with malignant melanoma, accounting for 9480 deaths.53,69 The incidence of melanoma is rising faster than most other solid malignancies, and these numbers likely represent an underestimation given the many in situ and thin melanoma cases that are underreported. These tumors primarily arise from melanocytes at the epidermal-dermal junction but may also originate from mucosal surfaces of the oropharynx, nasopharynx, eyes, proximal esophagus, anorectum, and female genitalia. Their pathogenesis is not completely understood, but they are believed to originate from nests of melanocytes that have undergone dysplastic changes. A well-known environmental risk factor is exposure to solar UV radiation. It was recently reported that greater than 10 tanning bed sessions by adolescents and young adults increased their relative risk of developing melanoma by twofold.70 Nonenvironmental risk factors include a personal history of melanoma, which is associated with a 10-fold increase in risk. Individuals with dysplastic nevi have a 10% overall lifetime risk of melanoma, with tumors arising from pre-existing nevi or de novo. Dysplastic nevus syndrome (B-K mole syndrome) has an autosomal dominant transmission with high penetrance and is associated with a nearly 100% lifetime risk in being diagnosed with cutaneous melanoma. Congenital nevi increase risk for melanoma proportionally with size; giant congenital nevi are associated with a 5% to 8% lifetime risk. Five to ten percent of cutaneous melanomas occur in patients with a family history of melanoma, and these individuals have an earlier age of disease onset, commonly express dysplastic nevi, and more commonly have more than one primary lesion. Melanoma development is strongly associated with the p16/CDK4,6/Rb and p14ARF/HMD2/p53 tumor suppressor pathways and the RAFMEK-ERK and PI3K-Akt oncogenic pathways.71 Pathogenesis and Clinical Presentation. Melanoma growth most commonly starts as a localized, radial growth phase followed by a vertical growth phase that determines metastatic risk. The subtypes of melanoma include lentigo maligna, superficial spreading, acral lentiginous, mucosal, nodular, polypoid, desmoplastic, amelanotic, and soft tissue. The most common subtype is superficial spreading, accounting for 70% of cases (Fig. 16-10). These melanomas are found anywhere on the body Figure 16-10. Primary cutaneous melanoma seen in the scalp of a 61-year-old male. Figure 16-11. Nodular melanoma seen in the leg of a 55-year-old male. with the exception of the hands and feet. Nodular melanoma accounts for 15% to 30% of melanomas, and this variant is unique in that it begins with a vertical growth phase that partly accounts for its worse prognosis (Fig. 16-11). Lentigo maligna is typically found in older individuals and primarily located in the head and neck region. The acral lentiginous variant accounts for 29% to 72% of melanomas in dark-skinned individuals, is occasionally seen in Caucasians, and is found on palmar, plantar, and subungual surfaces. Melanoma most commonly manifests as cutaneous disease, and clinical characteristics include an Asymmetric outline, changing irregular Borders, Color variations, Diameter greater than 6 mm, and Elevation (ABCDE). Other key clinical characteristics include a pigmented lesion that has enlarged, ulcerated, or bled. Amelanotic lesions appear as raised pink, purple, or normal-colored skin papules and are often diagnosed late. Diagnosis and Staging. Workup should begin with a history and physical exam. The entire skin should be checked for synchronous primaries, satellite lesions, and in-transit metastases, and all nodal basins should be examined for lymphadenopathy. Suspicious lesions should undergo excisional biopsy with 1- to 2-mm margins; however, tumors that are large or in a cosmetically or anatomically challenging area can be approached by incisional biopsy, including punch biopsy. Tissue specimen should include full thickness of the lesion and a small section of normal adjacent skin to aid the pathologist in diagnosis. Suspicious lymph nodes should undergo fine-needle aspiration (FNA). Melanoma is characterized according to the American Joint Committee on Cancer (AJCC) as localized disease (stage I and II), regional disease (stage III), or distant metastatic disease (stage IV). Overall tumor thickness, ulceration, and mitotic rate are the most important prognostic indicators of survival.72,73 If a sentinel node contains metastatic melanoma, the number of positive nodes; thickness, mitotic rate, and ulceration of the primary tumor; and patient age determine prognosis. With 7 clinically positive nodes, the number of positive nodes, primary tumor ulceration, and patient age determine prognosis.74 The site of metastasis is strongly associated with prognosis for stage IV disease, and elevated lactate dehydrogenase (LDH) is associated with a worse prognosis.75 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Management of the Primary Tumor and Lymph Nodes. The appropriate excision margin is based on primary tumor depth. Although there are no randomized trials studying margins for melanoma in situ, most surgical oncologists believe Primary melanoma Inguinal nodes Popliteal nodes A FLOW INJ SITE FLOW Axillary NODE ANT POST B Tympho Melanoma Primary Injection Site Submanibular Lymph nodes C Figure 16-12. After injection of radioactive technetium-99– labeled sulfur colloid tracer at the primary cutaneous melanoma site, sentinel lymph node basins are identified. A. Lymphoscintigraphy of 67-year-old male with a malignant melanoma of the right heel; sentinel lymph nodes in both the right popliteal fossa and inguinal region. B. Lymphoscintigraphy of 52-year-old male with a malignant melanoma of the posterior right upper arm; sentinel lymph node in the right axillary region. C. Lymphoscintigraphy of 69-year-old male with a facial melanoma; sentinel lymph nodes in the submandibular region. ANT = anterior; INJ = injection; POST = posterior. Sentinel lymph node Sentinel lymph node Afferent lymphatic channels B A Injection site 489 Sentinel lymph node Surgical exposure of sentinel lymph node VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 16-13. Technique of sentinel lymph node biopsy for cutaneous melanoma. After injection of radioactive technetium-99–labeled sulfur colloid tracer at a lower abdominal wall primary cutaneous melanoma site, sentinel lymph node basins are identified. (From Gershenwald JE, Ross MI. Sentinel-lymph node biopsy for cutaneous melanoma. N Engl J Med. 2011;364:1738-1745. Copyright © 2011 Massachusetts Medical Society. Reprinted with ­permission.) CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE There is no supporting evidence for chest x-ray or CT in the staging of patients unless there is positive regional lymph node disease (and even in this case, the indications are not so clear).41 However, high-risk melanoma (i.e., T4b), especially of the lower extremities, may warrant further imaging to stage with modalities such as a positron emission tomography (PET)-CT or CT of the pelvis.41 In addition, patients with clinically palpable regional lymph nodes are at high risk for distant metastases and should receive additional imaging that includes CT of the chest, abdomen, and pelvis; whole-body PET-CT; or brain MRI. The sentinel lymph node biopsy (SLNB) technique for melanoma was introduced in 1992 and has become a cornerstone in the management of melanoma, although its role in management continues to be refined. SLNB is a standard staging procedure to evaluate the regional nodes for patients with clinically node-negative malignant melanoma. This technique identifies the first draining lymph node from the primary and has shown excellent accuracy and significantly less morbidity compared to complete resection of nodal basins. The SLNB technique involves preoperative lymphoscintigraphy with intradermal injections of technetium-sulfur colloid to delineate lymphatic drainage and intraoperative intradermal injection of 1 mL of isosulfan or methylene blue dye near the tumor or biopsy site (Figs. 16-12 and 16-13). The radioactive tracer-dye combination allows the sentinel node to be identified in 98% of cases. An incision over the lymph node basin of interest allows nodes to be excised and studied with hematoxylin and eosin and immunohistochemistry (S100, HMB45, and MART-1/Melan-A) staining (Fig. 16-14). Risks of this technique are uncommon but include skin necrosis near the site of injection, anaphylactic shock, lymphedema, surgical site infections, seromas, and hematomas. 490 UNIT II PART SPECIFIC CONSIDERATIONS A B Figure 16-14. Operation of sentinel lymph node biopsy for cutaneous melanoma. After preoperative injection of radioactive technetium-99– labeled sulfur colloid tracer and intraoperative injection of Lymphazurin blue dye around the primary melanoma excision site, the nodal basin of interest is identified. An incision is made directly overlying the lymph node basin in the posterior axillary space. The sentinel lymph nodes are identified and excised. that margins of 0.5 to 1.0 cm are sufficient. We believe that 1.0-cm margins should be obtained in anatomically feasible areas given the possibility of an incidental finding of a small invasive component in permanent sections. The World Health Organization (WHO) trial by Veronesi and colleagues provided the first prospective randomized controlled trial guiding appropriate margin management.76 In this trial, 612 patients with melanoma <2 mm in thickness were randomized to 1- or 3-cm margins. The results demonstrated no difference in overall survival or recurrence-free survival between groups. A trial from the Swedish Melanoma Study Group supported the WHO trial. The Swedish study examined patients with <2-mm thick melanoma who were randomized to 2- or 5-cm margins.77 There was no difference in recurrence-free survival (73% vs. 74%; P = .88) or overall survival (75% vs. 74%; P = .77) between the groups. The Intergroup Melanoma Trial randomized 468 patients with intermediate-thickness melanoma (1–4 mm) to 2- or 4-cm margins of excision.78,79 They did not find a significant difference in 10-year overall survival (70% vs. 77%; P = .074) or local recurrence (2.1% vs. 2.6%) between the two cohorts. A British trial suggested that there is a limit to how narrow margins can be for melanomas >2 mm thick in showing that 1-cm margins provide worse outcomes compared to 3-cm margins. Tumors <1 mm thick require 1-cm margins, tumors 1 to 2 mm thick require 1- to 2-cm margins, tumors 2 to 4 mm thick require 2-cm margins, and tumors >4 mm thick require 2-cm margins, although there are no randomized data to support this last point. Technically challenging locations should be treated in a similar fashion. For facial and scalp lesions, advancement flaps usually suffice for closure, as do wedge resections for lesions of the ear helix. When tumors are situated near critical structures (e.g., eye, lip), the best should be done to remove the primary tumor with adequate margins. SLNBs are recommended for melanomas 1 to 4 mm thick according to the National Comprehensive Cancer Network (NCCN) guideline recommendations.41 The incidence of regional lymph node metastasis in <1-mm thick melanomas is 5% or less. According to the NCCN guidelines, SLNB may be considered for thin melanoma with adverse features (i.e., >0.75 mm, >1 mitosis per mm, ulcerated), and literature that supports this approach states that SLNB provides prognostic information and is therapeutic for low-volume disease.41,80 For tumors that are >4 mm, the incidence of regional lymph node positivity is 35% to 40% and SLNB may provide prognostic information for these thick melanomas.81-83 The role for SLNB is supported by the Multicenter Selective Lymphadenectomy Trial (MSLT)-1, which looked at patients with melanoma 1.5 to 4 mm thick and randomized them to SLNB (and completion lymphadenectomy if positive) vs. no SLNB (and delayed complete lymphadenectomy for recurrent lymph node disease).84 SLNBs provided prognostic information but did not affect survival. However, when patients who were lymph node positive only were compared, 5-year overall survival was better if the lymphadenectomy was done at the time of a positive sentinel node vs. when it was delayed until the patients presented with clinical findings. Completion lymphadenectomy is commonly performed for sentinel nodes with metastatic disease, but it has been shown that most of these nodal basins do not have additional disease. Thus, many ­surgeons do not perform routine completion lymphadenectomy for positive nodes, and data from the MSLT-2 may provide guidance. Several studies evaluated the indications and benefit for extended lymphadenectomy. Three retrospective studies showed a 12% to 24% improved 5-year overall survival in patients with micrometastasis in elective regional lymphadenectomy specimens compared with patients undergoing therapeutic lymphadenectomy for clinically palpable disease. 85-87 The last large prospective randomized controlled trial showed a trend toward improved survival in patients with intermediatethickness (1.5–4 mm) melanomas who underwent immediate elective lymphadenectomy as opposed to nodal observation (77% vs. 73%; P = .12).88 For patients with clinically evident local regional lymphadenopathy, FNA biopsies can confirm metastatic disease. If metastatic workup including PET-CT excludes VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgery for Regional and Distant Metastasis. Nonmetastatic, in-transit disease should undergo excision to clear margins when feasible. However, disease not amenable to complete excision derives benefit from isolated limb perfusion (ILP) and isolated limb infusion (ILI) (Fig. 16-15). These two modalities are used to treat regional disease, and their purpose is to administer high doses of chemotherapy, commonly melphalan, to an affected limb while avoiding systemic drug toxicity. ILI was shown to provide a 31% response rate in one study, while hyperthermic ILP provided a 63% complete response rate in an independent study.89-92 The most common sites of distant metastasis are the lung and liver followed by the brain, gastrointestinal tract, distant skin, and subcutaneous tissue. A limited subset of patients with small-volume, limited distant metastases to the brain, gastrointestinal tract, or distant skin will be cured with resection or gamma knife radiation. Liver metastases are better dealt without surgical resection unless they arise from an ocular primary. Adjuvant therapy after resection of metastatic lesions is not standard of care; however, there are ongoing clinical trials addressing whether drugs and vaccines will be beneficial in this setting.55 Surgery may provide palliation for patients with gastrointestinal obstruction, gastrointestinal hemorrhage, and nongastrointestinal hemorrhage. Radiotherapy for symptomatic bony or brain metastases provides palliation in diffuse disease. Adjuvant and Palliative Therapies. Eastern Cooperative Oncology Group (ECOG) Trials 1684, 1690, and 1694 were prospective randomized controlled trials that demonstrated diseasefree survival advantages in patients with melanoma thicker than 4 mm with or without lymph node involvement if they received adjuvant treatment with high-dose interferon (IFN).93-95 A European Organization for Research and Treatment of Cancer (EORTC) trial also showed recurrence-free survival benefit with pegylated IFN.96 It is important to note that IFN therapy is not well tolerated, and the pooled analysis of these trials did not show an improvement in overall survival benefit. Most patients with metastatic melanoma will not be surgical candidates. Although the medical options for metastatic melanoma have historically been poor, several recent studies have shown promise in drug therapy for metastatic melanoma. BRAF inhibitors (sorafenib), anti-PD1 antibodies, CTLA antibodies (ipilimumab), and high-dose interleukin-2 (IL-2) with and without vaccines have been shown in randomized studies to provide survival benefit in metastatic disease.97-101 Despite the excitement of recent drugs, surgery will likely play an adjunct role in treating individuals who develop resistance to these drugs over time. Special Circumstances. Special circumstances of note are melanoma in pregnant women, melanoma of unknown primaries, and noncutaneous melanomas (i.e., ocular). The prognosis of pregnant patients is similar to women who are not pregnant. Extrapolation of studies examining the SLNB technique in pregnant women with breast cancer suggests lymphoscintigraphy may be done safely during pregnancy without risk to the fetus. (Blue dye is contraindicated.) General anesthesia should be avoided during the first trimester, and local anesthetics should be used at this time. It has been suggested by some that after excising the primary tumor during pregnancy, the SLNB may be performed after delivery. Unknown primary melanoma most commonly presents in lymph nodes (2% of cases and <5% of metastatic presentation). A thorough search for the primary lesion should be sought, including eliciting a history about prior skin lesions, skin procedures (e.g., curettage and electrodesiccation, excision, laser), and review of any prior “benign” pathology. The surgeon should be aware that melanoma is known to spontaneously regress because of an immune response. Ocular melanoma is the most common noncutaneous disease site, and treatment includes photocoagulation, partial resection, radiation, or enucleation.102-104 Ocular melanomas exclusively metastasize to the liver and not regional lymph nodes, and some patients benefit from liver resection. Melanoma of the mucous membranes most commonly presents in Overhead heater Drug in pre-warmed saline Pneumatic tourniquet Hot air blanket Arterial catheter Pump chamber Esmarch bandage Venous catheter 25cc Syringe Warming coil VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 16-15. Isolated limb infusion. Schematic of isolated limb infusion of lower extremity. (From Testori A, Verhoef C, Kroon HM, et al. Treatment of melanoma metastasis in a limb by isolated limb perfusion and isolated limb infusion. J Surg Oncol. 2011;104:397-404. Copyright 2011 John Wiley and Sons. Reprinted with permission.) 491 CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE distant disease, resection of the primary melanoma lesion and a completion lymphadenectomy should be performed. Individuals with face, anterior scalp, and ear primaries who have a positive SLNB should undergo a superficial parotidectomy in addition to a modified radical neck dissection. Patients with positive sentinel nodes in the inguino-femoral nodes should undergo an inguino-femoral lymphadenectomy that includes removal of Cloquet’s node. If Cloquet’s node is positive or the patient has three or more nodes that contain melanoma metastases, this is an indication for an ilio-obdurator lymphadenectomy.41 492 the oral cavity, oropharynx, nasopharynx, paranasal sinus, anus, rectum, and female genitalia. Patients with this presentation have a worse prognosis (10% 5-year survival) than individuals with cutaneous melanomas. Management should be excision to negative margins, and radical resections (i.e., abdominoperineal resection) should be avoided because the role of surgery is locoregional control, not cure. Generally speaking, lymph node dissection should be avoided because the benefit is unclear. Merkel Cell Carcinoma UNIT II PART SPECIFIC CONSIDERATIONS This is a rare and aggressive neuroendocrine tumor of the skin most commonly found in white men and diagnosed at a mean age of 70 years (Fig. 16-16). Risk factors include UV radiation, PUVA, and immunosuppression. Approximately one in three cases present on the face, with the remainder occurring on sunexposed skin. A rapidly growing, flesh-colored papule or plaque characterizes the disease. Regional lymph nodes are involved in 30% of patients, and 50% will develop systemic disease (skin, lymph nodes, liver, lung, bone, brain).105,106 There are no standardized diagnostic imaging studies for staging, but CT of the chest, abdomen, and pelvis and octreotide scans may provide useful information when clinically indicated. After examining the entire skin for other lesions, treatment should begin by evaluating the nodal basins. Patients without clinical nodal disease should undergo an SLNB preceding a wide local excision because studies suggest a benefit.107 In patients with sentinel lymph nodes with metastatic disease, completion lymphadenectomy and/or radiation therapy may follow, and in patients with node-negative disease, observation or radiation therapy should be considered.107 SLNB is ­important for staging and treatment, and the literature suggests that it predicts recurrence and relapse-free survival. Elective lymph node dissection may decrease regional nodal recurrence and in-transit metastases. Patients with clinically positive nodes should have an FNA to confirm disease. If positive, a metastatic staging workup should follow, and if negative, treatment of the primary and nodal basin as managed for sentinel lymph node– positive disease should be considered. A negative FNA and open biopsy-negative disease should be managed by treatment of the primary disease alone. Patients with metastatic disease should be managed according to consensus from a multidisciplinary tumor board. Important surgical principles for excision of the primary lesion are to excise with wide margins down to fascia and complete circumferential and peripheral deep-margin assessment. Recommended management for margins is 1- to 3-cm margins, and given the rarity of the tumor, there are no randomized trials further defining these margins. Moh’s microsurgery may play a role to ensure negative margins. Chemotherapy is commonly used, but there are no data to support a specific regimen or that demonstrate a definitive survival benefit. Recurrence is common, and one study of 95 patients showed a 47% recurrence, with 80% of recurrences occurring within 2 years and 96% occurring within 5 years.108,109 Regional lymph node disease is common, and 70% of patients will have nodal spread within 2 years of disease presentation. Five-year overall survival of head and neck disease in surgically treated patients is between 40% and 68%. Kaposi’s Sarcoma Kaposi’s sarcoma is characterized by the proliferation and inflammation of endothelial-derived spindle cell lesions. There are five major forms of this angioproliferative disorder: classic (Mediterranean), African endemic, HIV-negative men having sex with men (MSM)–associated, AIDS-associated, and immunosuppression-associated; they are all driven by the human herpesvirus (HHV-8).68 Kaposi’s sarcoma is diagnosed after the fifth decade of life and predominantly found on the skin but can occur anywhere in the body. In North America, the Kaposi’s sarcoma herpes virus is transmitted via sexual and nonsexual routes and predominantly affects individuals with compromised immune systems such as those with HIV and transplant recipients on immune-suppressing medications. Clinically, Kaposi’s sarcoma appears as multifocal, rubbery blue nodules. Treatment of AIDS-associated Kaposi’s sarcoma is with antiviral therapy, and many patients experience a dramatic treatment response.110,111 Those individuals who do not respond and have limited mucocutaneous disease may benefit from cryotherapy, photodynamic therapy, radiation therapy, intralesional injections, and topical therapy. Surgical biopsy is important for disease diagnosis, but given the high local recurrence and the fact that Kaposi’s sarcoma represents more of a systemic rather than local disease, the benefit of surgery is limited and generally should not be pursued except for palliation. Dermatofibrosarcoma Protuberans Figure 16-16. Merkel cell carcinoma seen just above the left knee in a 44-year-old female. This rare, low-grade sarcoma of fibroblast origin commonly afflicts individuals during their third decade of life. It has low distant metastatic potential but behaves aggressively locally with finger-like extensions. Tumor depth is the most important prognostic variable. Presentation is characteristically a slowgrowing, asymptomatic, violaceous plaque involving the trunk, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ head, neck, or extremities. Treatment is wide local excision with 3-cm margins down to deep underlying fascia or Moh’s microsurgery in cosmetically sensitive areas where maximum tissue preservation will benefit.112 No nodal dissection is needed, and both approaches provide similar local control.113 Some clinicians have used radiation therapy and biologic agents (imatinib) with some success in patients with advanced disease. Local recurrence occurs in 50% to 75% of cases, usually within 3 years of treatment, and thus, clinical follow-up is important. Recurrent tumors should be resected whenever possible. This uncommon, cutaneous, spindle-cell, soft tissue sarcoma occurs in the extremities, head, and neck of elderly patients. They present as solitary, soft to firm, skin-colored subcutaneous nodules. Complete surgical resection is the treatment of choice, and adjuvant radiation therapy provides local control; patients with positive margins benefit most from this combination. Nevertheless, patients undergoing complete gross resection will experience recurrence in 30% to 35% of cases.71 Up to 50% of patients may present with distant metastasis, and this is a contraindication to surgical resection. Angiosarcoma Angiosarcoma is an uncommon, aggressive cancer that arises from vascular endothelial cells and occurs in four variants, all of which have a poor prognosis.114 The head and neck variant presents in individuals older than 40 years as an ill-defined red patch on the face or scalp, often with satellite lesions and distant metastasis, and has a median survival of 18 to 28 months. Lymphedema-associated angiosarcoma (Stewart-Treves) develops on an extremity ipsilateral to an axillary lymphadenectomy. It appears on the upper, medial arm as a violaceous plaque in an individual with nonpitting edema and has a poor survival. Radiation-induced angiosarcoma occurs 4 to 25 years after radiation therapy for benign (acne) and malignant (i.e., breast cancer) conditions. Finally, the epithelioid variant of angiosarcoma involves the lower extremities and also has a poor prognosis. Surgical excision with wide margins is the treatment of choice for localized disease, but the rate of recurrence is high. Adjuvant radiation therapy can be considered in a multidisciplinary fashion. Cases of extremity disease can be considered for amputation. For widely metastatic disease, chemotherapy and radiation may provide palliation, but these modalities do not prolong overall survival.55 Extramammary Paget’s Disease This rare adenocarcinoma of apocrine glands arises in perianal and axillary regions and in genitalia of men and women.115 Clinical presentation is that of erythematous or nonpigmented plaques with an eczema-like appearance that often persist after failed treatment from other therapies. An important characteristic and one that the surgeon must be acutely aware of is the high incidence of concomitant other malignancies with this cutaneous disease. Forty percent of cases are associated with primary gastrointestinal and genitourinary malignancies, and a diligent search should be made after a diagnosis of extramammary Paget’s disease is made. Treatment is surgical resection with negative microscopic margins, and adjuvant radiation may provide additional locoregional control. The skin is the largest organ in the human body and is composed of three organized layers that are the source of numerous pathologies. Recognition and management of cutaneous and subcutaneous diseases require an astute clinician to optimize clinical outcomes. Improvements in drugs therapies and healthcare practices have helped recovery from skin injuries. Skin and subcutaneous diseases are often managed medically, although surgery frequently complements treatment. Benign tumors are surgical diseases, while malignant tumors are primarily treated surgically, and additional modalities including chemotherapy and radiation therapy are sometimes required. The management of melanoma is at an exciting phase, requiring the coordinated multidisciplinary care of medical oncologists, surgical oncologists, radiation oncologists, dermatopathologists, and plastic and reconstructive surgeons. The advent of new drug therapies will redefine the role of surgery in this disease in the coming years. 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Toxic epidermal necrolysis: review of pathogenesis and management. J Am Acad Dermatol. 2012;66:995-1003. 18. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review. Crit Care Med. 2011;39:1521-1532. 19. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428:486. 20. French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharmacol. 2006;6:543-549. 21. Trent J, Halem M, French LE, Kerdel F. Toxic epidermal necrolysis and intravenous immunoglobulin: a review. Semin Cutan Med Surg. 2006;25:91-93. 22. Battie C, Verschoore M. Cutaneous solar ultraviolet exposure and clinical aspects of photodamage. Indian J Dermatol Venereol Leprol. 2012;78(Suppl 1):S9-S14. 23. Eliya MC, Banda GW. Primary closure versus delayed closure for nonbite traumatic wounds within 24 hours post injury. Cochrane Database Syst Rev. 2011;9:CD008574. 24. Presutti RJ. Bite wounds. Early treatment and prophylaxis against infectious complications. Postgrad Med. 1997;101: 243-244, 246-252, 254. 25. Abrahamian FM, Goldstein EJ. Microbiology of animal bite wound infections. Clin Microbiol Rev. 2011;24:231-246. 26. Robson M, Krizek T, Heggers J. Biology of surgical infection. Curr Probl Surg. 1973:1-62. 27. Hardwicke J, Hunter T, Staruch R, Moiemen N. Chemical burns—an historical comparison and review of the literature. Burns. 2012;38:383-387. 28. Kumar RJ, Pegg SP, Kimble RM. Management of extravasation injuries. ANZ J Surg. 2001;71:285-289. 29. Frye KE, Luterman A. Thermal Burns. 2nd ed. Philadelphia, PA: Mosby, Elsevier; 2010. 30. Britt LD, Dascombe WH, Rodriguez A. New horizons in management of hypothermia and frostbite injury. Surg Clin North Am. 1991;71:345-370. 31. Lindan O, Greenway RM, Piazza JM. Pressure distribution on the surface of the human body. I. Evaluation in lying and sitting positions using a “bed of springs and nails.” Arch Phys Medicine Rehabil. 1965;46:378-385. 32. Lyder CH. Pressure ulcer prevention and management. JAMA. 2003;289:223-226. 33. Cannon BC, Cannon JP. Management of pressure ulcers. Am J Health Syst Pharm. 2004;61:1895-1905; quiz 1906-1907. 34. Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg. 1997;38:563-576; discussion 577. 35. Limova M. Active wound coverings: bioengineered skin and dermal substitutes. Surg Clin North Am. 2010;90:1237-1255. 36. Rajan S. Skin and soft-tissue infections: classifying and treating a spectrum. Cleve Clin J Med. 2012;79:57-66. 37. Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microbiol Infect Dis. 2007;57:7-13. 38. Cardoso JC, Calonje E. Cutaneous manifestations of human papillomaviruses: a review. Acta Dermatovenerol Alp Panonica Adriat. 2011;20:145-154. 39. Rogers HD, Macgregor JL, Nord KM, et al. Acquired epidermodysplasia verruciformis. J Am Acad Dermatol. 2009;60: 315-320. 40. Jacobelli S, Laude H, Carlotti A, et al. Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy. Arch Dermatol. 2011;147:590-596. 41. National Comprehensive Cancer Network. Melanoma, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Melanoma, Version 2.2013. Fort Washington, PA: National Comprehensive Cancer Network; 2012. 42. Davis PA, Wastell C. A comparison of biomechanical properties of excised mature scars from HIV patients and non-HIV controls. Am J Surg. 2000;180:217-222. 43. Krengel S, Hauschild A, Schafer T. Melanoma risk in congenital melanocytic naevi: a systematic review. Br J Dermatol. 2006;155:1-8. 44. Schaffer JV. Pigmented lesions in children: when to worry. Curr Opin Pediatr. 2007;19:430-440. 45. Satyaprakash AK, Sheehan DJ, Sangueza OP. Proliferating trichilemmal tumors: a review of the literature. Dermatol Surg. 2007;33:1102-1108. 46. Fu W, Cockerell CJ. The actinic (solar) keratosis: a 21st-century perspective. Arch Dermatol. 2003;139:66-70. 47. Robins P, Gupta AK. The use of topical fluorouracil to treat actinic keratosis. Cutis. 2002;70:4-7. 48. Epstein JH. Photocarcinogenesis, skin cancer, and aging. J Am Acad Dermatol. 1983;9:487-502. 49. Luce EA. Oncologic considerations in nonmelanotic skin cancer. Clin Plast Surg. 1995;22:39-50. 50. Marks R, Kopf AW. Cancer of the skin in the next century. Int J Dermatol. 1995;34:445-447. 51. Mentzel T. Cutaneous lipomatous neoplasms. Semin Diagn Pathol. 2001;18:250-257. 52. Sober AJ, Burstein JM. Precursors to skin cancer. Cancer. 1995;75:645-650. 53. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300. 54. National Comprehensive Cancer Network. Basal Cell and Squamous Cell Skin Cancers, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Version 2.2012. Fort Washington, PA: National Comprehensive Cancer Network; 2012. 55. Reszko A, Wilson LD, Leffell DJ. Devita, Hellman, Rosenberg’s Cancer: Principles and Practice. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 56. Rowe DE, Carroll RJ, Day CL Jr. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol. 1989;15:424-431. 57. Rowe DE, Carroll RJ, Day CL Jr. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol. 1989;15:315-328. 58. Kopf AW, Bart RS, Schrager D, Lazar M, Popkin GL. Curettageelectrodesiccation treatment of basal cell carcinomas. Arch Dermatol. 1977;113:439-443. 59. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehiclecontrolled studies. J Am Acad Dermatol. 2004;50:722-733. 60. Marks R, Gebauer K, Shumack S, et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol. 2001;44:807-813. 61. Schulze HJ, Cribier B, Requena L, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe. Br J Dermatol. 2005;152:939-947. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 82. Gershenwald JE, Mansfield PF, Lee JE, Ross MI. Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (> or = 4 mm) primary melanoma. Ann Surg Oncol. 2000;7:160-165. 83. Gutzmer R, Satzger I, Thoms KM, et al. Sentinel lymph node status is the most important prognostic factor for thick (> or = 4 mm) melanomas. J Dtsch Dermatol Ges. 2008;6:198-203. 84. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302-311; discussion 311-313. 85. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA. A multifactorial analysis of melanoma: III. Prognostic factors in melanoma patients with lymph node metastases (stage II). Ann Surg. 1981;193:377-388. 86. Callery C, Cochran AJ, Roe DJ, et al. Factors prognostic for survival in patients with malignant melanoma spread to the regional lymph nodes. Ann Surg. 1982;196:69-75. 87. Roses DF, Provet JA, Harris MN, Gumport SL, Dubin N. Prognosis of patients with pathologic stage II cutaneous malignant melanoma. Ann Surg. 1985;201:103-107. 88. Balch CM, Soong S, Ross MI, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0–4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol. 2000;7:87-97. 89. Beasley GM, Caudle A, Petersen RP, et al. A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US. J Am Coll Surg. 2009;208:706-715; discussion 715-717. 90. Boesch CE, Meyer T, Waschke L, et al. Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treatment of locoregionally metastasised malignant melanoma of the extremities. Int J Hyperthermia. 2010;26:16-20. 91. Lens MB, Dawes M. Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials. Lancet Oncol. 2003;4:359-364. 92. Lindner P, Doubrovsky A, Kam PC, Thompson JF. Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol. 2002;9:127-136. 93. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and lowdose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444-2458. 94. Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10:1670-1677. 95. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14: 7-17. 96. Eggermont AM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008;372:117-126. 97. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116. 98. Chapman PB, Hauschild A, Robert C, et al. Improved ­survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 99. Hodi FS, O’Day SJ, McDermott DF, et al. Improved ­survival with ipilimumab in patients with metastatic melanoma.­ N Engl J Med. 2010;363:711-723. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 495 CHAPTER 16 THE SKIN AND SUBCUTANEOUS TISSUE 62. Shumack S, Robinson J, Kossard S, et al. Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Arch Dermatol. 2002;138:1165-1171. 63. Vidal D, Matias-Guiu X, Alomar A. Open study of the efficacy and mechanism of action of topical imiquimod in basal cell carcinoma. Clin Exp Dermatol. 2004;29:518-525. 64. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26:976-990. 65. Kao GF. Carcinoma arising in Bowen’s disease. Arch Dermatol. 1986;122:1124-1126. 66. Honeycutt WM, Jansen GT. Treatment of squamous cell carcinoma of the skin. Arch Dermatol. 1973;108:670-672. 67. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one. J Cutan Pathol. 2006;33:191-206. 68. Ramirez-Amador V, Anaya-Saavedra G, Martinez-Mata G. Kaposi’s sarcoma of the head and neck: a review. Oral Oncol. 2010;46:135-145. 69. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2013;63:11-30. 70. Cust AE, Armstrong BK, Goumas C, et al. Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma. Int J Cancer. 2011;128:2425-2435. 71. Chudnovsky Y, Khavari PA, Adams AE. Melanoma genetics and the development of rational therapeutics. J Clin Invest. 2005;115:813-824. 72. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199-6206. 73. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622-3634. 74. Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28:2452-2459. 75. Weide B, Elsasser M, Buttner P, et al. Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis. Br J Cancer. 2012;107:422-428. 76. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med. 1988;318:1159-1162. 77. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8–2.0 mm. Cancer. 2000;89:1495-1501. 78. Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8:101-108. 79. Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1–4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg. 1993;218:262-267; discussion 267-269. 80. Wright BE, Scheri RP, Ye X, et al. Importance of sentinel lymph node biopsy in patients with thin melanoma. Arch Surg. 2008;143:892-899; discussion 899-900. 81. Ferrone CR, Panageas KS, Busam K, Brady MS, Coit DG. Multivariate prognostic model for patients with thick cutaneous ­melanoma: importance of sentinel lymph node status. Ann Surg Oncol. 2002;9:637-645. 496 UNIT II PART SPECIFIC CONSIDERATIONS 100. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907-913. 101. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14:5610-5618. 102. Albert DM, Ryan LM, Borden EC. Metastatic ocular and cutaneous melanoma: a comparison of patient characteristics and prognosis. Arch Ophthalmol. 1996;114:107-108. 103. Inskip PD, Devesa SS, Fraumeni JF Jr. Trends in the incidence of ocular melanoma in the United States, 1974-1998. Cancer Causes Control. 2003;14:251-257. 104. Starr OD, Patel DV, Allen JP, McGhee CN. Iris melanoma: pathology, prognosis, and surgical intervention. Clin Exp Ophthalmol. 2004;32:294-296. 105. Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol. 2000;43:755-767. 106. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken SW. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol. 2001;8:204-208. 107. National Comprehensive Cancer Network. Merkel Cell Carcinoma, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Version 1.2012. Fort Washington, PA: National Comprehensive Cancer Network; 2012. 108. Bichakjian CK, Lowe L, Lao CD, et al. Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer. 2007;110:1-12. 109. Ott MJ, Tanabe KK, Gadd MA, et al. Multimodality management of Merkel cell carcinoma. Arch Surg. 1999;134:388-392; discussion 92-93. 110. Bower M, Weir J, Francis N, et al. The effect of HAART in 254 consecutive patients with AIDS-related Kaposi’s ­sarcoma. AIDS. 2009;23:1701-1706. 111. Martinez V, Caumes E, Gambotti L, et al. Remission from Kaposi’s sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy. Br J Cancer. 2006;94:1000-1006. 112. Fields RC, Hameed M, Qin LX, et al. Dermatofibrosarcoma protuberans (DFSP): predictors of recurrence and the use of systemic therapy. Ann Surg Oncol. 2011;18:328-336. 113. Meguerditchian AN, Wang J, Lema B, Kraybill WG, Zeitouni NC, Kane JM III. Wide excision or Mohs micrographic surgery for the treatment of primary dermatofibrosarcoma protuberans. Am J Clin Oncol. 2010;33:300-303. 114. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol. 1998;38:143-175; quiz 176-178. 115. Wagner G, Sachse MM. Extramammary Paget disease: clinical appearance, pathogenesis, management. J Dtsch Dermatol Ges. 2011;9:448-454. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 17 chapter A Brief History of Breast Cancer Therapy 497 Embryology and Functional Anatomy of the Breast 499 Embryology / 499 Functional Anatomy / 500 Physiology of the Breast 503 The Breast Kelly K. Hunt, John F.R. Robertson, and Kirby I. Bland Epidemiology and Natural History of Breast Cancer Breast Development and Function / 503 Pregnancy, Lactation, and Senescence / 504 Gynecomastia / 505 Epidemiology / 517 Natural History / 518 Infectious and Inflammatory Disorders of the Breast Carcinoma In Situ / 519 Invasive Breast Carcinoma / 520 506 Common Benign Disorders and Diseases of the Breast Surgical Techniques In Breast Cancer Therapy 517 519 522 Examination / 523 Imaging Techniques / 523 Breast Biopsy / 529 507 Aberrations of Normal Development and Involution / 507 Pathology of Nonproliferative Disorders / 508 Pathology of Proliferative Disorders Without Atypia / 509 Pathology of Atypical Proliferative Diseases / 510 Treatment of Selected Benign Breast Disorders and Diseases / 510 Risk Factors for Breast Cancer Histopathology of Breast Cancer Diagnosis of Breast Cancer Bacterial Infection / 506 Mycotic Infections / 506 Hidradenitis Suppurativa / 506 Mondor’s Disease / 507 Local-Regional Recurrence / 543 Breast Cancer Prognosis / 544 Hormonal and Nonhormonal Risk Factors / 511 Risk Assessment Models / 511 Risk Management / 512 BRCA Mutations / 514 Breast Cancer Staging and Biomarkers 531 Breast Cancer Staging / 531 Biomarkers / 531 Overview of Breast Cancer Therapy 511 536 In Situ Breast Cancer (Stage 0) / 537 Early Invasive Breast Cancer (Stage I, IIA, or IIB) / 538 Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB) / 541 Internal Mammary Lymph Nodes / 543 Distant Metastases (Stage IV) / 543 A BRIEF HISTORY OF BREAST CANCER THERAPY Breast cancer has captured the attention of surgeons throughout the ages. The Smith Surgical Papyrus (3000–2500 b.c.) is the earliest known document to refer to breast cancer. The cancer was in a man, but the description encompassed most of the common clinical features. In reference to this cancer, the author concluded, “There is no treatment.”1 There were few other historical references to breast cancer until the first century. In De Medicina, Celsus commented on the value of operations for early breast cancer: “None of these may be removed but the cacoethes (early cancer), the rest are irritated by every method of cure. The more violent the operations are, the more angry they grow.”2 In the second century, Galen inscribed his classical clinical observation: “We have often seen in the breast a tumor 544 Excisional Biopsy with Needle Localization / 544 Sentinel Lymph Node Dissection / 545 Breast Conservation / 547 Mastectomy and Axillary Dissection / 547 Modified Radical Mastectomy / 548 Reconstruction of the Breast and Chest Wall / 549 Nonsurgical Breast Cancer Therapies 550 Radiation Therapy / 550 Chemotherapy Adjuvant / 550 Antiestrogen Therapy / 552 Ablative Endocrine Therapy / 553 Anti–HER-2/neu Therapy / 553 Special Clinical Situations 554 Axillary Lymph Node Metastases in the Setting of an Unknown Primary Cancer / 554 Breast Cancer During Pregnancy / 554 Male Breast Cancer / 554 Phyllodes Tumors / 555 Inflammatory Breast Carcinoma / 555 Rare Breast Cancers / 556 exactly resembling the animal the crab. Just as the crab has legs on both sides of his body, so in this disease the veins extending out from the unnatural growth take the shape of a crab’s legs. We have often cured this disease in its early stages, but after it has reached a large size, no one has cured it. In all operations we attempt to excise the tumor in a circle where it borders on the healthy tissue.”3 The galenic system of medicine ascribed cancers to an excess of black bile and concluded that excision of a local bodily outbreak could not cure the systemic imbalance. Theories espoused by Galen dominated medicine until the Renaissance. In 1652 Tulp introduced the idea that cancer was contagious when he reported an elderly woman and her housemaid who both developed breast cancer (N. Tulp, Observationes medicae 1652). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 UNIT II PART SPECIFIC CONSIDERATIONS 498 3 4 5 The breast receives its principal blood supply from perforating branches of the internal mammary artery, lateral branches of the posterior intercostal arteries, and branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery. The axillary lymph nodes usually receive >75% of the lymph drainage from the breast, and the rest flows through the lymph vessels that accompany the perforating branches of the internal mammary artery and enters the parasternal (internal mammary) group of lymph nodes. Breast development and function are initiated by a variety of hormonal stimuli, with the major trophic effects being modulated by estrogen, progesterone, and prolactin. Benign breast disorders and diseases are related to the normal processes of reproductive life and to involution, and there is a spectrum of breast conditions that ranges from normal to disorder to disease (aberrations of normal development and involution classification). To calculate breast cancer risk using the Gail model, a woman’s risk factors are translated into an overall risk score by multiplying her relative risks from several categories. This risk score is then compared with an adjusted population risk of breast cancer to determine the woman’s individual risk. This model is not appropriate for use in women with a This single incidence was accepted as conclusive evidence and started an idea which persisted into the 20th century among some lay people. The majority of respected surgeons considered operative intervention to be a futile and ill-advised endeavor. The Renaissance and the wars of the 16th and 17th centuries brought developments in surgery, particularly in anatomical understanding. However there were no new theories espoused in relation to cancer. Beginning with Morgagni, surgical resections were more frequently undertaken, including some early attempts at mastectomy and axillary dissection. The 17th century saw the start of the Age of Enlightenment which lasted until the 19th century. In terms of medicine, this resulted in the abandonment of Galen’s humoral pathology which was repudiated by Le Dran and the subsequent rise in cellular pathology as espoused by Virchow. Le Dran stated that breast cancer was a local disease that spread by way of lymph vessels to axillary lymph nodes. When operating on a woman with breast cancer, he routinely removed any enlarged axillary lymph nodes.4 In the 19th century, Moore, of the Middlesex Hospital, London, emphasized complete resection of the breast for cancer and stated that palpable axillary lymph nodes also should be removed.5 In a presentation before the British Medical Association in 1877, Banks supported Moore’s concepts and advocated the resection of axillary lymph nodes even when palpable lymphadenopathy was not evident, recognizing that occult involvement of axillary lymph nodes was frequently present. In 1894, Halsted and Meyer reported their operations for treatment of breast cancer.6 By demonstrating superior local-regional control rates after radical resection, these surgeons established radical mastectomy as state-of-the-art treatment for that era. 6 7 8 9 10 known BRCA1 or BRCA2 mutation or women with lobular or ductal carcinoma in situ. Routine use of screening mammography in women ≥50 years of age reduces mortality from breast cancer by 25%. MRI screening is recommended in women with BRCA mutations and may be considered in women with a greater than 20% to 25% lifetime risk of developing breast cancer. Core-needle biopsy is the preferred method for diagnosis of palpable or nonpalpable breast abnormalities. When a diagnosis of breast cancer is made, the surgeon should determine the clinical stage, histologic characteristics, and appropriate biomarker levels before initiating local therapy. Sentinel node dissection is the preferred method for staging of the regional lymph nodes in women with clinically node-negative invasive breast cancer. Axillary dissection may be avoided in women with 1 to 2 positive sentinel nodes who are treated with breast conserving surgery, whole breast radiation and systemic therapy. Local-regional and systemic therapy decisions for an individual patient with breast cancer are best made using a multidisciplinary treatment approach. The sequencing of therapies is dependent on patient and tumor related factors including breast cancer subtype. Halsted and Meyer advocated complete dissection of axillary lymph node levels I to III. Both routinely resected the long thoracic nerve and the thoracodorsal neurovascular bundle with the axillary contents. In 1943, Haagensen and Stout described the grave signs of breast cancer, which included: (a) edema of the skin of the breast, (b) skin ulceration, (c) chest wall fixation, (d) an axillary lymph node >2.5 cm in diameter, and (e) fixed axillary lymph nodes. Women with two or more signs had a 42% local recurrence rate and only a 2% five-year disease-free survival rate.7 Based on these findings, they declared that women with grave signs were beyond cure by radical surgery. In 1948, Patey and Dyson of the Middlesex Hospital, London, advocated a modified radical mastectomy for the management of advanced operable breast cancer, explaining, “Until an effective general agent for treatment of carcinoma of the breast is developed, a high proportion of these cases are doomed to die.”8 Their technique included removal of the breast and axillary lymph nodes with preservation of the pectoralis major muscle. They showed that removal of the pectoralis minor muscle allowed access to and clearance of axillary lymph node levels I to III. During the 1970s, there was a transition from the Halsted radical mastectomy to the modified radical mastectomy as the surgical procedure most frequently used by American surgeons to treat breast cancer. This transition acknowledged that: (a) fewer patients were presenting with advanced local disease with or without the grave signs described by Haagensen, (b) extirpation of the pectoralis major muscle was not essential for localregional control in stage I and II breast cancer, and (c) neither the modified radical mastectomy nor the Halsted radical mastectomy consistently achieved local-regional control of stage III VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ trials in order to examine the impact of adjuvant treatments for breast cancer on recurrence and mortality. The EBCTCG overview has demonstrated that anthracycline containing regimens are superior to CMF, and more recently, that the addition of a taxane to an anthracycline-based regimen reduces breast cancer mortality by one third.11 The overview has also demonstrated that tamoxifen is of benefit only in patients with estrogen receptor (ER) positive breast cancer and that tamoxifen may decrease mortality from breast cancer by as much as 50%.13 Importantly, the EBCTCG data have shown that proportional reduction in risk was not significantly affected by standard clinical and pathologic factors such as tumor size, ER status, and nodal status.14 This underscores the importance of stratification of risk in determining adjuvant therapy decisions in order to minimize the toxicities of therapies in those unlikely to benefit, yet realize the substantial benefits gained in local-regional control and survival in those at higher risk. Many early randomized clinical trials considered all patients similarly in terms of treatment viewing breast cancer as more of a homogeneous disease. Breast cancer has traditionally been defined by pathologic determinants using conventional light microscopy and basic histologic techniques. In the 1980s immunohistochemistry allowed assessment of the expression of individual tumor markers (most commonly proteins) while DNA was initially assessed in terms of its ploidy status. Subsequently, breast cancer specimens have been interrogated at the level of the DNA by labeling genes of interest and allowing fluorescent dyes to quantify the abundance of a particular gene and comparing a large number of genes simultaneously in a single breast cancer specimen. Gene expression arrays have shown that breast cancers cluster according to their intrinsic gene expression patterns into at least five intrinsic subtypes and these intrinsic subtypes correlate with breast cancer outcomes.15 Breast cancers are now classified by molecular subtypes and these are being used for risk stratification and decision making in terms of local-regional and systemic therapies. Currently, 50% of American women will consult a surgeon regarding breast disease, 25% will undergo breast biopsy for diagnosis of an abnormality, and 12% will develop some variant of breast cancer. Considerable progress has been made in the integration of surgery, radiation therapy, and systemic therapy to control local-regional disease, enhance survival, and improve the quality of life of breast cancer survivors. Surgeons are traditionally the first physician consulted for breast care and it is critical for them to be well trained in all aspects of the breast from embryologic development, to growth and development, and to benign and malignant disease processes. This will allow the greatest opportunity to achieve optimal outcomes for patients and their families. EMBRYOLOGY AND FUNCTIONAL ANATOMY OF THE BREAST Embryology At the fifth or sixth week of fetal development, two ventral bands of thickened ectoderm (mammary ridges, milk lines) are evident in the embryo.16 In most mammals, paired breasts develop along these ridges, which extend from the base of the forelimb (future axilla) to the region of the hind limb (inguinal area). These ridges are not prominent in the human embryo and disappear after a short time, except for small portions that may VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 499 CHAPTER 17 The Breast breast cancer. Radiation therapy was incorporated into the management of advanced breast cancer and demonstrated improvements in local-regional control. The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized trial in the early 1970s to determine the impact of local and regional treatments on survival in operable breast cancer. In the B-04 trial, 1665 women were enrolled and stratified by clinical assessment of the axillary lymph nodes. The clinically nodenegative women were randomized into three treatment groups: (a) Halsted radical mastectomy; (b) total mastectomy plus radiation therapy; and (c) total mastectomy alone. Clinically node-positive women were randomized to Halsted radical mastectomy or total mastectomy plus radiation therapy. This trial accrued patients between 1971 and 1974, an era that predated widespread availability of effective systemic therapy for breast cancer and therefore reflect survival associated with localregional therapy alone. There were no differences in survival between the three groups of node-negative women or between the two groups of node-positive women. These overall survival equivalence patterns have persisted at 25 years of follow-up.9 The next major advance in the surgical management of breast cancer was the development of breast conserving surgery. Breast conserving surgery and radium treatment was first reported by Geoffrey Keynes of St Bartholomew’s Hospital, London in the British Medical Journal in 1937.10 Several decades later, the NSABP launched the B-06 trial, a phase III study that randomized 1851 patients to total mastectomy, lumpectomy alone, or lumpectomy with breast irradiation. The results showed no difference in disease-free, distant disease-free, and overall survival among the three groups; however, the omission of radiation therapy resulted in significantly higher rates of ipsilateral breast tumor recurrence in those who received lumpectomy alone.11 The B-06 trial excluded patients who had palpable axillary lymph nodes and those patients randomized to breast conserving surgery had frozen sections performed and if on frozen section the margins were involved the surgeon proceeded to perform a mastectomy but the patient was included in the analysis as though they had a breast conserving operation. Furthermore, in B-06 local in-breast recurrences were regarded as “non-events” in terms of disease-free survival. Both NSABP B-04 and B-06 trials were taken to refute the Halstedian concept that cancer spread throughout a region of the breast to lymphatics and then on to distant sites. Bernard Fisher proposed the “alternative hypothesis” that breast cancer was a systemic disease at diagnosis and that tumor cells had access to both the blood and lymphatic systems and that regional lymph nodes were a marker of systemic disease and not a barrier to the dissemination of cancer cells. He proposed that host factors were important in the development of metastasis and that variations in the local-regional approach to breast cancer were not likely to substantially impact survival. This idea was dominant for a number of years but has been challenged by the Early Breast Cancer Trialists’ Collaborative Group overview analysis which reported that “the avoidance of recurrence in a conserved breast …. avoids about one breast cancer death over the next 15 years for every four such recurrences avoided.”12 Indicating that not all breast cancer is a systemic disease at presentation. During the 1970s, clinical trials were initiated to determine the value of systemic therapy in the postoperative setting as an adjuvant to surgery. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) was established in 1985 to coordinate the meta-analysis of data from randomized clinical abnormalities, arthrogryposis). Supernumerary breasts may occur in any configuration along the mammary milk line but most frequently occur between the normal nipple location and the symphysis pubis. Turner’s syndrome (ovarian agenesis and dysgenesis) and Fleischer’s syndrome (displacement of the nipples and bilateral renal hypoplasia) may have polymastia as a component. Accessory axillary breast tissue is uncommon and usually is bilateral. 500 Functional Anatomy UNIT II PART SPECIFIC CONSIDERATIONS Figure 17-1. The mammary milk line (Visual Art: © 2012.The University of Texas MD Anderson Cancer Center.) persist in the pectoral region. Accessory breasts (polymastia) or accessory nipples (polythelia) may occur along the milk line (Fig. 17-1) when normal regression fails. Each breast develops when an ingrowth of ectoderm forms a primary tissue bud in the mesenchyme. The primary bud, in turn, initiates the development of 15 to 20 secondary buds. Epithelial cords develop from the secondary buds and extend into the surrounding mesenchyme. Major (lactiferous) ducts develop, which open into a shallow mammary pit. During infancy, a proliferation of mesenchyme transforms the mammary pit into a nipple. If there is failure of a pit to elevate above skin level, an inverted nipple results. This congenital malformation occurs in 4% of infants. At birth, the breasts are identical in males and females, demonstrating only the presence of major ducts. Enlargement of the breast may be evident and a secretion, historically referred to as witch’s milk, may be produced. These transitory events occur in response to maternal hormones that cross the placenta. The breast remains undeveloped in the female until puberty, when it enlarges in response to ovarian estrogen and progesterone, which initiate proliferation of the epithelial and connective tissue elements. However, the breasts remain incompletely developed until pregnancy occurs. Absence of the breast (amastia) is rare and results from an arrest in mammary ridge development that occurs during the sixth fetal week. Poland’s syndrome consists of hypoplasia or complete absence of the breast, costal cartilage and rib defects, hypoplasia of the subcutaneous tissues of the chest wall, and brachysyndactyly. Breast hypoplasia also may be iatrogenically induced before puberty by trauma, infection, or radiation therapy. Symmastia is a rare anomaly recognized as webbing between the breasts across the midline. Accessory nipples (polythelia) occur in <1% of infants and may be associated with abnormalities of the urinary tract (renal agenesis and cancer), abnormalities of the cardiovascular system (conduction disturbances, hypertension, congenital heart anomalies), and other conditions (pyloric stenosis, epilepsy, ear The breast is composed of 15 to 20 lobes (Fig. 17-2), which are each composed of several lobules.17 Fibrous bands of connective tissue travel through the breast (Cooper’s suspensory ligaments), insert perpendicularly into the dermis, and provide structural support. The mature female breast extends from the level of the second or third rib to the inframammary fold at the sixth or seventh rib. It extends transversely from the lateral border of the sternum to the anterior axillary line. The deep or posterior surface of the breast rests on the fascia of the pectoralis major, serratus anterior, and external oblique abdominal muscles, and the upper extent of the rectus sheath. The retromammary bursa may be identified on the posterior aspect of the breast between the investing fascia of the breast and the fascia of the pectoralis major muscles. The axillary tail of Spence extends laterally across the anterior axillary fold. The upper outer quadrant of the breast contains a greater volume of tissue than do the other quadrants. The breast has a protuberant conical form. The base of the cone is roughly circular, measuring 10 to 12 cm in diameter. Considerable variations in the size, contour, and density of the breast are evident among individuals. The nulliparous breast has a hemispheric configuration with distinct flattening above the nipple. With the hormonal stimulation that accompanies pregnancy and lactation, the breast becomes larger and increases in volume and density, whereas with senescence, it assumes a flattened, flaccid, and more pendulous configuration with decreased volume. Figure 17-2. Anatomy of the breast. Tangential and cross-sectional (sagittal) views of the breast and associated chest wall. (Reproduced with permission from Romrell LJ, Bland KI. Anatomy of the breast, axilla, chest wall, and related metastatic sites. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: Saunders, 2009. Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Inactive and Active Breast. Each lobe of the breast terminates in a major (lactiferous) duct (2–4 mm in diameter), which opens through a constricted orifice (0.4–0.7 mm in diameter) into the ampulla of the nipple (see Fig. 17-2). Immediately below the nipple-areola complex, each major duct has a dilated portion (lactiferous sinus), which is lined with stratified squamous epithelium. Major ducts are lined with two layers of cuboidal cells, whereas minor ducts are lined with a single layer of columnar or cuboidal cells. Myoepithelial cells of ectodermal origin reside between the epithelial cells in the basal lamina and contain myofibrils. In the inactive breast, the epithelium is sparse and consists primarily of ductal epithelium (Fig. 17-3). In the early phase of the menstrual cycle, minor ducts are cordlike with small lumina. With estrogen stimulation at the time of ovulation, alveolar epithelium increases in height, duct lumina become more prominent, and some secretions accumulate. When the hormonal stimulation decreases, the alveolar epithelium regresses. With pregnancy, the breast undergoes proliferative and developmental maturation. As the breast enlarges in response to hormonal stimulation, lymphocytes, plasma cells, and Figure 17-3. Inactive human breast (100x). The epithelium, which is primarily ductal, is embedded in loose connective tissue. Dense connective tissue surrounds the terminal duct lobular units (TDLU). (Photo used with permission of Dr. Sindhu Menon, Consultant Histopathologist & Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.) 501 Figure 17-4. Active human breast: pregnancy and lactation (160x). The alveolar epithelium becomes conspicuous during the early proliferative period. The alveolus is surrounded by cellular connective tissue. (Photo used with permission of Dr. Sindhu Menon, Consultant Histopathologist & Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.) eosinophils accumulate within the connective tissues. The minor ducts branch and alveoli develop. Development of the alveoli is asymmetric, and variations in the degree of development may occur within a single lobule (Fig. 17-4). With parturition, enlargement of the breasts occurs via hypertrophy of alveolar epithelium and accumulation of secretory products in the lumina of the minor ducts. Alveolar epithelium contains abundant endoplasmic reticulum, large mitochondria, Golgi complexes, and dense lysosomes. Two distinct substances are produced by the alveolar epithelium: (a) the protein component of milk, which is synthesized in the endoplasmic reticulum (merocrine secretion); and (b) the lipid component of milk (apocrine secretion), which forms as free lipid droplets in the cytoplasm. Milk released in the first few days after parturition is called colostrum and has low lipid content but contains considerable quantities of antibodies. The lymphocytes and plasma cells that accumulate within the connective tissues of the breast are the source of the antibody component. With subsequent reduction in the number of these cells, the production of colostrum decreases and lipid-rich milk is released. Blood Supply, Innervation, and Lymphatics. The breast receives its principal blood supply from: (a) perforating branches of the internal mammary artery; (b) lateral branches of the posterior intercostal arteries; and (c) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery (Fig. 17-5). The second, third, and fourth anterior intercostal perfora1 tors and branches of the internal mammary artery arborize in the breast as the medial mammary arteries. The lateral thoracic artery gives off branches to the serratus anterior, pectoralis major and pectoralis minor, and subscapularis muscles. It also gives rise to lateral mammary branches. The veins of the breast and chest wall follow the course of the arteries, with venous drainage being toward the axilla. The three principal groups of veins are: (a) perforating branches of the internal thoracic vein, (b) perforating branches of the posterior intercostal veins, and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast Nipple-Areola Complex. The epidermis of the nipple-areola complex is pigmented and is variably corrugated. During puberty, the pigment becomes darker and the nipple assumes an elevated configuration. Throughout pregnancy, the areola enlarges and pigmentation is further enhanced. The areola contains sebaceous glands, sweat glands, and accessory glands, which produce small elevations on the surface of the areola (Montgomery’s tubercles). Smooth muscle bundle fibers, which lie circumferentially in the dense connective tissue and longitudinally along the major ducts, extend upward into the nipple, where they are responsible for the nipple erection that occurs with various sensory stimuli. The dermal papilla at the tip of the nipple contains numerous sensory nerve endings and Meissner’s corpuscles. This rich sensory innervation is of functional importance, because the sucking of the infant initiates a chain of neurohumoral events that results in milk letdown. 502 UNIT II PART SPECIFIC CONSIDERATIONS Figure 17-5. Arterial supply to the breast, axilla, and chest wall. (Reproduced with permission from Romrell LJ, Bland KI. Anatomy of the breast, axilla, chest wall, and related metastatic sites. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: Saunders, 2009. Copyright Elsevier.) (c) tributaries of the axillary vein. Batson’s vertebral venous plexus, which invests the vertebrae and extends from the base of the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system. Lymph vessels generally parallel the course of blood vessels. Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation of the breast (lateral mammary branches) and of the anterolateral chest wall. These branches exit the intercostal spaces between slips of the serratus anterior muscle. Cutaneous branches that arise from the cervical plexus, specifically the anterior branches of the supraclavicular nerve, supply a limited area of skin over the upper portion of the breast. The intercostobrachial nerve is the lateral cutaneous branch of the second intercostal nerve and may be visualized during surgical dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm. The boundaries for lymph drainage of the axilla are not well demarcated, and there is considerable variation in the position of the axillary lymph nodes. The six axillary lymph node groups recognized by surgeons (Figs. 17-6 and 17-7) are: (a) the axillary vein group (lateral), which consists of four to six lymph nodes that lie medial or posterior to the vein and receive most of the lymph drainage from the upper extremity; (b) the external mammary group (anterior or pectoral group), which consists of five to six lymph nodes that lie along the lower border of the pectoralis minor muscle contiguous with the lateral thoracic vessels and receive most of the lymph drainage from the lateral aspect of the breast; (c) the scapular group (posterior or subscapular), which consists of five to seven lymph nodes that lie along the posterior wall of the axilla at the lateral border of the scapula contiguous with the subscapular vessels and receive lymph drainage principally from the lower posterior neck, the posterior trunk, and the posterior shoulder; (d) the central group, which consists of three or four sets of lymph nodes that are Figure 17-6. Lymphatic pathways of the breast. Arrows indicate the direction of lymph flow. (Visual Art: © 2012. The University of Texas MD Anderson Cancer Center.) embedded in the fat of the axilla lying immediately posterior to the pectoralis minor muscle and receive lymph drainage both from the axillary vein, external mammary, and scapular groups of lymph nodes, and directly from the breast; (e) the subclavicular Figure 17-7. Axillary lymph node groups. Level I includes lymph nodes located lateral to the pectoralis minor muscle; level II includes lymph nodes located deep to the pectoralis minor; and level III includes lymph nodes located medial to the pectoralis minor. The axillary vein with its major tributaries and the supraclavicular lymph node group are also illustrated. (Visual Art: © 2012.The University of Texas MD Anderson Cancer Center.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ PHYSIOLOGY OF THE BREAST Breast Development and Function Breast development and function are initiated by a variety of hormonal stimuli, including estrogen, progesterone, prolactin, oxytocin, thyroid hormone, cortisol, and growth hormone.17,18 Estrogen, progesterone, and prolactin especially have pro3 found trophic effects that are essential to normal breast development and function. Estrogen initiates ductal development, whereas progesterone is responsible for differentiation of epithelium and for lobular development. Prolactin is the primary hormonal stimulus for lactogenesis in late pregnancy and the postpartum period. It upregulates hormone receptors and stimulates epithelial development. Figure 17-8 depicts the secretion of neurotrophic hormones from the hypothalamus, which H -R pa Do F CR TR H mi ne Ox y/A DH LH RF G group of lymph nodes. Some lymph vessels may travel directly to the subscapular (posterior, scapular) group of lymph nodes. From the upper part of the breast, a few lymph vessels pass directly to the subclavicular (apical) group of lymph nodes. The axillary lymph nodes usually receive >75% of the lymph drainage from the breast. The rest is derived primarily from 2 the medial aspect of the breast, flows through the lymph vessels that accompany the perforating branches of the internal mammary artery, and enters the parasternal (internal mammary) group of lymph nodes. - Figure 17-8. Overview of the neuroendocrine control of breast development and function. ADH = antidiuretic hormone; CRF = corticotropin-releasing factor; GRF = growth hormone releasing factor; LH-RH = luteinizing hormone–releasing hormone; Oxy = oxytocin; TRH = thyrotropin-releasing hormone. (Reproduced with permission from Kass R et al. Breast physiology: normal and abnormal development and function. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: Saunders, 2009. Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 503 CHAPTER 17 The Breast group (apical), which consists of six to twelve sets of lymph nodes that lie posterior and superior to the upper border of the pectoralis minor muscle and receive lymph drainage from all of the other groups of axillary lymph nodes; and (f) the interpectoral group (Rotter’s lymph nodes), which consists of one to four lymph nodes that are interposed between the pectoralis major and pectoralis minor muscles and receive lymph drainage directly from the breast. The lymph fluid that passes through the interpectoral group of lymph nodes passes directly into the central and subclavicular groups. As indicated in Fig.17-7, the lymph node groups are assigned levels according to their anatomic relationship to the pectoralis minor muscle. Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle are referred to as level I lymph nodes, which include the axillary vein, external mammary, and scapular groups. Lymph nodes located superficial or deep to the pectoralis minor muscle are referred to as level II lymph nodes, which include the central and interpectoral groups. Lymph nodes located medial to or above the upper border of the pectoralis minor muscle are referred to as level III lymph nodes, which consist of the subclavicular group. The plexus of lymph vessels in the breast arises in the interlobular connective tissue and in the walls of the lactiferous ducts and communicates with the subareolar plexus of lymph vessels. Efferent lymph vessels from the breast pass around the lateral edge of the pectoralis major muscle and pierce the clavipectoral fascia, ending in the external mammary (anterior, pectoral) 504 UNIT II PART SPECIFIC CONSIDERATIONS is responsible for regulation of the secretion of the hormones that affect the breast tissues. The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate the release of estrogen and progesterone from the ovaries. In turn, the release of LH and FSH from the basophilic cells of the anterior pituitary is regulated by the secretion of gonadotropinreleasing hormone (GnRH) from the hypothalamus. Positive and negative feedback effects of circulating estrogen and progesterone regulate the secretion of LH, FSH, and GnRH. These hormones are responsible for the development, function, and maintenance of breast tissues (Fig. 17-9A). In the female neonate, circulating estrogen and progesterone levels decrease after birth and remain low throughout childhood because of the sensitivity of the hypothalamic-pituitary axis to negative feedback from these hormones. With the onset of puberty, there is a decrease in the sensitivity of the hypothalamic-pituitary axis to negative feedback and an increase in its sensitivity to positive feedback from estrogen. These physiologic events initiate an increase in GnRH, FSH, and LH secretion and ultimately an increase in estrogen and progesterone secretion by the ovaries, leading to establishment of the menstrual cycle. At the beginning of the menstrual cycle, there is an increase in the size and density of the breasts, which is followed by engorgement of the breast tissues and epithelial proliferation. With the onset of menstruation, the breast engorgement subsides and epithelial proliferation decreases. Pregnancy, Lactation, and Senescence A dramatic increase in circulating ovarian and placental estrogens and progestins is evident during pregnancy, which initiates striking alterations in the form and substance of the breast (see Fig. 17-9B).17-19 The breast enlarges as the ductal and lobular epithelium proliferates, the areolar skin darkens, and the accessory areolar glands (Montgomery’s glands) become prominent. In the first and second trimesters, the minor ducts branch and develop. During the third trimester, fat droplets accumulate in A B C Figure 17-9. The breast at different physiologic stages. The central column contains three-dimensional depictions of microscopic structures. A. Adolescence. B. Pregnancy. C. Lactation. D. Senescence. D VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Gynecomastia Gynecomastia refers to an enlarged breast in the male.20 Physiologic gynecomastia usually occurs during three phases of life: the neonatal period, adolescence, and senescence. Common to each of these phases is an excess of circulating estrogens in relation to circulating testosterone. Neonatal gynecomastia is caused by the action of placental estrogens on neonatal breast tissues, whereas in adolescence, there is an excess of estradiol relative to testosterone, and with senescence, the circulating testosterone level falls, which results in relative hyperestrinism. In gynecomastia, the ductal structures of the male breast enlarge, elongate, and branch with a concomitant increase in epithelium. During puberty, the condition often is unilateral and typically occurs between ages 12 and 15 years. In contrast, senescent gynecomastia is usually bilateral. In the nonobese male, breast tissue measuring at least 2 cm in diameter must be present before a diagnosis of gynecomastia may be made. Mammography and ultrasonography are used to differentiate breast tissues. Dominant masses or areas of firmness, irregularity, and asymmetry suggest the possibility of a breast cancer, particularly in the older male. Gynecomastia generally does not predispose the male breast to cancer. However, the hypoandrogenic state of Klinefelter’s syndrome (XXY), in which gynecomastia is usually evident, is associated with an increased risk of breast cancer. Gynecomastia is graded based on the degree of breast enlargement, the position of the nipple with reference to the inframammary fold and the degree of breast ptosis and skin redundancy: Grade 1: mild breast enlargement without skin redundancy; Grade IIa: moderate breast enlargement without skin redundancy; Grade IIb: moderate breast enlargement with skin redundancy; and Grade 3: marked breast enlargement with skin redundancy and ptosis. Table 17-1 identifies the pathophysiologic mechanisms that may initiate gynecomastia: estrogen excess states; androgen deficiency states; pharmacologic causes; and idiopathic causes. Estrogen excess results from an increase in the secretion of estradiol by the testicles or by nontesticular tumors, nutritional alterations such as protein and fat deprivation, endocrine disorders (hyperthyroidism, hypothyroidism), and hepatic disease (nonalcoholic and alcoholic cirrhosis). Refeeding gynecomastia Table 17-1 505 Pathophysiologic mechanisms of gynecomastia I. Estrogen excess states A. Gonadal origin 1. True hermaphroditism 2. Gonadal stromal (nongerminal) neoplasms of the testis a. Leydig cell (interstitial) b. Sertoli cell c. Granulosa-theca cell 3. Germ cell tumors a. Choriocarcinoma b. Seminoma, teratoma c. Embryonal carcinoma B. Nontesticular tumors 1. Adrenal cortical neoplasms 2. Lung carcinoma 3. Hepatocellular carcinoma C. Endocrine disorders D. Diseases of the liver—nonalcoholic and alcoholic cirrhosis E. Nutrition alteration states II. Androgen deficiency states A. Senescence B. Hypoandrogenic states (hypogonadism) 1. Primary testicular failure a. Klinefelter’s syndrome (XXY) b. Reifenstein’s syndrome c. Rosewater-Gwinup-Hamwi familial gynecomastia d. Kallmann syndrome e. Kennedy’s disease with associated gynecomastia f. Eunuchoidal state (congenital anorchia) g. Hereditary defects of androgen biosynthesis h. Adrenocorticotropic hormone deficiency 2. Secondary testicular failure a. Trauma b. Orchitis c. Cryptorchidism d. Irradiation C. Renal failure III. Pharmacologic causes IV. Systemic diseases with idiopathic mechanisms is related to the resumption of pituitary gonadotropin secretion after pituitary shutdown. Androgen deficiency may initiate gynecomastia. Concurrently occurring with decreased circulating testosterone levels is an elevated level of circulating testosteronebinding globulin, which results in a reduction of free testosterone. This senescent gynecomastia usually occurs in men aged 50 to 70 years. Hypoandrogenic states can be from primary testicular failure or secondary testicular failure. Klinefelter’s syndrome (XXY) is an example of primary testicular failure which is manifested by gynecomastia, hypergonadotropic hypogonadism, and azoospermia. Secondary testicular failure may result from trauma, orchitis, and cryptorchidism. Renal failure, regardless of cause, also may initiate gynecomastia. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast the alveolar epithelium and colostrum fills the alveolar and ductal spaces. In late pregnancy, prolactin stimulates the synthesis of milk fats and proteins. After delivery of the placenta, circulating progesterone and estrogen levels decrease, permitting full expression of the lactogenic action of prolactin. Milk production and release are controlled by neural reflex arcs that originate in nerve endings of the nipple-areola complex. Maintenance of lactation requires regular stimulation of these neural reflexes, which results in prolactin secretion and milk letdown. Oxytocin release results from the auditory, visual, and olfactory stimuli associated with nursing. Oxytocin initiates contraction of the myoepithelial cells, which results in compression of alveoli and expulsion of milk into the lactiferous sinuses. After weaning of the infant, prolactin and oxytocin release decreases. Dormant milk causes increased pressure within the ducts and alveoli, which results in atrophy of the epithelium (Fig. 17-9C). With menopause there is a decrease in the secretion of estrogen and progesterone by the ovaries and involution of the ducts and alveoli of the breast. The surrounding fibrous connective tissue increases in density, and breast tissues are replaced by adipose tissues (Fig. 17-9D). 506 UNIT II PART SPECIFIC CONSIDERATIONS Pharmacologic causes of gynecomastia include drugs with estrogenic activity (digitalis, estrogens, anabolic steroids, marijuana) or drugs that enhance estrogen synthesis (human chorionic gonadotropin). Drugs that inhibit the action or synthesis of testosterone (cimetidine, ketoconazole, phenytoin, spironolactone, antineoplastic agents, diazepam) also have been implicated. Drugs such as reserpine, theophylline, verapamil, tricyclic antidepressants, and furosemide induce gynecomastia through idiopathic mechanisms. When gynecomastia is caused by androgen deficiency, then testosterone administration may cause regression. When it is caused by medications, then these are discontinued if possible. When endocrine defects are responsible, then these receive specific therapy. As soon asgynecomastia is progressive and does not respond to other treatments, surgical therapy is considered. Techniques include local excision, liposuction or subcutaneous mastectomy. Attempts to reverse gynecomastia with danazol have been successful, but the androgenic side effects of the drug are considerable. INFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREAST Infections in the postpartum period remain proportionately the most common time for breast infections to occur. Infections of the breast unrelated to lactation are proportionately less common, however, are still a relatively common presentation to breast specialists. The latter are classified as intrinsic (secondary to abnormalities in the breast) or extrinsic (secondary to an infection in an adjacent structure, e.g., skin, thoracic cavity) the most common being probably periductal mastitis and infected sebaceous cyst, respectively. Bacterial Infection Staphylococcus aureus and Streptococcus species are the organisms most frequently recovered from nipple discharge from an infected breast.17 Typically breast abscesses are seen in staphylococcal infections and present with point tenderness, erythema, and hyperthermia. When these abscesses are related to lactation they usually occur within the first few weeks of breastfeeding. If there is progression of a staphylococcal infection, this may result in subcutaneous, subareolar, interlobular (periductal), and retromammary abscesses (unicentric or multicentric). Previously almost all breast abscesses were treated by operative incision and drainage but now the initial approach is antibiotics and repeated aspiration of the abscess, usually ultrasound guided aspiration.21 Operative drainage is now reserved for those cases which don’t resolve with repeated aspiration and antibiotic therapy or if there is some other indication for incision and drainage (e.g., thinning or necrosis of the overlying skin). Preoperative ultrasonography is effective in delineating the required extent of the drainage procedure. While staphylococcal infections tend to be more localized and may be situated deep in the breast tissues, streptococcal infections usually present with diffuse superficial involvement. They are treated with local wound care, including application of warm compresses, and the administration of IV antibiotics (penicillins or cephalosporins). Breast infections may be chronic, possibly with recurrent abscess formation. In this situation, cultures are performed to identify acid-fast bacilli, anaerobic and aerobic bacteria, and fungi. Uncommon organisms may be encountered, and long-term antibiotic therapy may be required. Biopsy of the abscess cavity wall should be considered at the time of incision and drainage to rule out underlying breast cancer in patients where antibiotics and drainage have been ineffective. Nowadays hospital-acquired puerperal infections of the breast are much less common, but nursing women who present with milk stasis or noninfectious inflammation may still develop this problem. Epidemic puerperal mastitis is initiated by highly virulent strains of methicillin-resistant S. aureus that are transmitted via the suckling neonate and may result in substantial morbidity and occasional mortality. Purulent fluid may be expressed from the nipple. In this circumstance, breastfeeding is stopped, antibiotics are started, and surgical therapy is initiated. Nonepidemic (sporadic) puerperal mastitis refers to involvement of the interlobular connective tissue of the breast by an infectious process. The patient develops nipple fissuring and milk stasis, which initiates a retrograde bacterial infection. Emptying of the breast using breast suction pumps shortens the duration of symptoms and reduces the incidence of recurrences. The addition of antibiotic therapy results in a satisfactory outcome in >95% of cases. Zuska’s disease, also called recurrent periductal mastitis, is a condition of recurrent retroareolar infections and abscesses.22,23 Smoking has been implicated as a risk factor for this condition.24,25 This syndrome is managed symptomatically by antibiotics coupled with incision and drainage as necessary. Attempts to obtain durable long-term control by wide débridement of chronically infected tissue and/or terminal duct resection have been reported and can be curative but equally can be frustrated by postoperative infections.26 Mycotic Infections Fungal infections of the breast are rare and usually involve blastomycosis or sporotrichosis.27 Intraoral fungi that are inoculated into the breast tissue by the suckling infant initiate these infections, which present as mammary abscesses in close proximity to the nipple-areola complex. Pus mixed with blood may be expressed from sinus tracts. Antifungal agents can be administered for the treatment of systemic (noncutaneous) infections. This therapy generally eliminates the necessity of surgical intervention, but occasionally drainage of an abscess, or even partial mastectomy, may be necessary to eradicate a persistent fungal infection. Candida albicans affecting the skin of the breast presents as erythematous, scaly lesions of the inframammary or axillary folds. Scrapings from the lesions demonstrate fungal elements (filaments and binding cells). Therapy involves the removal of predisposing factors such as maceration and the topical application of nystatin. Hidradenitis Suppurativa Hidradenitis suppurativa of the nipple-areola complex or axilla is a chronic inflammatory condition that originates within the accessory areolar glands of Montgomery or within the axillary sebaceous glands.27 Women with chronic acne are predisposed to developing hidradenitis. When located in and about the nipple-areola complex, this disease may mimic other chronic inflammatory states, Paget’s disease of the nipple, or invasive breast cancer. Involvement of the axillary skin is often multifocal and contiguous. Antibiotic therapy with incision and drainage of fluctuant areas is appropriate treatment. Excision of the involved areas may be required. Large areas of skin loss may necessitate coverage with advancement flaps or split-thickness skin grafts. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Mondor’s Disease COMMON BENIGN DISORDERS AND DISEASES OF THE BREAST Benign breast disorders and diseases encompass a wide range of clinical and pathologic entities. Surgeons require an in-depth understanding of benign breast disorders and diseases so that clear explanations may be given to affected women, appropriate treatment instituted, and unnecessary long-term follow up avoided. The basic principles underlying the aberrations of normal development and involution (ANDI) classification of benign breast conditions are the following: (a) benign breast disorders and diseases are related to the normal processes of reproductive life and to involution; (b) there is a spectrum of breast conditions that ranges from normal to disorder to disease; and (c) the ANDI classification encompasses all aspects of the breast condition, including pathogenesis and the degree of abnormality .30 4 The horizontal component of Table 17-2 defines ANDI along a spectrum from normal, to mild abnormality (disorder), to severe abnormality (disease). The vertical component indicates the period during which the condition develops. Early Reproductive Years. Fibroadenomas are seen and present symptomatically predominantly in younger women aged 15 to 25 years (Fig. 17-10).31 Fibroadenomas usually grow to 1 or 2 cm in diameter and then are stable but may grow to a larger size. Small fibroadenomas (≤1 cm in size) are considered normal, whereas larger fibroadenomas (≤3 cm) are disorders and giant fibroadenomas (>3 cm) are disease. Similarly, multiple fibroadenomas (more than five lesions in one breast) are very uncommon and are considered disease. It is noted that with the introduction of mammographic screening, asymptomatic fibroadenomas are sometimes found in an older screened population. The precise etiology of adolescent breast hypertrophy is unknown. A spectrum of changes from limited to massive stromal hyperplasia (gigantomastia) is seen. Nipple inversion is a disorder of development of the major Table 17-2 ANDI classification of benign breast disorders Early reproductive years (age 15–25 y) Normal Disorder Disease Lobular development Fibroadenoma Giant fibroadenoma Stromal development Adolescent hypertrophy Gigantomastia Nipple eversion Nipple inversion Subareolar abscess Mammary duct fistula Later reproductive years (age 25–40 y) Cyclical changes of menstruation Cyclical mastalgia Incapacitating mastalgia Nodularity Involution (age 35–55 y) Epithelial hyperplasia of pregnancy Bloody nipple discharge Lobular involution Macrocysts — Sclerosing lesions Duct involution Dilatation Duct ectasia Periductal mastitis Sclerosis Nipple retraction — Epithelial hyperplasia Epithelial hyperplasia with atypia Epithelial turnover ANDI = aberrations of normal development and involution. Source: Reproduced with permission from Hughes LE: Aberrations of normal development and involution (ANDI): A concept of benign breast disorders based on pathogenesis. In: Mansel RE, et al, eds. Hughes, Mansel & Webster’s Benign Disorders and Diseases of the Breast. London: Saunders, 2009. Copyright Elsevier. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 507 CHAPTER 17 The Breast Mondor’s disease is a variant of thrombophlebitis that involves the superficial veins of the anterior chest wall and breast.28 In 1939, Mondor described the condition as “string phlebitis,” a thrombosed vein presenting as a tender, cord-like structure.29 Frequently involved veins include the lateral thoracic vein, the thoracoepigastric vein, and, less commonly, the superficial epigastric vein. Typically, a woman presents with acute pain in the lateral aspect of the breast or the anterior chest wall. A tender, firm cord is found to follow the distribution of one of the major superficial veins. Rarely, the presentation is bilateral, and most women have no evidence of thrombophlebitis in other anatomic sites. This benign, self-limited disorder is not indicative of a cancer. When the diagnosis is uncertain, or when a mass is present near the tender cord, biopsy is indicated. Therapy for Mondor’s disease includes the liberal use of anti-inflammatory medications and application of warm compresses along the symptomatic vein. The process usually resolves within 4 to 6 weeks. When symptoms persist or are refractory to therapy, excision of the involved vein segment may be considered. Aberrations of Normal Development and Involution 508 UNIT II PART A SPECIFIC CONSIDERATIONS Figure 17-10. Fibroadenoma (40x). These benign tumors are typically well circumscribed and are comprised of both stromal and glandular elements. (Photo used with permission of Dr. Sindhu Menon, Consultant Histopathologist & Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.) ducts, which prevents normal protrusion of the nipple. Mammary duct fistulas arise when nipple inversion predisposes to major duct obstruction, leading to recurrent subareolar abscess and mammary duct fistula. Later Reproductive Years. Cyclical mastalgia and nodularity usually are associated with premenstrual enlargement of the breast and are regarded as normal. Cyclical pronounced mastalgia and severe painful nodularity are viewed differently than are physiologic discomfort and lumpiness. Painful nodularity that persists for >1 week of the menstrual cycle is considered a disorder. In epithelial hyperplasia of pregnancy, papillary projections sometimes give rise to bilateral bloody nipple discharge. B Figure 17-11. A. Ductal epithelial hyperplasia. The irregular intracellular spaces and variable cell nuclei distinguish this process from carcinoma in situ. B. Lobular hyperplasia. The presence of alveolar lumina and incomplete distention distinguish this process from carcinoma in situ. (Photos used with permission of Dr. R.L. Hackett.) Involution. Involution of lobular epithelium is dependent on the specialized stroma around it. However, an integrated involution of breast stroma and epithelium is not always seen, and disorders of the process are common. When the stroma involutes too quickly, alveoli remain and form microcysts, which are precursors of macrocysts. The macrocysts are common, often subclinical, and do not require specific treatment. Sclerosing adenosis is considered a disorder of both the proliferative and the involutional phases of the breast cycle. Duct ectasia (dilated ducts) and periductal mastitis are other important components of the ANDI classification. Periductal fibrosis is a sequela of periductal mastitis and may result in nipple retraction. About 60% of women ≥70 years of age exhibit some degree of epithelial hyperplasia (Fig. 17-11). Atypical proliferative diseases include ductal and lobular hyperplasia, both of which display some features of carcinoma in situ. Women with atypical ductal or lobular hyperplasia have a fourfold increase in breast cancer risk (Table 17-3). Pathology of Nonproliferative Disorders Of paramount importance for the optimal management of benign breast disorders and diseases is the histologic differentiation of benign, atypical, and malignant changes.32,33 Determining the clinical significance of these changes is a problem that is compounded by inconsistent nomenclature. The classification Table 17-3 Cancer risk associated with benign breast disorders and in situ carcinoma of the breast Abnormality Relative Risk Nonproliferative lesions of the breast No increased risk Sclerosing adenosis No increased risk Intraductal papilloma No increased risk Florid hyperplasia 1.5 to 2-fold Atypical lobular hyperplasia 4-fold Atypical ductal hyperplasia 4-fold Ductal involvement by cells of atypical ductal hyperplasia 7-fold Lobular carcinoma in situ 10-fold Ductal carcinoma in situ 10-fold Source: Modified from Dupont WD, et al: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146, 1985. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ diameter, firm, and sharply circumscribed. Adenolipomas consist of sharply circumscribed nodules of fatty tissue that contain normal breast lobules and ducts. Table 17-4 Classification of benign breast disorders Fibrocystic Disease. The term fibrocystic disease is nonspecific. Too frequently, it is used as a diagnostic term to describe symptoms, to rationalize the need for breast biopsy, and to explain biopsy results. Synonyms include fibrocystic changes, cystic mastopathy, chronic cystic disease, chronic cystic mastitis, Schimmelbusch’s disease, mazoplasia, Cooper’s disease, Reclus’ disease, and fibroadenomatosis. Fibrocystic disease refers to a spectrum of histopathologic changes that are best diagnosed and treated specifically. Pathology of Proliferative Disorders Without Atypia Source: Modified from Consensus Meeting: Is “fibrocystic disease” of the breast precancerous? Arch Pathol Lab Med. 1986;110:171. system originally developed by Page separates the various types of benign breast disorders and diseases into three clinically relevant groups: nonproliferative disorders, proliferative disorders without atypia, and proliferative disorders with atypia (Table 17-4). Nonproliferative disorders of the breast account for 70% of benign breast conditions and carry no increased risk for the development of breast cancer. This category includes cysts, duct ectasia, periductal mastitis, calcifications, fibroadenomas, and related disorders. Breast macrocysts are an involutional disorder, have a high frequency of occurrence, and are often multiple. Duct ectasia is a clinical syndrome characterized by dilated subareolar ducts that are palpable and often associated with thick nipple discharge. Haagensen regarded duct ectasia as a primary event that led to stagnation of secretions, epithelial ulceration, and leakage of duct secretions (containing chemically irritating fatty acids) into periductal tissue.34 This sequence was thought to produce a local inflammatory process with periductal fibrosis and subsequent nipple retraction. An alternative theory considers periductal mastitis to be the primary process, which leads to weakening of the ducts and secondary dilatation. It is possible that both processes occur and together explain the wide spectrum of problems seen, which include nipple discharge, nipple retraction, inflammatory masses, and abscesses. Calcium deposits are frequently encountered in the breast. Most are benign and are caused by cellular secretions and debris or by trauma and inflammation. Calcifications that are associated with cancer include microcalcifications, which vary in shape and density and are <0.5 mm in size, and fine, linear calcifications, which may show branching. Fibroadenomas have abundant stroma with histologically normal cellular elements. They show hormonal dependence similar to that of normal breast lobules in that they lactate during pregnancy and involute in the postmenopausal period. Adenomas of the breast are well circumscribed and are composed of benign epithelium with sparse stroma, which is the histologic feature that differentiates them from fibroadenomas. They may be divided into tubular adenomas and lactating adenomas. Tubular adenomas are seen in young nonpregnant women, whereas lactating adenomas are seen during pregnancy or during the postpartum period. Hamartomas are discrete breast tumors that are usually 2 to 4 cm in Proliferative breast disorders without atypia include sclerosing adenosis, radial scars, complex sclerosing lesions, ductal epithelial hyperplasia, and intraductal papillomas.32,33 Sclerosing adenosis is prevalent during the childbearing and perimenopausal years and has no malignant potential. Histologic changes are both proliferative (ductal proliferation) and involutional (stromal fibrosis, epithelial regression). Sclerosing adenosis is characterized by distorted breast lobules and usually occurs in the context of multiple microcysts, but occasionally presents as a palpable mass. Benign calcifications are often associated with this disorder. Sclerosing adenosis can be managed by observation as long as the imaging features and pathologic findings are concordant. Central sclerosis and various degrees of epithelial proliferation, apocrine metaplasia, and papilloma formation characterize radial scars and complex sclerosing lesions of the breast. Lesions up to 1 cm in diameter are called radial scars, whereas larger lesions are called complex sclerosing lesions. Radial scars originate at sites of terminal duct branching where the characteristic histologic changes radiate from a central area of fibrosis. All of the histologic features of a radial scar are seen in the larger complex sclerosing lesions, but there is a greater disturbance of structure with papilloma formation, apocrine metaplasia, and occasionally sclerosing adenosis. Distinguishing between a radial scar and invasive breast carcinoma can be challenging based on core needle biopsy sampling. Often the imaging features of a radial scar (which can be quite similar to an invasive cancer) will dictate the need for either a vacuum assisted biopsy or surgical excision in order to exclude the possibility of carcinoma. Mild ductal hyperplasia is characterized by the presence of three or four cell layers above the basement membrane. Moderate ductal hyperplasia is characterized by the presence of five or more cell layers above the basement membrane. Florid ductal epithelial hyperplasia occupies at least 70% of a minor duct lumen. It is found in >20% of breast tissue specimens, is either solid or papillary, and is associated with an increased cancer risk (see Table 17-3). Intraductal papillomas arise in the major ducts, usually in premenopausal women. They generally are <0.5 cm in diameter but may be as large as 5 cm. A common presenting symptom is nipple discharge, which may be serous or bloody. Grossly, intraductal papillomas are pinkish tan, friable, and usually attached to the wall of the involved duct by a stalk. They rarely undergo malignant transformation, and their presence does not increase a woman’s risk of developing breast cancer (unless accompanied by atypia). However, multiple intraductal papillomas, which occur in younger women and are VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast Nonproliferative disorders of the breast Cysts and apocrine metaplasia Duct ectasia Mild ductal epithelial hyperplasia Calcifications Fibroadenoma and related lesions Proliferative breast disorders without atypia Sclerosing adenosis Radial and complex sclerosing lesions Ductal epithelial hyperplasia Intraductal papillomas Atypical proliferative lesions Atypical lobular hyperplasia Atypical ductal hyperplasia 509 510 less frequently associated with nipple discharge, are susceptible to malignant transformation. Pathology of Atypical Proliferative Diseases UNIT II PART SPECIFIC CONSIDERATIONS The atypical proliferative diseases have some of the features of carcinoma in situ but either lack a major defining feature of carcinoma in situ or have the features in less than fully developed form.34 Atypical ductal hyperplasia (ADH) appears similar to low grade ductal carcinoma in situ (DCIS) histologically and is composed of monotonous round, cuboidal, or polygonal cells enclosed by basement membrane with rare mitoses. A lesion will be considered to be ADH if it is up to 2 or 3 mm in size but would be called DCIS if it is larger than 3 mm. The diagnosis can be difficult to establish with core needle biopsy specimen alone and most cases will require excisional biopsy specimen for classification. Individuals with a diagnosis of ADH are at increased risk for development of breast cancer and should be counseled appropriately regarding risk reduction strategies. In 1978, Haagensen et al described lobular neoplasia, a spectrum of disorders ranging from atypical lobular hyperplasia to lobular carcinoma in situ (LCIS).35Atypical lobular hyperplasia (ALH) results in minimal distention of lobular units with cells that are similar to those seen in LCIS. The diagnosis of LCIS is made when small monomorphic cells that distend the terminal ductal lobular unit are noted. In cases of LCIS the acini are full and distended while the overall lobular architecture is maintained (Fig. 17-12). Classic LCIS is not associated with a specific mammographic or palpable abnormality but is an incidental finding noted on breast biopsy. There is a variant of LCIS that has been termed pleomorphic LCIS. In the case of pleomorphic LCIS, there can be calcifications or other suspicious mammographic changes that dictate the need for biopsy. Classic LCIS is not treated with excision as the patient is at risk for developing invasive breast cancer in either breast and therefore the patient is counseled regarding appropriate risk reduction strategies. Pleomorphic LCIS can be difficult to distinguish from high-grade DCIS and there are some proponents who have suggested that patients with pleomorphic LCIS be Figure 17-12. Lobular carcinoma in situ (100x). There are small monomorphic cells which distend the terminal duct lobular unit, without necrosis or mitoses. (Photo used with permission of Dr. Sindhu Menon, Consultant Histopathologist & Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.) managed similar to those with DCIS with attention to margins and consideration for radiation therapy in the setting of breast conserving treatment. The use of immunohistochemical staining for E-cadherin can help to discriminate between LCIS and DCIS. In lobular neoplasias, such as ALH and LCIS, there is a lack of E-cadherin expression whereas the majority of ductal lesions will demonstrate E-cadherin reactivity. Treatment of Selected Benign Breast Disorders and Diseases Cysts. Because needle biopsy of breast masses may produce artifacts that make mammography assessment more difficult, many multidisciplinary teams prefer to image breast masses before performing either fine needle aspiration or core needle biopsy.36,37 In practice, however, the first investigation of palpable breast masses may be a needle biopsy, which allows for the early diagnosis of cysts. A 21-gauge needle attached to a 10-mL syringe is placed directly into the mass, which is fixed by fingers of the nondominant hand. The volume of a typical cyst is 5 to 10 mL, but it may be 75 mL or more. If the fluid that is aspirated is not bloodstained, then the cyst is aspirated to dryness, the needle is removed, and the fluid is discarded, because cytologic examination of such fluid is not cost effective. After aspiration, the breast is carefully palpated to exclude a residual mass. In most cases however imaging has been performed prior to a needle being introduced into the breast and indeed the majority of cysts are now aspirated under ultrasound guidance. If a mass was noted on initial ultrasound or there is a residual mass post-aspiration then a tissue specimen is obtained usually by core biopsy. When cystic fluid is bloodstained, fluid can be sent for cytologic examination. A simple cyst is rarely of concern, but a complex cyst may be the result of an underlying malignancy. A pneumocystogram can be obtained by injecting air into the cyst and then obtaining a repeat mammogram. When this technique is used, the wall of the cyst cavity can be more carefully assessed for any irregularities. Fibroadenomas. Most fibroadenomas are self-limiting and many go undiagnosed, so a more conservative approach is reasonable. Careful ultrasound examination with core-needle biopsy will provide for an accurate diagnosis. Ultrasonography may reveal specific features that are pathognomonic for fibroadenoma and in a young woman (e.g., under 25 years) where the risk of breast cancer is already very low a core-needle biopsy may not be necessary. In patients where biopsy is performed, the patient is counseled concerning the ultrasound and biopsy results, and surgical excision of the fibroadenoma may be avoided. Cryoablation and ultrasound-guided vacuum assisted biopsy are approved treatments for fibroadenomas of the breast, especially lesions <3 cm. Larger lesions are often still best removed by excision. With short-term follow-up a significant percentage of fibroadenomas will decrease in size and will no longer be palpable.38 However, many will remain palpable, especially those larger than 2 cm.39 Therefore, women should be counseled that the options for treatment include surgical removal, cryoablation, vacuum assisted biopsy, or observation. Sclerosing Disorders. The clinical significance of sclerosing adenosis lies in its imitation of cancer. On physical examination, it may be confused with cancer, by mammography, and at gross pathologic examination. Excisional biopsy and histologic examination are frequently necessary to exclude the diagnosis of cancer. The diagnostic work-up for radial scars and complex VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ sclerosing lesions frequently involves stereotactic biopsy. It usually is not possible to differentiate these lesions with certainty from cancer by mammographic features, so a larger tissue biopsy is recommended either by way of vacuum assisted biopsy or an open surgical excisional biopsy. The mammographic appearance of a radial scar or sclerosing adenosis (mass density with spiculated margins) will usually lead to an assessment that the results of a core-needle biopsy specimen showing benign disease are discordant with the radiographic findings. Table 17-5 Treatment of recurrent subareolar sepsis Suitable for Fistulectomy Suitable for Total Duct Excision Small abscess localized to one segment Large abscess affecting >50% of the areolar circumference Recurrence involving the same segment Recurrence involving a different segment Mild or no nipple inversion Marked nipple inversion Patient unconcerned about nipple inversion Patient requests correction of nipple inversion Younger patient Older patient No discharge from other Purulent discharge from other ducts ducts No prior fistulectomy Recurrence after fistulectomy Source: Modified with permission from Hughes LE: The duct ectasia/ periductal mastitis complex, in Hughes LE, et al (eds): Benign Disorders and Diseases of the Breast: Concepts and Clinical Management. London: WB Saunders, 2000, p 162. Copyright © Elsevier. Nipple Inversion. More women request correction of congenital nipple inversion than request correction for the nipple inversion that occurs secondary to duct ectasia. Although the results are usually satisfactory, women seeking correction for cosmetic reasons should always be made aware of the surgical complications of altered nipple sensation, nipple necrosis, and postoperative fibrosis with nipple retraction. Because nipple inversion is a result of shortening of the subareolar ducts, a complete division of these ducts is necessary for permanent correction of the disorder. RISK FACTORS FOR BREAST CANCER Hormonal and Nonhormonal Risk Factors Increased exposure to estrogen is associated with an increased risk for developing breast cancer, whereas reducing exposure is thought to be protective.42-48 Correspondingly, factors that increase the number of menstrual cycles, such as early menarche, nulliparity, and late menopause, are associated with increased risk. Moderate levels of exercise and a longer lactation period, factors that decrease the total number of menstrual cycles, are protective. The terminal differentiation of breast epithelium associated with a full-term pregnancy is also protective, so older age at first live birth is associated with an increased risk of breast cancer. Finally, there is an association between obesity and increased breast cancer risk. Because the major source of estrogen in postmenopausal women is the conversion of androstenedione to estrone by adipose tissue, obesity is associated with a long-term increase in estrogen exposure. Nonhormonal risk factors include radiation exposure. Young women who receive mantle radiation therapy for Hodgkin’s lymphoma have a breast cancer risk that is 75 times greater than that of age-matched control subjects. Survivors of the atomic bomb blasts in Japan during World War II have a very high incidence of breast cancer, likely because of somatic mutations induced by the radiation exposure. In both circumstances, radiation exposure during adolescence, a period of active breast development, magnifies the deleterious effect. Studies also suggest that the risk of breast cancer increases as the amount of alcohol a woman consumes increases.49 Alcohol consumption is known to increase serum levels of estradiol. Finally, evidence suggests that long-term consumption of foods with a high fat content contributes to an increased risk of breast cancer by increasing serum estrogen levels. Risk Assessment Models The average lifetime risk of breast cancer for newborn U.S. females is 12%.50,51 The longer a woman lives without cancer, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 511 CHAPTER 17 The Breast Periductal Mastitis. Painful and tender masses behind the nipple-areola complex are aspirated with a 21-gauge needle attached to a 10-mL syringe. Any fluid obtained is submitted for culture using a transport medium appropriate for the detection of anaerobic organisms. In the absence of pus, women are started on a combination of metronidazole and dicloxacillin while awaiting the results of culture. Antibiotics are then continued based on sensitivity tests. Many cases respond satisfactorily to antibiotics alone, but when considerable purulent material is present, repeated ultrasound guided aspiration is performed and ultimately in a proportion of cases surgical treatment is required. Unlike puerperal abscesses, a subareolar abscess is usually unilocular and often is associated with a single duct system. Ultrasound will accurately delineate its extent. In those cases which come to surgery, the surgeon may either undertake simple drainage with a view toward formal surgery, should the problem recur, or proceed with definitive surgery. In a woman of childbearing age, simple drainage is preferred, but if there is an anaerobic infection, recurrent infection frequently develops. Recurrent abscess with fistula is a difficult problem. Treatment of periductal fistula was initially recommended to be opening up of the fistulous track and allowing it to granulate.40 This approach may still be used especially if the fistula is recurrent after previous attempts at fistulectomy. However, nowadays the preferred initial surgical treatment is by fistulectomy and primary closure with antibiotic coverage.41 Excision of all the major ducts is an alternative option depending on the circumstances (Table 17-5). When a localized periareolar abscess recurs at the previous site and a fistula is present, the preferred operation is fistulectomy, which has minimal complications and a high degree of success. However, when subareolar sepsis is diffuse rather than localized to one segment or when more than one fistula is present, total duct excision is the most expeditious approach. The first circumstance is seen in young women with squamous metaplasia of a single duct, whereas the latter circumstance is seen in older women with multiple ectatic ducts. Age is not always a reliable guide, however, and fistula excision is the preferred initial procedure for localized sepsis irrespective of age. Antibiotic therapy is useful for recurrent infection after fistula excision, and a 2- to 4-week course is recommended before total duct excision. 512 UNIT II PART SPECIFIC CONSIDERATIONS the lower her risk of developing breast cancer. Thus, a woman aged 50 years has an 11% lifetime risk of developing breast cancer, and a woman aged 70 years has a 7% lifetime risk of developing breast cancer. Because risk factors for breast cancer interact, evaluating the risk conferred by combinations of risk factors is difficult. There are several risk assessment models available to predict the risk of breast cancer. From the Breast Cancer Detection Demonstration Project, a mammography screening program conducted in the 1970s, Gail et al developed the model most frequently used in the United States, which incorporates age, age at menarche, age at first live birth, the number of breast biopsy specimens, any history of atypical hyperplasia, and number of first-degree relatives with breast cancer.52 It predicts the cumulative risk of breast cancer according to decade of life. To calculate breast cancer risk using the Gail model, a woman’s risk factors are translated into an overall risk score by multiplying her relative risks from several categories (Table 17-6). This risk score is then compared 5 to an adjusted population risk of breast cancer to determine a woman’s individual or absolute risk. The output is a five-year risk and a lifetime risk of developing breast cancer. A software program incorporating the Gail model is available from the National Cancer Institute at http://bcra.nci.nih.gov/brc. This model was recently modified to more accurately assess risk in African American women.52,53 The Gail model is the most widely used model in the United States. Gail and colleagues have also described a revised model that includes body weight and mammographic density but excludes age at menarche.54 Claus et al, using data from the Cancer and Steroid Hormone Study, a case-control study of breast cancer, developed the other frequently used risk assessment model, which is based on assumptions about the prevalence of high-penetrance breast cancer susceptibility genes.55 Compared with the Gail model, the Claus model incorporates more information about family history but excludes other risk factors. The Claus model provides individual estimates of breast cancer risk according to decade of life based on presence of first- and second-degree relatives with breast cancer and their age at diagnosis. Risk factors that are less consistently associated with breast cancer (diet, use of oral contraceptives, lactation) or are rare in the general population (radiation exposure) are not included in either the Gail or Claus risk assessment model. Other models have been proposed that account for mammographic breast density in assessing breast cancer risk.54,56 Neither the Gail model nor the Claus model accounts for the risk associated with mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (described in detail below). The BRCAPRO model is a Mendelian model that calculates the probability that an individual is a carrier of a mutation in one of the breast cancer susceptibility genes based on their family history of breast and ovarian cancer.57 The probability that an individual will develop breast or ovarian cancer is derived from this mutation probability based on age-specific incidence curves for both mutation carriers and noncarriers.58 Use of the BRCAPRO model in the clinic is challenging since it requires input of all family history information regarding breast and ovarian cancer. The Tyrer-Cuzick model attempts to utilize both family history information and individual risk information. It uses the family history to calculate the probability that an individual carries a mutation in one of the breast cancer susceptibility genes and then the risk is adjusted based on personal risk factors, including age at menarche, parity, age at first live birth, age at menopause, Table 17-6 Relative risk estimates for the Gail model Variable Age at menarche (years) ≥14 12–13 <12 Number of biopsy specimens/history of benign breast disease, age <50 y 0 1 ≥2 Number of biopsy specimens/history of benign breast disease, age ≥50 y 0 1 ≥2 Age at first live birth (years) <20 y   Number of first-degree relatives with history of breast cancer   0   1   ≥2 20–24 y   Number of first-degree relatives with history of breast cancer   0   1   ≥2 25–29 y  Number of first-degree relatives with history of breast cancer   0   1   ≥2 ≥30 y  Number of first-degree relatives with history of breast cancer   0   1   ≥2 Relative Risk 1.00 1.10 1.21 1.00 1.70 2.88 1.02 1.27 1.62 1.00 2.61 6.80 1.24 2.68 5.78 1.55 2.76 4.91 1.93 2.83 4.17 Source: Modified from Armstrong K, et al: Primary care: Assessing the risk of breast cancer. N Engl J Med. 342:564, 2000. history of atypical hyperplasia or LCIS, height and body mass index.59 Once a risk model has been utilized to assess breast cancer risk, this must be communicated to the individual and put into context with competing risk and medical comorbidities. This information can then be used to discuss options that are available to the individual for managing risk. Risk Management Several important medical decisions may be affected by a woman’s underlying risk of developing breast cancer.60-68 These decisions include when to use postmenopausal hormone replacement therapy, at what age to begin mammography screening or incorporate magnetic resonance imaging (MRI) screening, when VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ women will benefit from screening.75,76 In the United States, on a population basis, however, the benefits of screening mammography in women between the ages of 40 and 49 years is still felt to outweigh the risks; although targeting mammography to women at higher risk of breast cancer improves the balance of risks and benefits and is the approach some health care systems have taken. In one study of women aged 40 to 49 years, an abnormal mammography finding was three times more likely to be cancer in a woman with a family history of breast cancer than in a woman without such a history. Furthermore, as noted previously in the section Risk Assessment Models, mounting data regarding mammographic breast density demonstrate an independent correlation with breast cancer risk. Incorporation of breast density measurements into breast cancer risk assessment models appears to be a promising strategy for increasing the accuracy of these tools. Unfortunately, widespread application of these modified models is hampered by inconsistencies in the reporting of mammographic density. Ultrasonography can also be used for breast cancer screening in women with dense breasts but there is no data available that the additional cancers detected with this modality reduce mortality from breast cancer. Current recommendations by the United States Preventive Services Task Force are that women undergo biennial mammographic screening between the ages of 50 and 74 years.77 The American Cancer Society (ACS) continues to recommend annual mammography for women beginning at age 40 years to continue as long as she is in good health. In addition, a clinical breast examination by a health professional is recommended annually. The use of MRI for breast cancer screening is recommended by the ACS for women with a 20% to 25% or greater lifetime risk using risk assessment tools based mainly on family history, BRCA mutation carriers, those individuals who have a family member with a BRCA mutation who have not been tested themselves, individuals who received radiation to the chest between the ages of 10 to 30 years, and those individuals with a history of Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome or those who have a first-degree relative with one of these syndromes. MRI is an extremely sensitive screening tool that is not limited by the density of the breast tissue as mammography is, however, its specificity is moderate leading to more false-positive events and the increased need for biopsy. Chemoprevention. Tamoxifen, a selective estrogen receptor modulator, was the first drug shown to reduce the incidence of breast cancer in healthy women. There have been 4 prospective studies published evaluating tamoxifen vs. placebo for reducing the incidence of invasive breast cancer for women at increased risk. The largest trial was the Breast Cancer Prevention Trial (NSABP P-01) which randomly assigned >13,000 women with a 5-year Gail relative risk of breast cancer of 1.66% or higher or LCIS to receive tamoxifen or placebo. After a mean follow-up period of 4 years, the incidence of breast cancer was reduced by 49% in the group receiving tamoxifen.60 The decrease was evident only in ER-positive breast cancers with no significant change in ER-negative tumors. The Royal Marsden Hospital Tamoxifen Chemoprevention Trial78, the Italian Tamoxifen Prevention Trial79, and the International Breast Cancer Intervention Study I (IBIS-I) trial all80 showed a reduction in ERpositive breast cancers with the use of tamoxifen compared with placebo. There was no effect on mortality; however, the trials were not powered to assess either breast cancer mortality or allcause mortality events. The adverse events were similar in all VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 513 CHAPTER 17 The Breast to use tamoxifen to prevent breast cancer, and when to perform prophylactic mastectomy to prevent breast cancer. Postmenopausal hormone replacement therapy was widely prescribed in the 1980s and 1990s because of its effectiveness in controlling the symptoms of estrogen deficiency; namely, vasomotor symptoms such as hot flashes, night sweats and their associated sleep deprivation, osteoporosis, and cognitive changes. Furthermore, these hormone supplements were thought to reduce coronary artery disease as well. Use of combined estrogen and progesterone became standard for women who had not undergone hysterectomy, because unopposed estrogen increases the risk of uterine cancer. Concerns of prolonging a woman’s lifetime exposure to estrogen, coupled with conflicting data regarding the impact of these hormones on cardiovascular health, motivated the implementation of large-scale phase III clinical trials to definitively evaluate the risks vs. benefits of postmenopausal hormone replacement therapy. The Women’s Health Initiative was therefore designed by the National Institutes of Health as a series of clinical trials to study the effects of diet, nutritional supplements, and hormones on the risk of cancer, cardiovascular disease, and bone health in postmenopausal women. Findings from primary studies of postmenopausal hormone replacement therapy were released in 2002, demonstrating conclusively that breast cancer risk is threefold to fourfold higher after >4 years of use and there is no significant reduction in coronary artery or cerebrovascular risks. The Collaborative Group on Hormonal Factors in Breast Cancer combined and re-analyzed data from a number of studies totaling 52,705 women with breast cancer and 108,411 women without breast cancer. They found an increased risk of breast cancer with ever use of estrogen replacement therapy. They also reported increased risk among current users but not past users and risk increased with increasing duration of use of hormone replacement therapy.69 Cheblowski et al also reported from the WHI study that estrogen + progesterone increased the incidence of breast cancer.70 This was confirmed by the Million Women study which also showed that the increased risk was substantially greater for the combined estrogen + progesterone replacement therapy than other types of hormone replacement therapy.71 Breast Cancer Screening. Routine use of screening mammography in women ≥50 years of age has been reported to reduce mortality from breast cancer by 25%.72 This reduc6 tion comes at an acceptable economic cost. More recently, there has been debate over the potential harms associated with breast screening.73 As a result the United Kingdom recently established an independent expert panel to review the published literature and estimate the benefits and harms associated with screening women >50 years in its national screening program.74 The expert panel estimated that an invitation to breast screening delivers about a 20% reduction in breast cancer mortality while at the same time the panel estimated that in women invited to screening, about 11% of the cancers diagnosed in their lifetime constitute over-diagnosis. Despite the overdiagnosis, the panel concluded that breast screening confers significant benefit and should continue. The use of screening mammography in women <50 years of age is more controversial for several reasons: (a) breast density is greater and screening mammography is less likely to detect early breast cancer (i.e., reduced sensitivity); (b) screening mammography results in more false-positive test findings (i.e., reduced specificity), which results in unnecessary biopsy specimens; and (c) younger women are less likely to have breast cancer (i.e., lower incidence), so fewer young 514 UNIT II PART SPECIFIC CONSIDERATIONS 4 randomized trials including an increased risk of endometrial cancer, thromboembolic events, cataract formation, and vasomotor disturbances in individuals receiving tamoxifen. Tamoxifen therapy currently is recommended only for women who have a Gail relative risk of 1.66% or higher, who are aged 35 to 59, women over the age of 60 or women with a diagnosis of LCIS or atypical ductal or lobular hyperplasia. In addition, deep vein thrombosis occurs 1.6 times as often, pulmonary emboli 3.0 times as often, and endometrial cancer 2.5 times as often in women taking tamoxifen. The increased risk for endometrial cancer is restricted to early stage cancers in postmenopausal women. Cataract surgery is required almost twice as often among women taking tamoxifen. Gail et al subsequently developed a model that accounts for underlying risk of breast cancer as well as comorbidities to determine the net risk-benefit ratio of tamoxifen use for chemoprevention.81 The NSABP completed a second chemoprevention trial, designed to compare tamoxifen and raloxifene for breast cancer risk reduction in high-risk postmenopausal women. Raloxifene, another selective estrogen receptor modulator, was selected for the experimental arm in this follow-up prevention trial because its use in managing postmenopausal osteoporosis suggested that it might be even more effective at breast cancer risk reduction, but without the adverse effects of tamoxifen on the uterus. The P-2 trial, the Study of Tamoxifen and Raloxifene (known as the STAR trial), randomly assigned 19,747 postmenopausal women at high-risk for breast cancer to receive either tamoxifen or raloxifene. The initial report of the P-2 trial showed the two agents were nearly identical in their ability to reduce breast cancer risk, but raloxifene was associated with a more favorable adverse event profile.82 An updated analysis revealed that raloxifene maintained 76% of the efficacy of tamoxifen in prevention of invasive breast cancer with a more favorable side effect profile. The risk of developing endometrial cancer was significantly higher with tamoxifen use at longer follow-up.83 Although tamoxifen has been shown to reduce the incidence of LCIS and DCIS, raloxifene did not have an effect on the frequency of these diagnoses. Aromatase inhibitors (AIs) have been shown to be more effective than tamoxifen in reducing the incidence of contralateral breast cancers in postmenopausal women receiving AIs for adjuvant treatment of invasive breast cancer. The MAP.3 trial was the first study to evaluate an AI as a chemopreventive agent in postmenopausal women at high risk for breast cancer. The trial randomized 4,560 women to exemestane 25 mg daily vs. placebo for five years. After a median follow-up of 35 months, exemestane was shown to reduce invasive breast cancer incidence by 65%. Side effect profiles demonstrated more grade 2 or higher arthritis and hot flashes in patients taking exemestane.84 The IBIS II trial has recruited 6,000 patients randomized to the non-steroidal aromatase inhibitor, anastrozole, vs. placebo with a further randomization to bisphosphonate or not based on bone density.85 The trial also had an initial sub-study which looked at the effect of the aromatase inhibitor on cognitive function and reported no adverse effects.86 The American Society of Clinical Oncology recently updated recommendations for chemoprevention in women at increased risk of breast cancer as did the U.S. Preventive Services Task Force. Both groups recommend offering tamoxifen to women at increased risk for breast cancer or raloxifene to postmenopausal women who are noted to be at increased risk.87,88 The discussion with an individual patient should include risk assessment and potential risks and benefits with each agent. Risk-reducing Surgery. A retrospective study of women at high risk for breast cancer found that prophylactic mastectomy reduced their risk by >90%.62 However, the effects of prophylactic mastectomy on the long-term quality of life are poorly quantified. A study involving women who were carriers of a breast cancer susceptibility gene (BRCA) mutation found that the benefit of prophylactic mastectomy differed substantially according to the breast cancer risk conferred by the mutations. For women with an estimated lifetime risk of 40%, prophylactic mastectomy added almost 3 years of life, whereas for women with an estimated lifetime risk of 85%, prophylactic mastectomy added >5 years of life.66 Domchek et al evaluated a cohort of BRCA1/2 mutation carriers who were followed prospectively and reported on outcomes with risk-reducing surgery.89 They found that risk-reducing mastectomy was highly effective at preventing breast cancer in both BRCA1 and 2 mutation carriers. Risk-reducing salpingo-oophorectomy was highly effective at reducing the incidence of ovarian cancer and breast cancer in BRCA mutation carriers and was associated with a reduction in breast cancer-specific mortality, ovarian cancer-specific mortality, and all-cause mortality. While studies of bilateral prophylactic or risk-reducing mastectomy have reported dramatic reductions in breast cancer incidence among those without known BRCA mutations, there is little data to support a survival benefit. Another consideration is that while most patients are satisfied with their decision to pursue risk-reducing surgery, some are dissatisfied with the cosmetic outcomes mostly due to reconstructive issues. BRCA Mutations BRCA1. Up to 5% of breast cancers are caused by inheritance of germline mutations such as BRCA1 and BRCA2, which are inherited in an autosomal dominant fashion with varying degrees of penetrance (Table 17-7).90-96BRCA1 is located on chromosome arm 17q, spans a genomic region of approximately 100 kilobases (kb) of DNA, and contains 22 coding exons for 1863 amino acids. Both BRCA1 and BRCA2 function as tumorsuppressor genes, and for each gene, loss of both alleles is required for the initiation of cancer. Data accumulated since the isolation of the BRCA1 gene suggest a role in transcription, Table 17-7 Incidence of sporadic, familial, and hereditary breast cancer Sporadic breast cancer 65%–75% Familial breast cancer 20%–30% Hereditary breast cancer 5%–10% BRCA1 45% BRCA2 35% a p53 (Li-Fraumeni syndrome) 1% a STK11/LKB1 (Peutz-Jeghers syndrome) <1% PTENa (Cowden disease) <1% MSH2/MLH1a (Muir-Torre syndrome) <1% ATMa (Ataxia-telangiectasia) <1% Unknown 20% a Affected gene. Source: Adapted from Martin.92 a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ BRCA2. BRCA2 is located on chromosome arm 13q and spans a genomic region of approximately 70 kb of DNA. The 11.2-kb coding region contains 26 coding exons.90-96 It encodes a protein of 3418 amino acids. The BRCA2 gene bears no homology to any previously described gene, and the protein contains no previously defined functional domains. The biologic function of BRCA2 is not well defined, but like BRCA1, it is postulated to play a role in DNA damage response pathways. BRCA2 messenger RNA also is expressed at high levels in the late G1 and S phases of the cell cycle. The kinetics of BRCA2 protein regulation in the cell cycle is similar to that of BRCA1 protein, which suggests that these genes are coregulated. The mutational spectrum of BRCA2 is not as well established as that of BRCA1. To date, >250 mutations have been found. The breast cancer risk for BRCA2 mutation carriers is close to 85%, and the lifetime ovarian cancer risk, while lower than for BRCA1, is still estimated to be close to 20%. Breast cancer susceptibility in BRCA2 families is an autosomal dominant trait and has a high penetrance. Approximately 50% of children of carriers inherit the trait. Unlike male carriers of BRCA1 mutations, men with germline mutations in BRCA2 have an estimated breast cancer risk of 6%, which represents a 100-fold increase over the risk in the general male population. BRCA2-associated breast cancers are invasive ductal carcinomas, which are more likely to be well differentiated and to express hormone receptors than are BRCA1-associated breast cancers. BRCA2-associated breast cancer has a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases, a higher prevalence of bilateral breast cancer, and the presence of associated cancers in some affected individuals, specifically ovarian, colon, prostate, pancreatic, gallbladder, bile duct, and stomach cancers, as well as melanoma. A number of founder mutations have been identified in BRCA2. The 6174delT mutation is found in Ashkenazi Jews with a prevalence of 1.2% and accounts for 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.102 Another BRCA2 founder mutation, 999del5, is observed in Icelandic and Finnish populations while more recently 3036delACAA has been observed in a number of Spanish families.103-105 Identification of BRCA Mutation Carriers. Identifying hereditary risk for breast cancer is a four-step process that includes: (a) obtaining a complete, multigenerational family history, (b) assessing the appropriateness of genetic testing for a particular patient, (c) counseling the patient, and (d) interpreting the results of testing.106 Genetic testing should not be offered in isolation, but only in conjunction with patient education and counseling, including referral to a genetic counselor. Initial determinations include whether the individual is an appropriate candidate for genetic testing and whether genetic testing will be informative for personal and clinical decision making. A thorough and accurate family history is essential to this process, and the maternal and paternal sides of the family are both assessed, because 50% of the women with a BRCA mutation have inherited the mutation from their fathers. To help clinicians advise women about genetic testing, statistically based models that determine the probability that an individual carries a BRCA mutation have been developed. A method for calculating carrier probability which has been demonstrated to have acceptable performance (i.e., both in terms of calibration and discrimination) such as the Manchester scoring system and BODICEA should be used to offer referral to a specialist genetic clinic. A hereditary risk of breast cancer is considered if a family includes Ashkenazi Jewish heritage; a first-degree relative with breast cancer before age 50; a history of ovarian cancer at any age in the patient or first- or second-degree relative with ovarian cancer; breast and ovarian cancer in the same individual; two or more first- or second-degree relatives with breast cancer at any age; patient or relative with bilateral breast cancer; and male breast cancer in a relative at any age.107 The threshold for genetic testing is lower in individuals who are members of ethnic groups in whom the mutation prevalence is increased. BRCA Mutation Testing. Appropriate counseling for the individual being tested for a BRCA mutation is strongly recommended, and documentation of informed consent is required.106,108 The test that is clinically available for analyzing BRCA mutations is gene sequence analysis. In a family with a history suggestive of hereditary breast cancer and no previously tested member, the most informative strategy is first to test an affected family member. This person undergoes complete sequence analysis of both the BRCA1 and BRCA2 genes. If a mutation is identified, relatives are usually tested only for that specific mutation. An individual of Ashkenazi Jewish ancestry is tested initially for the three specific mutations that account for hereditary breast and ovarian cancer in that population. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 515 CHAPTER 17 The Breast cell-cycle control, and DNA damage repair pathways. More than 500 sequence variations in BRCA1 have been identified. It now is known that germline mutations in BRCA1 represent a predisposing genetic factor in as many as 45% of hereditary breast cancers and in at least 80% of hereditary ovarian cancers. Female mutation carriers have been reported to have up to a 85% lifetime risk (for some families) for developing breast cancer and up to a 40% lifetime risk for developing ovarian cancer. The initial families reported had high penetrance and subsequently the average lifetime risk has been reported to lie between 60%–70%. Breast cancer susceptibility in these families appears as an autosomal dominant trait with high penetrance. Approximately 50% of children of carriers inherit the trait. In general, BRCA1-associated breast cancers are invasive ductal carcinomas, are poorly differentiated, are in the majority hormone receptor negative and have a triple receptor negative (immunohistochemical profile: ER-negative, PR-negative and HER-2-negative) or basal phenotype (based on gene expression profiling). BRCA1-associated breast cancers have a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases; a higher prevalence of bilateral breast cancer; and the presence of associated cancers in some affected individuals, specifically ovarian cancer and possibly colon and prostate cancers. Several founder mutations have been identified in BRCA1. The two most common mutations are 185delAG and 5382insC, which account for 10% of all the mutations seen in BRCA1. These two mutations occur at a 10-fold higher frequency in the Ashkenazi Jewish population than in non-Jewish caucasians. The carrier frequency of the 185delAG mutation in the Ashkenazi Jewish population is 1% and, along with the 5382insC mutation, accounts for almost all BRCA1 mutations in this population. Analysis of germline mutations in Jewish and non-Jewish women with early-onset breast cancer indicates that 20% of Jewish women who develop breast cancer before age 40 years carry the 185delAG mutation. There are founder BRCA1 mutations in other populations including, among others, Dutch, Polish, Finnish, and Russian populations.97-101 516 UNIT II PART SPECIFIC CONSIDERATIONS If results of that test are negative, it may then be appropriate to fully analyze the BRCA1 and BRCA2 genes. A positive test result is one that discloses the presence of a BRCA mutation that interferes with translation or function of the BRCA protein. A woman who carries a deleterious mutation has a breast cancer risk of up to 85% (in some families) as well as a greatly increased risk of ovarian cancer. A negative test result is interpreted according to the individual’s personal and family history, especially whether a mutation has been previously identified in the family, in which case the woman is generally tested only for that specific mutation. If the mutation is not present, the woman’s risk of breast or ovarian cancer may be no greater than that of the general population. In addition, no BRCA mutation can be passed on to the woman’s children. In the absence of a previously identified mutation, a negative test result in an affected individual generally indicates that a BRCA mutation is not responsible for the familial cancer. However, the possibility remains of an unusual abnormality in one of these genes that cannot yet be identified through clinical testing. It also is possible that the familial cancer is indeed caused by an identifiable BRCA mutation but that the individual tested had sporadic cancer, a situation known as phenocopy. This is especially possible if the individual tested developed breast cancer close to the age of onset of the general population (age 60 years or older) rather than before age 50 years, as is characteristic of BRCA mutation carriers. Overall, the false-negative rate for BRCA mutation testing is <5%. Some test results, especially when a single base-pair change (missense mutation) is identified, may be difficult to interpret. This is because single base-pair changes do not always result in a nonfunctional protein. Thus, missense mutations not located within critical functional domains, or those that cause only minimal changes in protein structure, may not be disease associated and are usually reported as indeterminate results. In communicating indeterminate results to women, care must be taken to relay the uncertain cancer risk associated with this type of mutation and to emphasize that ongoing research might clarify its meaning. In addition, testing other family members with breast cancer to determine if a genetic variant tracks with their breast cancer may provide clarification as to its significance. Indeterminate genetic variance currently accounts for 12% of the test results. Concern has been expressed that the identification of hereditary risk for breast cancer may interfere with access to affordable health insurance. This concern refers to discrimination directed against an individual or family based solely on an apparent or perceived genetic variation from the normal human genotype. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) made it illegal in the United States for group health plans to consider genetic information as a preexisting condition or to use it to deny or limit coverage. Most states also have passed laws that prevent genetic discrimination in the provision of health insurance. In addition, individuals applying for health insurance are not required to report whether relatives have undergone genetic testing for cancer risk, only whether those relatives have actually been diagnosed with cancer. Currently there is little documented evidence of genetic discrimination resulting from findings of available genetic tests. Cancer Prevention for BRCA Mutation Carriers. Risk management strategies for BRCA1 and BRCA2 mutation carriers include the following: 1. Risk-reducing mastectomy and reconstruction 2. Risk-reducing salpingo-oophorectomy 3. Intensive surveillance for breast and ovarian cancer 4. Chemoprevention Although removal of breast tissue reduces the likelihood that BRCA1 and BRCA2 mutation carriers will develop breast cancer, mastectomy does not remove all breast tissue and women continue to be at risk because a germline mutation is present in any remaining breast tissue. For postmenopausal BRCA1 and BRCA2 mutation carriers who have not had a mastectomy, it may be advisable to avoid hormone replacement therapy, because no data exist regarding the effect of the therapy on the penetrance of breast cancer susceptibility genes. Because breast cancers in BRCA mutation carriers have the same mammographic appearance as breast cancers in noncarriers, a screening mammogram is likely to be effective in BRCA mutation carriers, provided it is performed and interpreted by an experienced radiologist with a high level of suspicion. Present screening recommendations for BRCA mutation carriers who do not undergo risk-reducing mastectomy include clinical breast examination every 6 months and mammography every 12 months beginning at age 25 years, because the risk of breast cancer in BRCA mutation carriers increases after age 30 years. Recent attention has been focused on the use MRI for breast cancer screening in high-risk individuals and known BRCA mutation carriers. MRI appears to be more sensitive at detecting breast cancer in younger women with dense breasts.109 However, as noted previously, MRI does lead to the detection of benign breast lesions that cannot easily be distinguished from malignancy, and these false-positive events can result in more interventions, including biopsy specimens. The current recommendations from the American Cancer Society are for annual MRI in women with a 20% to 25% or greater lifetime risk of developing breast cancer, including women with a strong family history of breast or ovarian cancer and women who were treated for Hodgkin’s disease in their teens or early twenties.110 Despite a 49% reduction in the overall incidence of breast cancer and a 69% reduction in the incidence of estrogen receptor positive tumors in high-risk women taking tamoxifen reported in the NSABP P1 trial, there is insufficient evidence to recommend the use of tamoxifen uniformly for BRCA1 mutation carriers.60 Cancers arising in BRCA1 mutation carriers are usually high grade and are most often hormone receptor negative. Approximately 66% of BRCA1-associated DCIS lesions are estrogen receptor negative, which suggests early acquisition of the hormone-independent phenotype. In the NSABP P1 trial there was a 62% reduction in the incidence of breast cancer in BRCA2 carriers, similar to the overall reduction seen in the P1 trial. In contrast, there was no reduction seen in breast cancer incidence in BRCA1 carriers who started tamoxifen in P1 age 35 years or older.111 Tamoxifen appears to be more effective at preventing estrogen receptor-positive breast cancers. The risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers ranges from 20% to 40%, which is 10 times higher than that in the general population. Risk-reducing salpingooophorectomy is a reasonable prevention option in mutation carriers. In women with a documented BRCA1 or BRCA2 mutation, consideration for bilateral risk-reducing salpingo-ophorectomy should be between the ages of 35 and 40 years at the completion of childbearing. Removing the ovaries reduces the risk of ovarian cancer and breast cancer when performed in premenopausal BRCA mutation carriers. Hormone replacement therapy is discussed with the patient at the time of oophorectomy. The Cancer Genetics Studies Consortium recommends yearly transvaginal VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ ultrasound timed to avoid ovulation and annual measurement of serum cancer antigen 125 levels beginning at age 25 years as the best screening modalities for ovarian carcinoma in BRCA mutation carriers who have opted to defer prophylactic surgery. Other hereditary syndromes associated with an increased risk of breast cancer include Cowden disease (PTEN mutations, in which cancers of the thyroid, GI tract, and benign skin and subcutaneous nodules are also seen), Li-Fraumeni syndrome (p53 mutations, also associated with sarcomas, lymphomas, and adrenocortical tumors), and syndromes of breast and melanoma. Epidemiology Breast cancer is the most common site-specific cancer in women and is the leading cause of death from cancer for women aged 20 to 59 years. It accounts for 29% of all newly diagnosed cancers in females and is responsible for 14% of the cancer-related deaths in women. It is predicted that approximately 234,580 breast cancers will be diagnosed in the United States in 2013 and that 40,030 individuals will die from breast cancer.112 Breast cancer was the leading cause of cancer-related mortality in women until 1987, when it was surpassed by lung cancer. In the 1970s, the probability that a woman in the United States would develop breast cancer at some point in her lifetime was estimated at 1 in 13; in 1980 it was 1 in 11; and in 2004 it was 1 in 8. Cancer registries in Connecticut and upper New York State document that the age-adjusted incidence of new breast cancer cases had steadily increased since the mid-1940s. The incidence in the United States, based on data from nine Surveillance, Epidemiology, and End Results (SEER) registries, has been decreasing by 23% per year since 2000. The increase had been approximately 1% per year from 1973 to 1980, and there was an additional increase in incidence of 4% between 1980 and 1987, which was characterized by frequent detection of small primary cancers. The increase in breast cancer incidence occurred primarily in women ≥55 years and paralleled a marked increase in the percentage of older women who had mammograms taken. At the same time, incidence rates for regional metastatic disease dropped and breast cancer mortality declined. From 1960 to 1963, 5-year overall survival rates for breast cancer were 63% and 46% in white and African American women, respectively, whereas the rates for 1981 to 1983 were 78% and 64%, respectively. For 2002 to 2008 rates were 92% and 78%, respectively. There is a 10-fold variation in breast cancer incidence among different countries worldwide. Cyprus and Malta have the highest age-adjusted mortality for breast cancer (29.6 per 100,000 population), whereas Haiti has the lowest (2.0 deaths per 100,000 population). The United States has an age-adjusted mortality for breast cancer of 19.0 cases per 100,000 population. Women living in less-industrialized nations tend to have a lower incidence of breast cancer than women living in industrialized countries, although Japan is an exception. In the United States, Mormons, Seventh Day Adventists, American Indians, Alaska natives, Hispanic/Latina Americans, and Japanese and Filipino women living in Hawaii have a below-average incidence of breast cancer, whereas nuns (due to nulliparity) and Ashkenazi Jewish women have an above-average incidence. The incidence rates of breast cancer increased in most countries through the 1990s. Since the estimates for 1990, there VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 517 CHAPTER 17 The Breast EPIDEMIOLOGY AND NATURAL HISTORY OF BREAST CANCER was an overall increase in incidence rates of approximately 0.5% annually. It was predicted that there would be approximately 1.4 million new cases in 2010. The cancer registries in China have noted annual increases in incidence of up to 3% to 4%, and in eastern Asia, increases are similar. Recent data from the SEER program reveal declines in breast cancer incidence over the past decade, and this is widely attributed to decreased use of hormone replacement therapy as a consequence of the Women’s Health Initiative reports.113 Breast cancer burden has well-defined variations by geography, regional lifestyle, and racial or ethnic background.114 In general, both breast cancer incidence and mortality are relatively lower among the female populations of Asia and Africa, relatively underdeveloped nations, and nations that have not adopted the Westernized reproductive and dietary patterns. In contrast, European and North American women and women from heavily industrialized or westernized countries have a substantially higher breast cancer burden. These international patterns are mirrored in breast cancer incidence and mortality rates observed for the racially, ethnically, and culturally diverse population of the United States.115 Although often related, the factors that influence breast cancer incidence may differ from those that affect mortality. Incidence rates are lower among populations that are heavily weighted with women who begin childbearing at young ages and who have multiple full-term pregnancies followed by prolonged lactation. These are features that characterize many underdeveloped nations and also many eastern nations. Breast cancer mortality rates should be lower in populations that have a lower incidence, but the mortality burden will simultaneously be adversely affected by the absence of effective mammographic screening programs for early detection and diminished access to multidisciplinary cancer treatment programs. These features are likely to account for much of the disproportionate mortality risks that are seen in underdeveloped nations. Similar factors probably account for differences in breast cancer burden observed among the various racial and ethnic groups within the United States. Interestingly, breast cancer incidence and mortality rates rise among second- and third-generation Asian Americans as they adopt Western lifestyles. Disparities in breast cancer survival among subsets of the American population are generating increased publicity because they are closely linked to disparities in socioeconomic status. Poverty rates and proportions of the population that lack health care insurance are two to three times higher among minority racial and ethnic groups such as African Americans and Hispanic/Latino Americans. These socioeconomic disadvantages create barriers to effective breast cancer screening and result in delayed breast cancer diagnosis, advanced stage distribution, inadequacies in comprehensive treatment, and ultimately increased mortality rates. Furthermore, the rapid growth in the Hispanic population is accompanied by increasing problems in health education because of linguistic barriers between physicians and recently immigrated, non-English-speaking patients. Recent studies also are documenting inequities in the treatments delivered to minority breast cancer patients, such as increased rates of failure to provide systemic therapy, use of sentinel lymph node dissection, and breast reconstruction. Some of the treatment delivery disparities are related to inadequately controlled comorbidities (such as hypertension and diabetes), which are more prevalent in minority populations. However, some studies that adjust for these factors report persistent and unexplained UNIT II PART SPECIFIC CONSIDERATIONS unevenness in treatment recommendations. It is clear that breast cancer disparities associated with racial or ethnic background have a multifactorial cause, and improvements in outcome will require correction of many public health problems at both the patient and provider levels. Advances in the ability to characterize breast cancer subtypes and the genetics of the disease are now provoking speculation regarding possible hereditary influences on breast cancer risk that are related to racial or ethnic ancestry.116 These questions become particularly compelling when one looks at disparities in breast cancer burden between African Americans and Caucasians. Lifetime risk of breast cancer is lower for African Americans, yet a paradoxically increased breast cancer mortality risk also is seen. African Americans also have a younger age distribution for breast cancer; among women <45 years of age, breast cancer incidence is highest among African Americans compared to other subsets of the American population. Lastly and most provocatively, African American women of all ages have notably higher incidence rates for estrogen receptornegative tumors. These same patterns of disease are seen in contemporary female populations of western, sub-Saharan Africa, who are likely to share ancestry with African American women as a consequence of the Colonial-era slave trade. Interestingly, male breast cancer also is seen with increased frequency among both African Americans and Africans. Natural History Bloom and colleagues described the natural history of breast cancer based on the records of 250 women with untreated breast cancers who were cared for on charity wards in the Middlesex Hospital, London, between 1805 and 1933. The median survival of this population was 2.7 years after initial diagnosis (Fig. 17-13).117 The 5- and 10-year survival rates Middlesex Hospital 1805-1933 (250 cases) 100 90 86% 83% 80 70 % Survival 518 60 68% 66% 54% 50 40 41% 44% 30 20 10 Natural survival 28% Survival untreated cases 18% 9% 3.6% 2% 0.8% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Median survival 2.7 years Duration of life from onset of symptoms (years) Figure 17-13. Survival of women with untreated breast cancer compared with natural survival. (Reproduced with permission from Bloom HJG, Richardson WW, Harries EJ. Natural history of untreated breast cancer [1803–1933]: Comparison of untreated and treated cases according to histological grade of malignancy. Br Med J. With permission from BMJ Publishing Group, Ltd.) for these women were 18.0% and 3.6%, respectively. Only 0.8% survived for 15 years or longer. Autopsy data confirmed that 95% of these women died of breast cancer, whereas the remaining 5% died of other causes. Almost 75% of the women developed ulceration of the breast during the course of the disease. The longest surviving patient died in the nineteenth year after diagnosis. Primary Breast Cancer. More than 80% of breast cancers show productive fibrosis that involves the epithelial and stromal tissues. With growth of the cancer and invasion of the surrounding breast tissues, the accompanying desmoplastic response entraps and shortens Cooper’s suspensory ligaments to produce a characteristic skin retraction. Localized edema (peaud’orange) develops when drainage of lymph fluid from the skin is disrupted. With continued growth, cancer cells invade the skin, and eventually ulceration occurs. As new areas of skin are invaded, small satellite nodules appear near the primary ulceration. The size of the primary breast cancer correlates with disease-free and overall survival, but there is a close association between cancer size and axillary lymph node involvement (Fig. 17-14). In general, up to 20% of breast cancer recurrences are localregional, >60% are distant, and 20% are both local-regional and distant. Axillary Lymph Node Metastases. As the size of the primary breast cancer increases, some cancer cells are shed into cellular spaces and transported via the lymphatic network of the breast to the regional lymph nodes, especially the axillary lymph nodes. Lymph nodes that contain metastatic cancer are at first ill-defined and soft but become firm or hard with continued growth of the metastatic cancer. Eventually the lymph nodes adhere to each other and form a conglomerate mass. Cancer cells may grow through the lymph node capsule and fix to contiguous structures in the axilla, including the chest wall. Typically, axillary lymph nodes are involved sequentially from the low (level I) to the central (level II) to the apical (level III) lymph node groups. Approximately 95% of the women who die of breast cancer have distant metastases, and traditionally the most important prognostic correlate of disease-free and overall survival was axillary lymph node status (see Fig. 17-14A). Women with node-negative disease had less than a 30% risk of recurrence, compared with as much as a 75% risk for women with node-positive disease. Distant Metastases. At approximately the twentieth cell doubling, breast cancers acquire their own blood supply (neovascularization). Thereafter, cancer cells may be shed directly into the systemic venous blood to seed the pulmonary circulation via the axillary and intercostal veins or the vertebral column via Batson’s plexus of veins, which courses the length of the vertebral column. These cells are scavenged by natural killer lymphocytes and macrophages. Successful implantation of metastatic foci from breast cancer predictably occurs after the primary cancer exceeds 0.5 cm in diameter, which corresponds to the twenty-seventh cell doubling. For 10 years after initial treatment, distant metastases are the most common cause of death in breast cancer patients. For this reason, conclusive results cannot be derived from breast cancer trials until at least 5 to 10 years have elapsed. Although 60% of the women who develop distant metastases will do so within 60 months of treatment, metastases may become evident as late as 20 to 30 years after treatment of the primary cancer.118 Patients with estrogen receptor negative breast cancers are proportionately more likely to develop VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 100 90 Percent survivors 80 315 * 297 * 636 173 N - (335) 177 70 531 * 321 60 144 50 * 142 263 * 234 * 40 * 92 30 * * N + (381) * 90 25 N + >3 (183) 10 4 2 A 6 8 HISTOPATHOLOGY OF BREAST CANCER 10 Years after mastectomy Carcinoma In Situ Proportion of patients with metastases 0.98 0.95 0.90 x 0.80 x 0.70 x x 0.60 x 0.50 x 0.40 xx 0.30 xx 0.20 10 100 Volume (ml) B 2 3 4 5 6 7 8 9 10 11 Diameter (cm) Figure 17-14. A. Overall survival for women with breast cancer according to axillary lymph node status. The time periods are years after radical mastectomy. (Reproduced with permission from Valagussa P, et al: Patterns of relapse and survival following radical mastectomy. Analysis of 716 consecutive patients. Cancer. 1978;11:1170. Copyright © American Cancer Society. This material is reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.) B. Risk of metastases according to breast cancer volume and diameter. (Reproduced with permission from Koscielny S et al. Breast cancer: Relationship between the size of the primary tumour and the probability of metastatic dissemination. Br J Cancer. 1984;49:709.) recurrence in the first 3 to 5 years, whereas those with estrogen receptor positive tumors have a risk of developing recurrence which drops off more slowly beyond 5 years than is seen with ER negative tumors.119 Recently a report showed that tumor size and nodal status remain powerful predictors of late recurrences compared to more recently developed tools such as the Cancer cells are in situ or invasive depending on whether or not they invade through the basement membrane.124,125 Broders’s original description of in situ breast cancer stressed the absence of invasion of cells into the surrounding stroma and their confinement within natural ductal and alveolar boundaries.124 Because areas of invasion may be minute, the accurate diagnosis of in situ cancer necessitates the analysis of multiple microscopic sections to exclude invasion. In 1941, Foote and Stewart published a landmark description of LCIS, which distinguished it from DCIS.125 In the late 1960s, Gallagher and Martin published their study of whole-breast sections and described a stepwise progression from benign breast tissue to in situ cancer and subsequently to invasive cancer. Before the widespread use of mammography, diagnosis of breast cancer was by physical examination. At that time, in situ cancers constituted <6% of all breast cancers, and LCIS was more frequently diagnosed than DCIS by a ratio of >2:1. However, when screening mammography became popular, a 14-fold increase in the incidence of in situ cancer (45%) was demonstrated, and DCIS was more frequently diagnosed than LCIS by a ratio of >2:1. Table 17-8 lists the clinical and pathologic characteristics of DCIS and LCIS. Multicentricity refers to the occurrence of a second breast cancer outside the breast quadrant of the primary cancer (or at least 4 cm away), whereas multifocality refers to the occurrence of a second cancer within the same breast quadrant as the primary cancer (or within 4 cm of it). Multicentricity occurs in 60% to 90% of women with LCIS, whereas the rate of multicentricity for DCIS is reported to be 40% to 80%. LCIS occurs bilaterally in 50% to 70% of cases, whereas DCIS occurs bilaterally in 10% to 20% of cases. Lobular Carcinoma In Situ. LCIS originates from the terminal duct lobular units and develops only in the female breast. It is characterized by distention and distortion of the terminal duct lobular units by cells which are large but maintain a normal nuclear: cytoplasmic ratio. Cytoplasmic mucoid globules are a distinctive cellular feature. LCIS may be observed in breast tissues that contain microcalcifications, but the calcifications associated with LCIS typically occur in adjacent tissues. This neighborhood calcification is a feature that is unique to LCIS and contributes to its diagnosis. The frequency of LCIS in the general population cannot be reliably determined because it usually presents as an incidental finding. The average age at diagnosis is 45 years, which is approximately 15 to 25 years younger than the age at diagnosis for invasive breast cancer. LCIS has a distinct racial predilection, occurring 12 times more frequently VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 519 CHAPTER 17 The Breast 20 Whole series (716) N + 1 (198) 65 immunohistochemical score (IHC4) and two gene expression profile tests (Recurrence Score and PAM50).120 Common sites of involvement, in order of frequency, are bone, lung, pleura, soft tissues, and liver. Brain metastases are less frequent overall although with the advent of adjuvant systemic therapies it has been reported that CNS disease may be seen earlier.121,122 There are also reports of factors which are associated with the risk of developing brain metastases.123 For example, they are more likely to be seen in patients with triple receptor negative breast cancer (ER-negative, PR-negative and HER2-negative) or patients with HER2-positive breast cancer who have received chemotherapy and HER2-directed therapies. 520 Table 17-8 Salient characteristics of in situ ductal (DCIS) and lobular (LCIS) carcinoma of the breast Age (years) Incidence a Clinical signs LCIS DCIS 44–47 54–58 2%–5% 5%–10% None Mass, pain, nipple discharge UNIT II PART SPECIFIC CONSIDERATIONS Mammographic signs None Microcalcifications Premenopausal 2/3 1/3 Incidence of synchronous invasive carcinoma 5% 2%–46% Multicentricity 60%–90% 40%–80% Bilaterality 50%–70% 10%–20% Axillary metastasis 1% 1%–2% 25%–35% 25%–70% Subsequent carcinomas: Incidence Laterality Bilateral Ipsilateral Interval to diagnosis 15–20 y 5–10 y Histologic type Ductal Ductal In biopsy specimens of mammographically detected breast lesions. Source: Reproduced with permission from Frykberg ER, et al: Current concepts on the biology and management of in situ (Tis, stage 0) breast carcinoma, in Bland KI, et al (eds): The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders;1998:1020. Copyright Elsevier. a in white women than in African American women. Invasive breast cancer develops in 25% to 35% of women with LCIS. Invasive cancer may develop in either breast, regardless of which breast harbored the initial focus of LCIS, and is detected synchronously with LCIS in 5% of cases. In women with a history of LCIS, up to 65% of subsequent invasive cancers are ductal, not lobular, in origin. For these reasons, LCIS is regarded as a marker of increased risk for invasive breast cancer rather than as an anatomic precursor. Individuals should be counseled regarding their risk of developing breast cancer and appropriate risk reduction strategies, including observation with screening, chemoprevention, and risk-reducing bilateral mastectomy. Ductal Carcinoma In Situ. Although DCIS is predominantly seen in the female breast, it accounts for 5% of male breast cancers. Published series suggest a detection frequency of 7% in all biopsy tissue specimens. The term intraductal carcinoma is frequently applied to DCIS, which carries a high risk for progression to an invasive cancer. Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina. Early in their development, the cancer cells do not show pleomorphism, mitoses, or atypia, which leads to difficulty in distinguishing early DCIS from benign hyperplasia. The papillary growths (papillary growth pattern) eventually coalesce and fill the duct lumina so that only scattered, rounded spaces remain between the clumps of atypical cancer cells, which show hyperchromasia and loss of polarity (cribriform growth pattern). Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and distend the ducts (solid growth pattern). With continued growth, these cells outstrip their blood supply and become necrotic (comedo growth pattern). Calcium deposition occurs in the areas of necrosis and is a common feature seen on mammography. DCIS is now frequently classified based on nuclear grade and the presence of necrosis (Table 17-9). Based on multiple consensus meetings, grading of DCIS has been recommended. Although there is no universal agreement on classification, most systems endorse the use of cytologic grade and presence or absence of necrosis.126 The risk for invasive breast cancer is increased nearly fivefold in women with DCIS.127 The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the DCIS that was originally detected, which suggests that DCIS is an anatomic precursor of invasive ductal carcinoma (Fig. 17-15A and B). Invasive Breast Carcinoma Invasive breast cancers have been described as lobular or ductal in origin.128-131 Early classifications used the term lobular to describe invasive cancers that were associated with LCIS, whereas all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by specific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. About 80% of invasive breast cancers are described as Table 17-9 Classification of breast ductal carcinoma in situ (DCIS) Determining Characteristics Histologic Subtype Nuclear Grade Necrosis DCIS Grade Comedo High Extensive High Intermediatea Intermediate Focal or absent Intermediate Noncomedob Low Absent Low Often a mixture of noncomedo patterns. b Solid, cribriform, papillary, or focal micropapillary. Source: Adapted with permission from Connolly JL, et al: Ductal carcinoma in situ of the breast: Histologic subtyping and clinical significance. PPO Updates 10:1, 1996. a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 521 B Figure 17-15. Ductal carcinoma in situ (DCIS). A. Craniocaudal mammographic view shows a poorly defined mass containing microcalcifications. (Photo used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening. Royal Derby Hospital.) B. Histopathologic preparation of the surgical specimen confirms DCIS with necrosis (100x) (Photo used with permission of Dr. Sindhu Menon, Consultant Histopathologist & Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.) invasive ductal carcinoma of no special type (NST). These cancers generally have a worse prognosis than special-type cancers. Foote and Stewart originally proposed the following classification for invasive breast cancer125: 1. Paget’s disease of the nipple 2. Invasive ductal carcinoma—Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST), 80% 3. Medullary carcinoma, 4% 4. Mucinous (colloid) carcinoma, 2% 5. Papillary carcinoma, 2% 6. Tubular carcinoma, 2% 7. Invasive lobular carcinoma, 10% 8. Rare cancers (adenoid cystic, squamous cell, apocrine) Paget’s disease of the nipple was described in 1874. It frequently presents as a chronic, eczematous eruption of the nipple, which may be subtle but may progress to an ulcerated, weeping lesion. Paget’s disease usually is associated with extensive DCIS and may be associated with an invasive cancer. A palpable mass may or may not be present. A nipple biopsy specimen will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget cells) in the rete pegs of the epithelium. Paget’s disease may be confused with superficial spreading melanoma. Differentiation from pagetoid intraepithelial melanoma is based on the presence of S-100 antigen immunostaining in melanoma and carcinoembryonic antigen immunostaining in Paget’s disease. Surgical therapy for Paget’s disease may involve lumpectomy or mastectomy, depending on the extent of involvement of the nipple-areolar complex and the presence of DCIS or invasive cancer in the underlying breast parenchyma. Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in up to 25% of screen-detected cases and up to 60% of symptomatic cases. This cancer occurs most frequently in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. It has poorly defined margins and its cut surfaces show a central stellate configuration with chalky white or yellow streaks extending into surrounding breast tissues. The cancer cells often are arranged in small clusters, and there is a broad spectrum of histologic types with variable cellular and nuclear grades (Fig. 17-16A and B). In a large patient series from the SEER database, 75% of ductal cancers showed estrogen receptor expression.132 Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a frequent phenotype of BRCA1 hereditary breast cancer. Grossly, the cancer is soft and hemorrhagic. A rapid increase in size may occur secondary to necrosis and hemorrhage. On physical examination, it is bulky and often positioned deep within the breast. Bilaterality is reported in 20% of cases. Medullary carcinoma is characterized microscopically by: (a) a dense lymphoreticular infiltrate composed predominantly of lymphocytes and plasma cells; (b) large pleomorphic nuclei that are poorly differentiated and show active mitosis; and (c) a sheet-like growth pattern with minimal or absent ductal or alveolar differentiation. Approximately 50% of these cancers are associated with DCIS, which characteristically is present at the periphery of the cancer, and <10% demonstrate hormone receptors. In rare circumstances, mesenchymal metaplasia or anaplasia is noted. Because of the intense lymphocyte response associated with the cancer, benign or hyperplastic enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging. Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular carcinoma. Mucinous carcinoma (colloid carcinoma), another specialtype breast cancer, accounts for 2% of all invasive breast cancers and typically presents in the elderly population as a bulky tumor. This cancer is defined by extracellular pools of mucin, which surround aggregates of low-grade cancer cells. The cut surface of this cancer is glistening and gelatinous in quality. Fibrosis is variable, and when abundant it imparts a firm consistency to the cancer. Over 90% of mucinous carcinomas display hormone receptors.132 Lymph node metastases occur in 33% VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast A 522 UNIT II PART SPECIFIC CONSIDERATIONS A B Figure 17-16. Invasive ductal carcinoma with productive fibrosis (scirrhous, simplex, no special type) A. 100x and B. 200x. (Used with permission of Dr. Sindhu Menon, Consultant Histopathologist & Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK). of cases, and 5- and 10-year survival rates are 73% and 59%, respectively. Because of the mucinous component, cancer cells may not be evident in all microscopic sections, and analysis of multiple sections is essential to confirm the diagnosis of a mucinous carcinoma. Papillary carcinoma is a special-type cancer of the breast that accounts for 2% of all invasive breast cancers. It generally presents in the seventh decade of life and occurs in a disproportionate number of nonwhite women. Typically, papillary carcinomas are small and rarely attain a size of 3 cm in diameter. These cancers are defined by papillae with fibrovascular stalks and multilayered epithelium. In a large series from the SEER database 87% of papillary cancers have been reported to express estrogen receptor.132 McDivitt and colleagues noted that these tumors showed a low frequency of axillary lymph node metastases and had 5- and 10-year survival rates similar to those for mucinous and tubular carcinoma.133 Tubular carcinoma is another special-type breast cancer and accounts for 2% of all invasive breast cancers. It is reported in as many as 20% of women whose cancers are diagnosed by mammographic screening and usually is diagnosed in the perimenopausal or early menopausal periods. Under low-power magnification, a haphazard array of small, randomly arranged tubular elements is seen. In a large SEER database 94% of tubular cancers were reported to express estrogen receptor.132 Approximately 10% of women with tubular carcinoma or with invasive cribriform carcinoma, a special-type cancer closely related to tubular carcinoma, will develop axillary lymph node metastases. However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%. Invasive lobular carcinoma accounts for 10% of breast cancers. The histopathologic features of this cancer include small cells with rounded nuclei, inconspicuous nucleoli, and scant cytoplasm (Fig. 17-17). Special stains may confirm the presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). At presentation, invasive Figure 17-17. Lobular carcinoma (100×). Uniform, relatively small lobular carcinoma cells are seen arranged in a single-file orientation (“Indian file”). (Used with permission of Dr. Sindhu Menon, Consultant Histopathologist & Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.) lobular carcinoma varies from clinically inapparent carcinomas to those that replace the entire breast with a poorly defined mass. It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammographic features, invasive lobular carcinoma may be difficult to detect. Over 90% of lobular cancers express estrogen receptor.132 DIAGNOSIS OF BREAST CANCER In~30% of cases, the woman discovers a lump in her breast. Other less frequent presenting signs and symptoms of breast cancer include: (a) breast enlargement or asymmetry; (b) nipple changes, retraction, or discharge; (c) ulceration or erythema of the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ skin of the breast; (d) an axillary mass; and (e) musculoskeletal discomfort. However, up to 50% of women presenting with breast complaints have no physical signs of breast pathology. Breast pain usually is associated with benign disease. Misdiagnosed breast cancer accounts for the greatest number of malpractice claims for errors in diagnosis and for the largest number of paid claims. Litigation often involves younger women, whose physical examination and mammogram may be misleading. If a young woman (≤45 years) presents with a palpable breast mass and equivocal mammographic findings, ultrasound examination and biopsy are used to avoid a delay in diagnosis. 523 Inspection. The surgeon inspects the woman’s breast with her arms by her side (Fig. 17-18A), with her arms straight up in the air (Fig. 17-18B), and with her hands on her hips (with and without pectoral muscle contraction).134,135 Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peaud’orange), nipple or skin retraction, or erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction. Figure 17-19. A breast examination record. (Reproduced with permission from Cliggott Publishing Co.) Palpation. As part of the physical examination, the breast is carefully palpated. With the patient in the supine position (see Fig. 17-18C) the surgeon gently palpates the breasts, making certain to examine all quadrants of the breast from the sternum laterally to the latissimus dorsi muscle and from the clavicle inferiorly to the upper rectus sheath. The surgeon performs the examination with the palmar aspects of the fingers, avoiding a grasping or pinching motion. The breast may be cupped or molded in the surgeon’s hands to check for retraction. A systematic search for lymphadenopathy then is performed. Figure 17-18D shows the position of the patient for examination of the axilla. By supporting the upper arm and elbow, the surgeon stabilizes the shoulder girdle. Using gentle palpation, the surgeon assesses all three levels of possible axillary lymphadenopathy. Careful palpation Figure 17-18. Examination of the breast. A. Inspection of the breast with arms at sides. B. Inspection of the breast with arms raised. C. Palpation of the breast with the patient supine. D. Palpation of the axilla. of supraclavicular and parasternal sites also is performed. A diagram of the chest and contiguous lymph node sites is useful for recording location, size, consistency, shape, mobility, fixation, and other characteristics of any palpable breast mass or lymphadenopathy (Fig. 17-19). Imaging Techniques Mammography. Mammography has been used in North America since the 1960s, and the techniques used continue to be modified and improved to enhance image quality.136-139 Conventional mammography delivers a radiation dose of 0.1 cGy per study. By comparison, chest radiography delivers 25% of this dose. However, there is no increased breast cancer risk associated with the radiation dose delivered with screening mammography. Screening mammography is used to detect unexpected breast cancer in asymptomatic women. In this regard, it supplements history taking and physical examination. With screening mammography, two views of the breast are obtained, the craniocaudal (CC) view (Fig. 17-20A and B) and the mediolateral oblique (MLO) view (Fig. 17-20 C and D). The MLO view images the greatest volume of breast tissue, including the upper outer quadrant and the axillary tail of Spence. Compared with the MLO view, the CC view provides better visualization of the medial aspect of the breast and permits greater breast compression. Diagnostic mammography is used to evaluate women with abnormal findings such as a breast mass or nipple discharge. In addition to the MLO and CC views, a diagnostic examination may use views that better define the nature of any abnormalities, such as the 90-degree lateral and spot compression views. The 90-degree lateral view is used along with the CC view to triangulate the exact location of an abnormality. Spot compression may be done in any projection by using a small compression device, which is placed directly over a mammographic abnormality that is obscured by overlying tissues (Fig. 17-21C). The compression device minimizes motion artifact, improves definition, separates overlying tissues, and decreases the radiation dose needed to penetrate the breast. Magnification techniques (×1.5) often are combined with spot compression to better resolve VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast Examination 524 UNIT II PART SPECIFIC CONSIDERATIONS A C B D Figure 17-20. A-D. Mammogram of a premenopausal breast with a dense fibroglandular pattern. E-H. Mammogram of a postmenopausal breast with a sparse fibroglandular pattern. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 525 CHAPTER 17 The Breast E F G H Figure 17-20. (Continued ) calcifications and the margins of masses. Mammography also is used to guide interventional procedures, including needle localization and needle biopsy. Specific mammographic features that suggest a diagnosis of breast cancer include a solid mass with or without stellate features, asymmetric thickening of breast tissues, and clustered microcalcifications. The presence of fine, stippled calcium in and around a suspicious lesion is suggestive of breast cancer and occurs in as many as 50% of nonpalpable cancers. These microcalcifications are an especially important sign of cancer in younger women, in whom it may be the only mammographic abnormality. The clinical impetus for screening mammography VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 526 UNIT II PART SPECIFIC CONSIDERATIONS A B C Figure 17-21. Mammogram revealing a small, spiculated mass in the right breast A. A small, spiculated mass is seen in the right breast with skin tethering (CC view). B. Mass seen on oblique view of the right breast. C. Spot compression mammography view of the cancer seen in A and B. The spiculated margins of the cancer are accentuated by compression. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK). came from the Health Insurance Plan study and the Breast Cancer Detection Demonstration Project, which demonstrated a 33% reduction in mortality for women after72 screening mammography. Mammography was more accurate than clinical examination for the detection of early breast cancers, providing a true-positive rate of 90%. Only 20% of women with nonpalpable cancers had axillary lymph node metastases, compared with 50% of women with palpable cancers.140 Current guidelines of the National Comprehensive Cancer Network suggest that normal-risk women ≥20 years of age should have a breast examination at least every 3 years. Starting at age 40 years, breast examinations should be performed yearly and a yearly mammogram should be taken. The benefits from screening mammography in women ≥50 years of age has been noted above to be between 20% and 25% reduction in breast cancer mortality.72,74 With the increased discussion about the potential harms associated with breast screening the United Kingdom recently established an independent expert panel to review the published literature and estimate the benefits and harms associated with its national screening program for women >50 years. The expert panel estimated that in women invited to screening, about 11% of the cancers diagnosed in their lifetime constitute over-diagnosis. Despite the over-diagnosis the panel concluded that breast screening programs confer significant benefit and should continue. The use of screening mammography in women <50 years of age is more controversial again for reasons noted above: (a) reduced sensitivity; (b) reduced specificity; and (c) lower incidence of breast cancer. For the combination of these three reasons targeting mammography screening to women <50 years at higher risk of breast cancer improves the balance of risks and benefits and is the approach some health care systems have taken. There are now a number of risk assessment models—as described earlier in that section—which can be used to estimate a younger woman’s risk of developing breast cancer to help assess the risks and benefits of regular screening. Screen film mammography has replaced xeromammography because it requires a lower dose of radiation and provides similar image quality. Digital mammography was developed to allow the observer to manipulate the degree of contrast in the image. This is especially useful in women with dense breasts and women <50 years of age. Recently, investigators directly compared digital vs. screen film mammography in a prospective (DMIST) trial enrolling over 42,000 women.141 They found that digital and screen film mammography had similar accuracy; however, digital mammography was more accurate in women <50 years of age, women with mammographically dense breasts, and premenopausal or perimenopausal women. The use of digital breast tomosynthesis with 3D images has been introduced as an alternative to standard 2D mammography imaging that is limited by superimposition of breast parenchyma and breast density. The STORM trial reported that in 7,292 women screened, 3D mammography had a higher cancer detection rate and fewer false-positive recalls than the standard 2D imaging.142 Randomized controlled trials are planned to further study tomosynthesis and its role in breast cancer screening. Ductography. The primary indication for ductography is nipple discharge, particularly when the fluid contains blood. Radiopaque contrast media is injected into one or more of the major ducts and mammography is performed. A duct is gently enlarged with a dilator and then a small, blunt cannula is inserted under sterile conditions into the nipple ampulla. With the patient in a supine position, 0.1 to 0.2 mL of dilute contrast media is injected and CC and MLO mammographic views VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 527 CHAPTER 17 The Breast A B Figure 17-22. Ductogram. Craniocaudal (A) and mediolateral oblique (B) mammographic views demonstrate a mass (arrows) posterior to the nipple and outlined by contrast, which also fills the proximal ductal structures. (Photos used with permission of B. Steinbach.) are obtained without compression. Intraductal papillomas are seen as small filling defects surrounded by contrast media (Fig. 17-22). Cancers may appear as irregular masses or as multiple intraluminal filling defects. Ultrasonography. Second only to mammography in frequency of use for breast imaging, ultrasonography is an important method of resolving equivocal mammographic findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities. On ultrasound examination, breast cysts are well circumscribed, with smooth margins and an echo-free center (Fig. 17-23). Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and welldefined anterior and posterior margins (Fig 17-24). Breast cancer characteristically has irregular walls (Fig. 17-25) but may have smooth margins with acoustic enhancement. Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle localization of breast lesions. Its findings are highly reproducible and it has a high patient acceptance rate, but it does not reliably detect lesions that are ≤1 cm in diameter. Ultrasonography can also be utilized to image the regional lymph nodes in patients with breast cancer (Fig. 17-26). The sensitivity of examination for the status of axillary nodes ranges from 35% to 82% and specificity ranges from 73% to 97%. The features of a lymph node involved with cancer include cortical thickening, change in shape of the node to more circular appearance, size larger than 10 mm, absence of a fatty hilum and hypoechoic internal echoes.143 Magnetic Resonance Imaging. In the process of evaluating magnetic resonance imaging (MRI) as a means of characterizing mammographic abnormalities, additional breast lesions have been detected. However, in the circumstance of negative findings on both mammography and physical examination, the probability of a breast cancer being diagnosed by MRI is extremely low. There is current interest in the use of MRI to screen the breasts of high-risk women and of women with a newly diagnosed breast cancer. In the first case, women who have a strong family history of breast cancer or who carry known genetic mutations require screening at an early age, because mammographic evaluation is limited due to the increased breast density in younger women. In the second case, an MRI study of the contralateral breast in women with a known breast cancer has shown a contralateral breast cancer in 5.7% of these women (Fig. 17-27). MRI can also detect additional tumors in the index breast (multifocal or multicentric disease) that may be missed on routine breast imaging and this may alter surgical decision making (Fig. 17-28). In fact, MRI has been advocated by some for routine use in surgical treatment planning based on the fact that additional disease can be identified with this advanced imaging modality and the extent of disease may be more accurately assessed. A randomized trial performed in the United Kingdom (COMICE trial) which enrolled 1,623 women did not show a decrease in rates of reoperation in those women randomized to undergo MRI in addition to mammography and ultrasonography (19%) compared to those undergoing standard breast imaging without MRI (19%).144 Houssami and colleagues performed a meta-analysis including 2 randomized trials and 7 comparative cohort studies to examine the effect of preoperative MRI compared to standard preoperative evaluation on surgical outcomes.145 They reported that the use of MRI was associated with increased mastectomy rates. This is problematic since there is no evidence that the additional disease detected by MRI is of clinical or biologic significance, particularly in light of the low local-regional failure rates currently reported in patients undergoing breast conserving surgery who receive whole breast irradiation and systemic therapies. The use of dedicated breast coils is mandatory in the MRI imaging of the breast. A BIRADS lexicon is assigned to each examination and an abnormality noted on MRI that is not seen VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 528 UNIT II PART SPECIFIC CONSIDERATIONS B A C Figure 17-23. Breast cyst. A. Simple cyst. Ultrasound image of the mass shows it to be anechoic with a well-defined back wall, characteristic of a cyst. B. Complex solid and cystic mass. (C) Complex solid and cystic mass characteristic of intracystic papillary tumor. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK). Figure 17-24. Ultrasonography images of benign breast tumors. A. Fibroadenoma. B. Intraductal papilloma. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 529 C D Figure 17-25. Ultrasonography images of malignant breast lesions. A. 25 mm irregular mass. B. Ultrasound 30 mm mass anterior to an implant. C. Ultrasound breast cancer with calcification. D. Ultrasound 9 mm spiculated mass with attenuation. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK). on mammography requires a focused ultrasound examination for further assessment. If the abnormality is not seen on corresponding mammogram or ultrasound then MRI guided biopsy is necessary. Some clinical scenarios where MRI may be useful include the evaluation of a patient who presents with nodal metastasis from breast cancer without an identifiable primary tumor; to assess response to therapy in the setting of neoadjuvant systemic treatment; to select patients for partial breast irradiation techniques; and evaluation of the treated breast for tumor recurrence. Breast Biopsy Nonpalpable Lesions. Image-guided breast biopsy specimens are frequently required to diagnose nonpalpable lesions.146 Ultrasound localization techniques are used when a mass is present, whereas stereotactic techniques are used when no mass is present (microcalcifications or architectural distortion only). The combination of diagnostic mammography, ultrasound or stereotactic localization, and fine-needle aspiration (FNA) biopsy achieves almost 100% accuracy in the preoperative diagnosis of breast cancer. However, although FNA biopsy permits cytologic evaluation, core-needle permits the analysis of breast tissue architecture and allows the pathologist to determine whether invasive cancer is present. This permits the surgeon and patient to discuss the specific management of a breast cancer before therapy begins. Core-needle biopsy is preferred over open biopsy for nonpalpable breast lesions because a single surgical procedure can be planned based on the results of the core biopsy. The 7 advantages of core-needle biopsy include a low complication rate, minimal scarring, and a lower cost compared with excisional breast biopsy. Palpable Lesions. FNA or core biopsy of a palpable breast mass can usually be performed in an outpatient setting. 147 A 1.5-in, 22-gauge needle attached to a 10-mL syringe or a 14 gauge core biopsy needle is used. For FNA, use of a syringe holder VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast B A 530 UNIT II PART B SPECIFIC CONSIDERATIONS A C Figure 17-26. Ultrasonography images of lymph nodes. A. Normal axillary lymph node. B. Indeterminate axillary lymph node. C. Malignant appearing axillary lymph node. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) Figure 17-27. MRI examination revealing contralateral breast cancer in a patient diagnosed with unilateral breast cancer on mammography. (Photo used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 531 enables the surgeon performing the FNA biopsy to control the syringe and needle with one hand while positioning the breast mass with the opposite hand. After the needle is placed in the mass, suction is applied while the needle is moved back and forth within the mass. Once cellular material is seen at the hub of the needle, the suction is released and the needle is withdrawn. The cellular material is then expressed onto microscope slides. Both air-dried and 95% ethanol–fixed microscopic sections are prepared for analysis. When a breast mass is clinically and mammographically suspicious, the sensitivity and specificity of FNA biopsy approaches 100%. Core-needle biopsy of palpable breast masses is performed using a 14-gauge needle, such as the Tru-Cut needle. Automated devices also are available. Vacuum assisted core biopsy devices (with 8–10 gauge needles) are commonly utilized with image guidance where between 4 and 12 samples can be acquired at different positions within a mass, area of architectural distortion or microcalcifications. If the target lesion was microcalcifications, the specimen should be radiographed to confirm appropriate sampling. A radiopaque marker should be placed at the site of the biopsy to mark the area for future intervention. In some cases the entire lesion is removed with the biopsy technique and clip placement allows for accurate targeting of the site for surgical resection. Tissue specimens are placed in formalin and then processed to paraffin blocks. Although the false-negative rate for core-needle biopsy specimens is very low, a tissue specimen that does not show breast cancer cannot conclusively rule out that diagnosis because a sampling error may have occurred. The clinical, radiographic, and pathologic findings should be in concordance. If the biopsy findings do not concur with the clinical and radiographic findings, the multi-disciplinary team (including clinician, radiologist, and pathologist) should review the findings and decide whether or not to recommend an image-guided or open biopsy to be certain that the target lesion has been adequately sampled for diagnosis. BREAST CANCER STAGING AND BIOMARKERS Breast Cancer Staging The clinical stage of breast cancer is determined primarily through physical examination of the skin, breast tissue, and regional lymph nodes (axillary, supraclavicular, and internal mammary).148 However, clinical determination of axillary lymph node metastases has an accuracy of only 33%. Ultrasound (US) is more sensitive than physical examination alone in determining axillary lymph node involvement during preliminary staging of breast carcinoma. Fine-needle aspiration (FNA) or core biopsy of sonographically indeterminate or suspicious lymph nodes can provide a more definitive diagnosis than US alone.143,149 Pathologic stage combines the findings from pathologic examination of the resected primary breast cancer and axillary or other regional lymph nodes. Fisher and colleagues found that accurate predictions regarding the occurrence of distant metastases were possible after resection and pathologic analysis of 10 or more level I and II axillary lymph nodes.150 A frequently used staging system is the TNM (tumor, nodes, and metastasis) system. The American Joint Committee on Cancer (AJCC) has modified the TNM system for breast cancer (Tables 17-10 and 17-11). 151Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary lymph node metastases (see Fig. 17-14B). Others have shown an association between tumor size, axillary lymph node metastases, and disease-free survival. One of the most important predictors of 10- and 20-year survival rates in breast cancer is the number of axillary lymph nodes involved with metastatic disease. Routine biopsy of internal mammary lymph nodes is not generally performed; however, it has been reported that in the context of a ‘triple node’ biopsy approach either the internal mammary node or a low axillary node when positive alone carried the same prognostic weight. When both nodes were positive the prognosis declined to the level associated with apical node positivity. A double node biopsy of the low axillary node and either the apical or the internal mammary node gave the same maximum prognostic information as a triple node biopsy.152 With the advent of sentinel lymph node dissection and the use of preoperative lymphoscintigraphy for localization of the sentinel nodes, surgeons have again begun to biopsy the internal mammary nodes but in a more targeted manner. The 7th edition of the AJCC staging system does allow for staging based on findings from the internal mammary sentinel nodes.151 Drainage to the internal mammary nodes is more frequent with central and medial quadrant cancers. Clinical or pathologic evidence of metastatic spread to supraclavicular lymph nodes is no longer considered stage IV disease, but routine scalene or supraclavicular lymph node biopsy is not indicated. Biomarkers Breast cancer biomarkers are of several types. Risk factor biomarkers are those associated with increased cancer risk.153-157 These include familial clustering and inherited germline abnormalities, proliferative breast disease with atypia, and mammographic densities. Exposure biomarkers are a subset of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast Figure 17-28. MRI imaging of the breast revealing multifocal tumors not detected with standard breast imaging. (Photo used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) 532 Table 17-10 TNM staging system for breast cancer Primary tumor (T) The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript “c” or “p” modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size. UNIT II PART SPECIFIC CONSIDERATIONS TX T0 Tis Tis (DCIS) Tis (LCIS) Tis (Paget’s) T1 T1mi T1a T1b T1c T2 T3 T4 T4a T4b T4c T4d Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Ductal carcinoma in situ Lobular carcinoma in situ Paget’s disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/ or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget’s disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget’s disease should still be noted Tumor ≤20 mm in greatest dimension Tumor ≤1 mm in greatest dimension Tumor >1 mm but ≤5 mm in greatest dimension Tumor >5 mm but ≤10 mm in greatest dimension Tumor >10 mm but ≤20 mm in greatest dimension Tumor >20 mm but ≤5 cm in greatest dimension Tumor >50 mm in greatest dimension Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)* Extension to chest wall, not including only pectoralis muscle adherence/invasion Ulceration and/or ipsilateral satellite nodules and/or edema (including peaud’orange) of the skin, which do not meet the criteria for inflammatory carcinoma Both T4a and T4b Inflammatory carcinoma** *Note: Invasion of the dermis alone does not qualify as T4 **Note: Inflammatory carcinoma is restricted to cases with typical skin changes involving a third or more of the skin of the breast. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer. Regional lymph nodes—Clinical (N) NX N0 N1 N2 N2a N2b N3 N3a N3b N3c Regional lymph nodes cannot be assessed (e.g., previously removed) No regional lymph node metastases Metastases to movable ipsilateral level I, II axillary lymph node(s) Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically detected* ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures Metastases only in clinically detected* ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases Metastasis in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in clinically detected* ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement Metastasis in ipsilateral infraclavicular lymph node(s) Metastasis in ipsilateral internal mammary lymph nodes(s) and axillary lymph node(s) Metastasis in ipsilateral supraclavicular lymph node(s) *Notes: “Clinically detected” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, e.g., cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, e.g., cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 533 Table 17-10 TNM staging system for breast cancer (continued) Regional lymph nodes—Pathologic (pN) pNX pN0b pN0(mol+) pN1 pN1mi pN1a pN1b pN1c pN2 pN2a pN2b pN3 pN3a pN3b pN3c Distant metastasis (M) M0 cM0(i+) M1 No clinical or radiographic evidence of distant metastases No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm Source: Reprinted with permission from American Joint Committee on Cancer: AJCC Cancer Staging Manual, 7th ed. New York: Springer; 2010:358-361. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source of the material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast pN0(i−) pN0(i+) pN0(mol−) Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for pathologic study) No regional lymph node metastasis identified histologically Note: Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated. No regional lymph node metastasis histologically, negative IHC Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including ITC) No regional lymph node metastasis histologically, negative molecular findings [reverse-transcriptase polymerase chain reaction (RT-PCR)] Positive molecular findings (RT-PCR)**, but no regional lymph node metastases detected by histology or IHC Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected*** Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm) Metastases in 1-3 axillary lymph nodes, at least one metastasis greater than 2.0 mm Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected*** Metastases in 1-3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected Metastases in 4-9 axillary lymph nodes; or in clinically apparent*** internal mammary lymph nodes in the absence of axillary lymph node metastases Metastases in 4-9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm) Metastases in clinically detected*** internal mammary lymph nodes in the absence of axillary lymph node metastases Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detected **** ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected***; or in ipsilateral supraclavicular lymph nodes Metastases in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes Metastases in clinically detected**** ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected*** Metastasis in ipsilateral supraclavicular lymph nodes * Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (sn) for “sentinel node,” e.g., pN0(sn). ** RT-PCR: reverse transcriptase/polymerase chain reaction. *** “Not clinically detected” is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination. **** “Clinically detected” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination. 534 Table 17-11 TNM stage groupings Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T0 N1mi M0 T1a N1mi M0 T0 N1b M0 T1a N1b M0 T2 N0 M0 T2 N1 M0 T3 N0 M0 T0 N2 M0 Stage IIA UNIT II PART Stage IIB SPECIFIC CONSIDERATIONS Stage IIIA a T1 N2 M0 T2 N2 M0 T3 N1 M0 T3 N2 M0 T4 N0 M0 T4 N1 M0 T4 N2 M0 Stage IIIC Any T N3 M0 Stage IV Any T Any N M1 a Stage IIIB T1 includes T1mi b T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB –M0 includes M0(i+). –The designation pM0 is not valid; any M0 should be clinical. –If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy. –Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy. –Postneoadjuvant therapy is designated with “yc” or “yp” prefix. Of note, no stage group is assigned if there is a complete pathologic response (CR) to neoadjuvant therapy, e.g., ypT0ypN0cM0. Source: Reprinted with permission from American Joint Committee on Cancer: AJCC Cancer Staging Manual, 7th ed. New York: Springer; 2010:360-361. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source of the material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com. a risk factors that include measures of carcinogen exposure such as DNA adducts. Surrogate endpoint biomarkers are biologic alterations in tissue that occur between cancer initiation and development. These biomarkers are used as endpoints in shortterm chemoprevention trials and include histologic changes, indices of proliferation, and genetic alterations leading to cancer. Prognostic biomarkers provide information regarding cancer outcome irrespective of therapy, whereas predictive biomarkers provide information regarding response to therapy.158 Candidate prognostic and predictive biomarkers and biologic targets for breast cancer include (a) the steroid hormone receptor pathway; (b) growth factors and growth factor receptors such as human epidermal growth factor receptor 2 (HER-2)/neu, epidermal growth factor receptor (EGFR), transforming growth factor, platelet-derived growth factor, and the insulin-like growth factor family; (c) indices of proliferation such as proliferating cell nuclear antigen (PCNA) and Ki-67; (d) indices of angiogenesis such as vascular endothelial growth factor (VEGF) and the angiogenesis index; (e) the mammalian target of rapamycin (mTOR) signaling pathway; (f) tumor-suppressor genes such as p53; (g) the cell cycle, cyclins, and cyclin-dependent kinases; (h) the proteasome; (i) the COX-2 enzyme; (j) the peroxisome proliferator-activated receptors (PPARs); and (k) indices of apoptosis and apoptosis modulators such as bcl-2 and the bax:bcl-2 ratio. Steroid Hormone Receptor Pathway. Hormones play an important role in the development and progression of breast cancer. Estrogens, estrogen metabolites, and other steroid hormones such as progesterone all have been shown to have an effect. Breast cancer risk is related to estrogen exposure over time. In postmenopausal women, hormone replacement therapy consisting of estrogen plus progesterone increases the risk of breast cancer by 26% compared to placebo.70 Patients with hormone receptor-positive tumors survive two to three times longer after a diagnosis of metastatic disease than do patients with hormone receptor-negative tumors. Patients with tumors negative for both estrogen receptors and progesterone receptors are not considered candidates for hormonal therapy. Tumors positive for estrogen or progesterone receptors have a higher response rate to endocrine therapy than tumors that do not express estrogen or progesterone receptors. Tumors positive for both receptors have a response rate of >50%, tumors negative for both receptors have a response rate of <10%, and tumors positive for one receptor but not the other have an intermediate response rate of 33%. The determination of estrogen and progesterone receptor status used to require biochemical evaluation of fresh tumor tissue. Today, however, estrogen and progesterone receptor status can be measured in archived tissue using immunohistochemical techniques. Hormone receptor status also can be measured in specimens obtained with fine-needle aspiration biopsy or core-needle biopsy, and this can help guide treatment planning. Testing for estrogen and progesterone receptors should be performed on all primary invasive breast cancer specimens. The tumor hormone receptor status should be ascertained for both premenopausal and postmenopausal patients to identify patients who are most likely to benefit from endocrine therapy. Growth Factor Receptors and Growth Factors. Overexpression of EGFR in breast cancer correlates with estrogen receptor– negative status and with p53 overexpression.159-161 Similarly, increased immunohistochemical membrane staining for the HER-2/neu growth factor receptor in breast cancer is associated with mutated p53, Ki-67 overexpression, and estrogen receptor– negative status. HER-2/neu is a member of the EGFR family of growth factor receptors in which ligand binding results in receptor homodimerization and tyrosine phosphorylation by tyrosine kinase domains within the receptor. Tyrosine phosphorylation is followed by signal transduction, which results in changes in cell behavior. An important property of this family of receptors is that ligand binding to one receptor type also may result in heterodimerization between two different receptor types that are coexpressed; this leads to transphosphorylation and transactivation of both receptors in the complex (transmodulation). In this context, the lack of a specific ligand for the HER-2/neu VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Indices of Proliferation. PCNA is a nuclear protein associated with a DNA polymerase whose expression increases in phase G1 of the cell cycle, reaches its maximum at the G1/S interface, and then decreases through G2.171-174 Immunohistochemical staining for PCNA outlines the proliferating compartments in breast tissue. Good correlation is noted between PCNA expression and (a) cell-cycle distributions seen on flow cytometry based on DNA content, and (b) uptake of bromodeoxyuridine and the proliferation-associated Ki-67 antigen. Individual proliferation markers are associated with slightly different phases of the cell cycle and are not equivalent. PCNA and Ki-67 expression are positively correlated with p53 overexpression, high S-phase fraction, aneuploidy, high mitotic index, and high histologic grade in human breast cancer specimens, and are negatively correlated with estrogen receptor content. Ki67 was included with three other widely measured breast cancer markers (ER, PR, and HER2) into a panel of four immunohistochemical makers (IHC4) which together provided similar prognostic information to that in the Genomic Health 21 Gene Recurrence Score.175 While there has been significant interest in using Ki67 as a biomarker, and while the IHC4 panel would be much less costly than the 21 Gene Recurrence Score there remain issues regarding reproducibility across laboratories. Indices of Angiogenesis. Angiogenesis is necessary for the growth and invasiveness of breast cancer and promotes cancer progression through several different mechanisms, including delivery of oxygen and nutrients and the secretion of growthpromoting cytokines by endothelial cells.176,177 VEGF induces its effect by binding to transmembrane tyrosine kinase receptors. Overexpression of VEGF in invasive breast cancer is correlated with increased microvessel density and recurrence in node-negative breast cancer. An angiogenesis index has been developed in which microvessel density (CD31 expression) is combined with expression of thrombospondin (a negative modulator of angiogenesis) and p53 expression. Both VEGF expression and the angiogenesis index may have prognostic and predictive significance in breast cancer. Antiangiogenesis breast cancer therapy is now being studied in human trials. Bevacizumab (a monoclonal antibody to VEGF) was approved by the U.S. Food and Drug Administration (FDA) for use in metastatic breast cancer in combination with paclitaxel chemotherapy. This approval was based on results from a phase III trial by the Eastern Cooperative Oncology Group. The group’s E2100 trial showed that when bevacizumab was added to paclitaxel chemotherapy, median progression-free survival increased to 11.3 months from the 5.8 months seen in patients who received paclitaxel alone.178 The results were not reproduced in other trials and the indication for the drug was revoked by the FDA in 2011. Indices of Apoptosis. Alterations in programmed cell death (apoptosis), which may be triggered by p53-dependent or p53-independent factors, may be important prognostic and predictive biomarkers in breast cancer.179-181 Bcl-2 family proteins appear to regulate a step in the evolutionarily conserved pathway for apoptosis, with some members functioning as inhibitors of apoptosis and others as promoters of apoptosis. Bcl-2 is the only oncogene that acts by inhibiting apoptosis rather than by directly increasing cellular proliferation. The death-signal protein bax is induced by genotoxic stress and growth factor deprivation in the presence of wild-type (normal) p53 and/or AP-1/ fos. The bax:bcl-2 ratio and the resulting formation of either bax-baxhomodimers, which stimulate apoptosis, or bax–bcl-2 heterodimers, which inhibit apoptosis, represent an intracellular regulatory mechanism with prognostic and predictive implications. In breast cancer, overexpression of bcl-2 and a decrease in the bax:bcl-2 ratio correlate with high histologic grade, the presence of axillary lymph node metastases, and reduced disease-free and overall survival rates. Similarly, decreased bax expression correlates with axillary lymph node metastases, a poor response to chemotherapy, and decreased overall survival. The remaining biomarkers and biologic targets listed earlier are still in preclinical and clinical trials evaluating their importance in breast cancer for both prognostic and predictive purposes. Coexpression of Biomarkers. Selection of optimal therapy for breast cancer requires both an accurate assessment of prognosis and an accurate prediction of response to therapy. The breast cancer markers that are most important in determining therapy are estrogen receptor, progesterone receptor, and HER2/neu. Clinicians evaluate clinical and pathologic staging and the expression of estrogen receptor, progesterone receptor, and HER-2/neu in the primary tumor to assess prognosis and assign therapy. Adjuvant! Online (http://www.adjuvantonline.com) is one of a number of programs available to clinicians that incorporates clinical and pathologic factors for an individual patient and calculates risk of recurrence and death due to breast cancer and then provides an assessment of the reduction in risk of recurrence that would be expected with the use of combination chemotherapy, endocrine therapy, or both of these. Adjuvant! Online was developed using information from the SEER database, the EBCTCG overview analyses, and results from other individual published trials.182 The website is updated and modified as new information becomes available. Clinicopathologic factors are used to separate breast cancer patients into broad VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 535 CHAPTER 17 The Breast receptor suggests that HER-2/neu may function solely as a coreceptor, modulating signaling by other EGFR family members. HER-2/neu is both an important prognostic factor and a predictive factor in breast cancer.162 When overexpressed in breast cancer, HER-2/neu promotes enhanced growth and proliferation, and increases invasive and metastatic capabilities. Clinical studies have shown that patients with HER-2/neu–overexpressing breast cancer have poorly differentiated tumors with high proliferation rates, positive lymph nodes, decreased hormone receptor expression, and an increased risk of recurrence and death due to breast cancer.162-166 Routine testing of the primary tumor specimen for HER-2/neu expression should be performed on all invasive breast cancers. This can be done with immunohistochemical analysis to evaluate for overexpression of the cell-surface receptor at the protein level or by using fluorescence in situ hybridization to evaluate for gene amplification. Patients whose tumors overexpress HER-2/neu are candidates for anti– HER-2/neu therapy. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against HER-2/neu. Randomized clinical trials have demonstrated that single-agent trastuzumab therapy is an active and well-tolerated option for first-line treatment of women with HER-2/neu–overexpressing metastatic breast cancer. More recently, adjuvant trials demonstrated that trastuzumab also was highly effective in the treatment of women with early-stage breast cancer when used in combination with chemotherapy. Patients who received trastuzumab in combination with chemotherapy had between a 40%–50% reduction in the risk of breast cancer recurrence and approximately a third reduction in breast cancer mortality compared with those who received chemotherapy alone.167-170 536 Table 17-12 Traditional prognostic and predictive factors for invasive breast cancer Tumor Factors Host Factors Nodal status Age Tumor size Menopausal status Histologic/nuclear grade Family history Lymphatic/vascular invasion Previous breast cancer UNIT II PART Pathologic stage Immunosuppression Hormone receptor status Nutrition DNA content (ploidy, S-phase fraction) Prior chemotherapy SPECIFIC CONSIDERATIONS Extent of intraductal component Prior radiation therapy HER-2/neu expression Source: Modified with permission from Beenken SW, et al: Breast cancer genetics, in Ellis N (ed): Inherited Cancer Syndromes. New York: Springer-Verlag;2003:112. With kind permission of Springer Science + Business Media. prognostic groups, and treatment decisions are made on this basis (Table 17-12). Other indices and programs which are validated and used include the Nottingham Prognostic Index, and PREDICT.183-185 When an approach, which combines prognostic factors is used, up to 70% of early breast cancer patients receive adjuvant chemotherapy that is either unnecessary or ineffective. As described earlier, a wide variety of biomarkers have been shown to individually predict prognosis and response to therapy, but they do not improve the accuracy of either the assessment of prognosis or the prediction of response to therapy. As knowledge regarding cellular, biochemical, and molecular biomarkers for breast cancer increases, prognostic indices are being developed that combine the predictive power of several individual biomarkers with the relevant clinicopathologic factors. Most recently, technologic advances have led to the ability to measure the expression of multiple genes in a tumor sample simultaneously. This gene expression profiling can provide information about tumor behavior that can be used in determining prognosis and therapy.186 These high-throughput analyses require bioinformatics support that can categorize and analyze the immense amount of data that are generated. This allows for a detailed stratification of breast cancer patients for assessment of prognosis and for prediction of response to therapy. The Oncotype DX is a 21-gene assay that has been validated in newly diagnosed patients with node-negative, estrogen receptor– positive breast cancer.187 A recurrence score is generated, and those patients with high recurrence scores are found to benefit the most from chemotherapy, whereas those with low recurrence scores benefit most from endocrine therapy and may not require chemotherapy. The 21-gene recurrence score assay has been validated to quantify the risk of recurrence in patients with ER-positive, node-negative breast cancer and also predicts the potential for chemotherapy benefit. Recent data have demonstrated that knowledge of the recurrence score alters treatment recommendations by oncologists and patients likewise change their decision to undergo treatment based on results of the recurrence score.188 A recently completed clinical trial, the Trial Assessing Individualized Options for Treatment for breast cancer (TAILORx), randomly assigned patients with an intermediate recurrence score to endocrine therapy alone or to chemotherapy followed by endocrine therapy. When these trial results mature we will learn whether this intermediate risk group of patients with hormone receptor positive disease benefit from the addition of chemotherapy. The MammaPrint test was approved by the FDA for use in patients with newly diagnosed, node-negative breast cancer. The MammaPrint test is based on a 70-gene profile, and although fresh tissue was initially required to perform the assay, it has recently been adapted for use in paraffin-embedded tissue samples. The MINDACT (MicroarrayInNode negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy) trial is a phase III randomized trial comparing MammaPrint to Adjuvant! Online for selecting node negative and node-positive (1-3 nodes) breast cancer patients for adjuvant chemotherapy. This trial has completed enrollment with 6,700 patients and will provide important information regarding the use of molecular over standard clinic-pathologic predictors in clinical practice. OVERVIEW OF BREAST CANCER THERAPY Before diagnostic biopsy, the surgeon must consider the possibility that a suspicious mass or mammographic finding may be a breast cancer. Once a diagnosis of breast cancer is made, the type of therapy offered to a breast cancer patient is determined by the stage of the disease, the biologic subtype and the general health status of the individual. Laboratory tests and imaging studies are performed based on the initial stage as presented in Table 17-13. Before therapy is initiated, the patient and the surgeon must share a clear perspective on the planned Table 17-13 Diagnostic studies for breast cancer patients Cancer Stage 0 I II III IV X X X X X Complete blood count, platelet count X X X Liver function tests and alkaline phosphatase level X X X History & physical Chest radiograph Bilateral diagnostic X mammograms, ultrasound as indicated Hormone receptor status X X X X X X X X X X X X X X Bone scan X X Abdominal (without or without pelvis) computed tomographic scan or ultrasound or magnetic resonance imaging X X HER-2/neu expression X X Abdominal imaging and bone scanning are indicated for evaluation of symptoms or abnormal laboratory test results at any presenting stage. Source: Adapted from Carlson RW, et al: Breast cancer, in NCCN Practice Guidelines in Oncology. Fort Washington, PA: National Comprehensive Cancer Network, 2006. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ course of treatment. Before initiating local therapy, the surgeon should determine the clinical stage, histologic characteristics, and appropriate biomarker levels. 8 In Situ Breast Cancer (Stage 0) Both LCIS and DCIS may be difficult to distinguish from atypical hyperplasia or from cancers with early invasion.60,189-194 Expert pathologic review is required in all cases. Bilateral mammography is performed to determine the extent of the in situ cancer and to exclude a second cancer. Because LCIS is considered a marker for increased risk rather than an inevitable precursor of invasive disease, the current treatment options for LCIS include observation, chemoprevention, and bilateral total mastectomy. The goal of treatment is to prevent or detect at an early stage the invasive cancer that subsequently develops in 25% to 35% of these women. There is no benefit to excising LCIS, because the disease diffusely involves both breasts in many cases and the risk of developing invasive cancer is equal for both breasts. The use of tamoxifen as a risk reduction strategy should be considered in women with a diagnosis of LCIS. Women with DCIS and evidence of extensive disease (>4 cm of disease or disease in more than one quadrant) usually require mastectomy (Fig. 17-29). For women with limited disease, lumpectomy and radiation therapy are generally recommended. For nonpalpable DCIS, needle localization or other image-guided techniques are used to guide the surgical resection. Specimen mammography is performed to ensure that all visible evidence of cancer is excised. Adjuvant tamoxifen therapy is considered for DCIS patients with ER-positive disease. A B Figure 17-29. Extensive DCIS seen on mammography. A. Extensive calcifications are seen throughout the breast on this CC view. B. Magnification view of calcifications. Due to the extent of the disease the patient is not a good candidate for breast conserving surgery. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 537 CHAPTER 17 The Breast The gold standard against which breast conservation therapy for DCIS is evaluated is mastectomy. Women treated with mastectomy have local recurrence and mortality rates of <2%. There is no randomized trial comparing mastectomy vs. breast conserving surgery and none of the randomised trials of breast conserving surgery with or without radiotherapy for DCIS were powered to show a difference in mortality. Women treated with lumpectomy and adjuvant radiation therapy have a local recurrence rate that is increased compared to mastectomy. About 45% of these recurrences will be invasive cancer when radiation therapy is not used. The B-17 trial was conducted by the NSABP to assess the need for radiation in patients treated with breast conserving surgery for DCIS.195 Patients were randomly assigned to lumpectomy with radiation or lumpectomy alone and after a mean follow-up time of 90 months, rates of both ipsilateral noninvasive and invasive recurrences were significantly lower in patients who received radiation. However in the B-17 trial the margins were not prospectively assessed and it is estimated that up to half the patients may have had tumor at the margin of resection. The benefit of the addition of radiation over breast-conserving surgery alone for DCIS has also been demonstrated in several other randomized trials where margins were prospectively assessed including the European Organization for Research and Treatment of Cancer (EORTC) protocol 10853; the United Kingdom, Australia, New Zealand DCIS Trial; and the Swedish Trial.189,196-198 Despite the data from randomized trials showing a benefit in all patient subgroups with the addition of radiation in DCIS there has been an interest in trying to define a subset where radiation could be avoided in order to minimize the cost and inconvenience 538 UNIT II PART SPECIFIC CONSIDERATIONS associated with radiation. In addition, there have been several studies published where patients were treated with excision alone and never developed invasive breast cancer even at 25 years of follow-up. Silverstein and colleagues have been proponents of avoiding radiation therapy in selected patients with DCIS who have widely negative margins after surgery.193 They reported that when greater than 10 mm margins were achieved, there was no additional benefit from radiation therapy. When margins were between 1- to 10-mm there was a relative risk of local recurrence of 1.49, compared to 2.54 for those with margins less than 1 mm. These data suggested that appropriately selected patients with DCIS might not require postoperative radiation therapy. The Eastern Cooperative Oncology Group (ECOG) initiated a prospective registry trial (ECOG 5194) to identify those patients who could safely undergo breast conserving surgery without radiation.199 Eligible patients were those with low or intermediate grade DCIS measuring 2.5 cm or less who had negative margins of at least 3 mm and those with high grade DCIS who had tumors measuring 1 cm or less with a negative margin of at least 3 mm. At a median follow-up of 6.2 years, patients with low or intermediate grade DCIS had an in-breast recurrence rate of 6.1% while those with high grade DCIS had a recurrence rate of 15.3%. Approximately 4% of patients developed a contralateral breast cancer during follow-up in both the low/intermediate and high grade groups. This study identified an acceptable recurrence rate for those patients with low or intermediate grade DCIS treated with excision alone with a margin of at least 3 mm. In contrast, patients with high grade DCIS had an unacceptably high local recurrence rate. The Radiation Therapy Oncology Group (RTOG) initiated the 9804 trial for patients with “good risk” DCIS and randomized them to lumpectomy vs. lumpectomy with whole breast irradiation. Eligible patients were those with unicentric, low or intermediate grade DCIS measuring 2.5 cm or less with a margin of 3 mm or greater. The trial was closed early due to slow accrual, however the results for 585 patients were recently reported with a median follow-up of 6.46 years.200 The local recurrence rate at 5 years was 0.4% for patients randomized to receive radiation and 3.2% for those who did not receive radiation. This study has only been reported in abstract form and continued follow-up for enrolled patients is planned. Solin et al utilized samples from the ECOG 5194 trial to develop a quantitative multigene RT-PCR assay for predicting recurrence risk in patients with DCIS treated with surgery alone.201 They were able to define low, intermediate and high risk groups using a DCIS Score. The DCIS Score was able to quantify the risk of recurrence in the breast for both DCIS and invasive events. This tool will need to be evaluated in additional studies but appears to be a promising tool for clinical use. When selecting therapy for patients with DCIS, one must consider clinical and pathologic factors, including tumor size, grade, mammographic appearance, and patient preference. There is no single correct surgical treatment and many patients will require extensive counseling in order to make a decision regarding surgical therapy. The role of axillary staging in patients with DCIS is limited. One consideration is for patients undergoing mastectomy. Since most lesions are currently diagnosed with needle core biopsy, there is about a 20% incidence of invasive breast cancer on final pathologic assessment of the primary tumor. Since it is not feasible to perform sentinel node dissection after mastectomy, most surgeons will recommend the use of sentinel node dissection at the time of mastectomy for DCIS. Results from the NSABP B-24 trial reported a significant reduction in local recurrence after 5 years of tamoxifen in women with ER-positive DCIS. Based on this some guidelines have advocated that all patients (women with ER-positive DCIS without contraindications to tamoxifen therapy) should be offered tamoxifen following surgery and radiation therapy for a duration of 5 years. The B-24 trial revealed a significant reduction in recurrence with adjuvant tamoxifen therapy for patients with DCIS, however the results were not initially assessed based on ER status.202 There were 1,804 women with DCIS randomized to lumpectomy and radiation with or without tamoxifen. The rate of breast cancer events was significantly lower in those who received tamoxifen at a median follow-up of 74 months (8.2% vs. 13.4%, P = 0.0009). Subsequently, Allred and colleagues evaluated 41% of patients with DCIS in the NSABP B-24 trial to determine the effect of tamoxifen based on ER status measured in the primary tumor.203 They found that 76% of women had DCIS that was ER-positive and these women had a greater reduction in ipsilateral breast tumor recurrence with tamoxifen than did patients with ER-negative DCIS (11% vs. 5.2%, P<0.001). However it should be noted that 15% of patients in B-24 had tumor at the resection margins for whom tamoxifen could be viewed as treating what by current standard would be viewed as inadequate local excision of the primary tumor. Five years of tamoxifen is not uniformly prescribed across the world as adjuvant therapy following breast conserving surgery and radiation therapy for DCIS. Early Invasive Breast Cancer (Stage I, IIA, or IIB) There have been six prospective randomized trials comparing breast conserving surgery to mastectomy in early stage breast cancer and all have shown equivalent survival rates regardless of the surgical treatment type. One caveat however is that the majority of studies had a restriction of tumor size; most were either 2 cm or 2.5 cm while the NSABP B-06 trial was 4 cm and the NCI trial was up to 5 cm. NSABP B-06, which is the largest of all the breast conservation trials, compared total mastectomy to lumpectomy with or without radiation therapy in the treatment of women with stage I and II breast cancer.11,204-210 After 5- and 8-year follow-up periods, the disease-free (DFS), distant disease-free, and overall survival (OS) rates for lumpectomy with or without radiation therapy were similar to those observed after total mastectomy. However, the incidence of ipsilateral breast cancer recurrence was higher in the group not receiving radiation therapy. These findings supported the use of lumpectomy and radiation therapy in the treatment of stage I and II breast cancer and this has since become the preferred method of treatment for women with early stage breast cancer who have unifocal disease and who are not known BRCA mutation carriers. Reanalysis of the B-06 study results was undertaken after 20 years of follow-up and confirmed that there was no difference in disease-free survival rates after total mastectomy or after lumpectomy with or without adjuvant radiation therapy. The in-breast recurrence rate was substantially higher in the lumpectomy alone group (39.2%) compared with the lumpectomy plus adjuvant radiation therapy group (14.3%) confirming the importance of radiation therapy in the management of patients with invasive disease. However it should be noted that there were several criteria in the B-06 study. There was a specific lymphadenopathy exclusion criteria. Secondly, all patients randomized to breast conserving surgery had a frozen section and if the margins were involved they were converted to mastectomy VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ include women 60 years of age or older with a unifocal, T1, ER-positive tumor with no lymphovascular invasion, and margins of at least 2 mm. They describe a group where there is uncertainty about the appropriateness of APBI (“cautionary” group) to include patients with invasive lobular histology, a tumor size of 2.1 cm to 3 cm, ER-negative disease, focal lymphovascular invasion, or margins less than 2 mm. Finally, a group felt to be “unsuitable” for APBI includes those with T3 or T4 disease, ER-negative disease, multifocality, multicentricity, extensive LVI, or positive margins. Currently, mastectomy with axillary staging and breast conserving surgery with axillary staging and radiation therapy are considered equivalent treatments for patients with stage I and II breast cancer. Breast conservation is considered for all patients because of the important cosmetic advantages and equivalent survival outcomes, however, this approach is not advised in women who are known BRCA mutation carriers due to the high lifetime risk for development of additional breast cancers. Relative contraindications to breast conservation therapy include (a) prior radiation therapy to the breast or chest wall, (b) persistently positive surgical margins after reexcision, (c) multicentric disease, and (d) scleroderma or lupus erythematosus. For most patients with early-stage disease, reconstruction can be performed immediately at the time of mastectomy. Immediate reconstruction allows for skin-sparing, thus optimizing cosmetic outcomes. Skin-sparing mastectomy with immediate reconstruction has been popularized over the past decade as reports of low local-regional failure rates have been reported and reconstructive techniques have advanced. There is a growing interest in the use of nipple-areolar sparing mastectomy although few reports on the long-term safety of this approach are available at this time. Patients who are planned for postmastectomy radiation therapy are not ideal candidates for nipple-sparing mastectomy because of the effects of radiation on the preserved nipple. In addition to providing optimal cosmesis from preservation of the skin and/or the nipple-areolar complex, immediate reconstruction allows patients to wake up with a breast mound which provides some psychological benefit for the patient. Immediate reconstruction is also more economical as both the extirpative and reconstructive surgery are combined in one operation. Immediate reconstruction can be performed using implants or autologous tissue; tissue flaps commonly used include the transverse rectus abdominis myocutaneous flap, deep inferior epigastric perforator flap, and latissimus dorsi flap (with or without an implant). If postmastectomy radiation therapy is needed, a tissue expander can be placed at the time of mastectomy to save the shape of the breast and reduce the amount of skin replacement needed at the time of definitive reconstruction. The expander can be deflated at the initiation of radiation therapy to allow for irradiation of the chest wall and regional nodal basins. Removal of the tissue expander and definitive reconstruction, usually with autologous tissue, can proceed 6 months to 1 year after completion of radiation therapy. Axillary lymph node status has traditionally been an important determinant in staging and prognosis for women with early stage breast cancer. Historically, axillary lymph node dissection (ALND) was utilized for axillary staging and regional control by removing involved lymph nodes. Randomized trials evaluating immediate ALND over ALND performed in a delayed fashion once clinically palpable axillary disease became evident have not shown any detriment in survival.9,215 With increased mammographic screening and detection of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 539 CHAPTER 17 The Breast but were included in the analysis as having had a breast conserving operation (on the basis of intention to treat). Finally, in the breast conserving group recurrences in the treated breast were considered as a ‘non event’. Data from all of the randomized trials where breast conservation was performed with or without radiation therapy have been examined by the EBCTCG.12 At 15 years of follow-up, the absolute reduction in mortality with the use of radiation therapy after lumpectomy was 5.1% in node-negative patients and 7.1% in node-positive patients. These data support the concept that the addition of radiation not only improves local control but also has an impact on survival. Similar to DCIS, clinicians have sought to identify subgroups of patients who may not benefit from the addition of radiation therapy, particularly older patients who may have a shorter life expectancy due to medical comorbidities. Two randomized trials have shown that in selected patients with small, low-grade tumors, lumpectomy alone without radiation therapy may be appropriate.211,212 The Cancer and Leukemia Group B (CALGB) C9343 trial enrolled women over the age of 70 with T1N0 breast cancer and randomized them to lumpectomy with or without radiation therapy. All patients received adjuvant tamoxifen. Although there were fewer local recurrences with radiation (1% vs. 4%, P<0.001), there were no differences in DFS and OS. A trial similar to CALGB C9343 was conducted in Canada where they enrolled women 50 years and older and randomized them to lumpectomy with or without radiation. Mean age was 68 years, and 80% of women had ER-positive tumors. Again, local recurrence rates were lower in women who received radiation (0.6% vs. 7.7%, P<0.001), however, at a median follow-up of 5.6 years, there were no differences in DFS or OS. These studies suggest that radiation can be avoided in early-stage breast cancer patients over the age of 70 when they are diagnosed with T1, N0, ER-positive breast cancer. Accelerated partial breast irradiation (APBI) is also an option for carefully selected patients with DCIS and earlystage breast cancer. Since the majority of recurrences after breast conservation occur in or adjacent to the tumor bed there has been interest in limiting the radiation to the area of the primary tumor bed with a margin of normal tissue. APBI is delivered in an abbreviated fashion (twice daily for 5 days) and at a lower total dose compared with the standard course of 5 to 6 weeks of radiation (50 Gray with or without a boost) in the case of whole breast irradiation. Proponents have suggested that this shortened course of treatment may increase the feasibility of breast conservation for some women and may improve radiation therapy compliance. The RTOG 04-13/ NSABP B-39 trial is a randomized comparison of whole breast irradiation to APBI in women with early stage breast cancer. The trial recently completed accrual and it will likely be several years before data are mature to report outcomes between the two radiation treatment strategies. TARGIT is another study which randomized 3,451 patients in 33 centers over 10 countries to intraoperative breast irradiation (IORT) or external beam radiotherapy (EBRT). The preliminary results were reported in 2012—with a median follow-up of 2.4 years use of IORT had a recurrence rate of 3.3% vs. 1.3% with EBRT, a 2% increased recurrence risk. 213 The American Society for Radiation Oncology (ASTRO) developed guidelines for the use of APBI outside of clinical trials based on data reported from published studies.214 The ASTRO guidelines describe patients “suitable” for APBI to 540 UNIT II PART SPECIFIC CONSIDERATIONS smaller, node-negative breast cancers, it became clear that routine use of ALND for axillary staging was not necessary in up to 75% percent of women with operable breast cancer presenting with a negative axilla at the time of screening. Lymphatic mapping and sentinel lymph node (SLN) dissection were initially developed for assessment of patients with clinically nodenegative melanoma. Given the changing landscape of newly diagnosed breast cancer patients with a clinically node-negative axilla, surgeons quickly began to explore the utility of SLN dissection as a replacement for ALND in axillary staging. In the early 1990s, David Krag at the University of Vermont began performing SLN dissection with injection of a radioisotope in the primary tumor site and localizing the SLN node with a handheld gamma probe.216 He was able to identify a SLN in 18 of 22 patients examined and the SLN was positive in all 7 patients with positive lymph nodes. Giuliano and colleagues initiated a pilot study in 1991 to examine the use of SLN dissection using blue dye in patients with clinically negative nodes. They reported successful identification of a SLN in 114 (65.5%) of 174 patients and in 109 (95.6%), the SLN accurately predicted the status of the axillary nodes.217,218 These studies along with initial work by Doug Reintgen and Charles Cox at the Moffitt Cancer Center and Umberto Veronesi and his colleagues at the European Institute of Oncology in Milan led the way toward validation of the technique in large single institution and multicenter studies. Following validation of the technique of SLN dissection for staging of the axilla by multiple centers, randomized trials were initiated in order to determine if SLN dissection could replace ALND in the contemporary management of breast cancer patients. The ALMANAC trial randomized 1,031 patients with primary operable breast cancer to SLN dissection vs. standard axillary surgery. The incidence of lymphedema and sensory loss for the SLN group was significantly lower than with the standard axillary treatment. At 12 months, drain usage, length of hospital stay, and time to resumption of normal day-today activities after surgery were also statistically significantly lower in the SLN group.219 The NSABP B-32 trial compared clinically node negative patients undergoing SLN dissection followed by ALND with patients undergoing SLN dissection with ALND only if a SLN was positive for metastatic disease.220 A total of 5,611 patients were randomized with a SLN identification rate of 97%, and a false-negative rate of 9.7%. A total of 26% of these clinically node-negative patients had a positive SLN. Over 60% of patients with positive SLNs had no additional positive lymph nodes within the ALND specimen. The B-32 trial and other randomized trials demonstrated no difference in DFS, OS, and local-regional recurrence rates between patients with negative SLNs who had SLN dissection alone compared with those who underwent ALND.221,222 Most important, patients who had SLN dissection alone were found to have decreased morbidity (arm swelling and range of motion) and improved quality of life vs. patients who underwent ALND.222,223 The American College of Surgeons Oncology Group (ACOSOG) initiated the Z0010 and Z0011 trials in order to evaluate the incidence and prognostic significance of occult metastases identified in the bone marrow and SLNs (Z0010) of early-stage node-negative patients and to evaluate the utility 9 clinically of ALND in patients with clinical T1-2, N0 breast cancer with 1 or 2 positive SLNs for patients treated with breast conserving surgery and whole breast irradiation (WBI) .224,225 The Z0010 study enrolled 5,539 patients with clinical T1-2 breast cancer planned for breast conserving surgery and WBI.224 There were 24% of patients who proved to have positive SLNs based on standard pathologic assessment and of the negative SLNs subjected to immunohistochemical staining for cytokeratin, 10.5% proved to have occult metastasis. Of the patients who had bone marrow aspiration, 3.0% had immunohistochemically detected tumor cells in the bone marrow. Although the presence of disease in the bone marrow identified a population at high risk for recurrence, neither immunohistochemical detection of disease in the SLNs or the bone marrow was statistically significant on multivariable analysis with clinicopathologic and treatment factors included. The investigators concluded that routine use of immunohistochemistry to detect occult disease in SLNs is not warranted. The Z0011 trial was a companion study to Z0010 and was designed to study the role of completion ALND on survival in women with positive SLNs. Patients were not eligible if they received neoadjuvant chemotherapy or neoadjuvant hormonal therapy or if their treatment plan included mastectomy, lumpectomy without radiation, or lumpectomy with APBI. WBI was to be administered using standard tangential fields without specific treatment of the axilla or additional fields targeting other nodal basins. Patients with 1 or 2 positive SLNs were randomized to completion ALND or no further surgery. Adjuvant systemic therapy recommendations were left to the treating clinicians. After median follow-up of 6.3 years, there was no difference between patients randomized to ALND and those randomized to no further surgery (SLN only) in terms of OS (91.9% and 92.5%, respectively; P=0.25) or DFS (82.2% and 83.8%, respectively; P=0.14). The morbidity of SLN dissection alone vs. SLN dissection with completion ALND has been reported by the ACOSOG investigators.226,227 Immediate effects of SLN dissection in the Z0010 trial included wound infection in 1%, axillary seroma in 7.1%, and axillary hematoma in 1.4%.226 At 6 months following surgery, axillary paresthesias were noted in 8.6% of patients, decreased range of motion in the upper extremity was reported in 3.8%, and 6.9% of patients had a change in the arm circumference of >2 cm on the ipsilateral side, which was reported as lymphedema. Younger patients were more likely to report paresthesias, whereas increasing age and body mass index were more predictive of lymphedema. When adverse surgical effects were examined in the Z0011 trial, patients undergoing SLN dissection with ALND had more wound infections, seromas, and paresthesias than those women undergoing SLN dissection alone. Lymphedema at one year after surgery was reported by 13% in the SLN plus ALND group but only 2% in the SLN dissection alone group. Arm circumference measurements were greater at one year in patients undergoing SLN dissection plus ALND, but the difference between study groups was not statistically significant.227 This supports the results published from the ALMANAC trial. Prior to the publication of ACOSOG Z0011, completion ALND was standard of care for patients with positive SLNs. Since the reporting of ACOSOG Z0011, the National Comprehensive Cancer Network (NCCN) guidelines now state that there was no OS difference for patients with 1 or 2 positive SLNs treated with breast conserving surgery who underwent completion ALND vs. those who had no further axillary surgery. In addition, the American Society of Breast Surgeons issued a consensus statement supporting omission of ALND for patients who meet Z0011 criteria.228 The results of ACOSOG Z0011 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ immediate ALND. With the findings of ACOSOG Z0011 that there is not a survival benefit to the use of ALND in selected patients, many surgeons have abandoned the intraoperative evaluation of SLNs. There are a number of nomograms and predictive models designed to determine which patients with a positive SLN are at risk for harboring additional positive nonSLNs in the axilla. These tools can be helpful in determining the likelihood of additional disease in the axilla and may be used clinically to counsel patients.231 In patients who present with axillary lymphadenopathy that is confirmed to be metastatic disease on FNA or core biopsy, SLN dissection is not necessary and patients can proceed directly to ALND or be considered for preoperative systemic therapy (see section on Neoadjuvant [Preoperative] Chemotherapy under Non-Surgical Breast Cancer Therapies). Initially there was controversy about the suitability of SLN dissection in women with larger primary tumors (T3) and those treated with neoadjuvant chemotherapy. The American Society of Clinical Oncology has included SLN dissection is its guidelines as appropriate for axillary staging in these patients.232 If a SLN cannot be identified, then ALND is generally performed for appropriate staging. However, this is not universally accepted and there are as yet no randomized studies which have assessed how a patient with a locally advanced cancer at presentation should be treated if their SLN dissection reveals no metastases or micrometastases after neoadjuvant therapy. Adjuvant chemotherapy for patients with early-stage invasive breast cancer is considered for patients with node-positive cancers, patients with cancers that are >1 cm, and patients with node-negative cancers of >0.5 cm when adverse prognostic features are present. Adverse prognostic factors include blood vessel or lymph vessel invasion, high nuclear grade, high histologic grade, HER-2/neu overexpression or amplification, and negative hormone receptor status. Adjuvant endocrine therapy is considered for women with hormone receptor-positive cancers, and use of an aromatase inhibitor is recommended if the patient is postmenopausal. There remains some debate as to whether patients should have 5 years of an aromatase inhibitor or two years of tamoxifen followed by 3 years of an aromatase inhibitor (the so called, ‘switch’ regime); the majority of clinicians appear to favor 5 years of an aromatase inhibitor, especially with increasing risk of recurrence. HER-2/neu status is determined for all patients with newly diagnosed invasive breast cancer and when positive, should be used to guide systemic therapy recommendations. Trastuzumab is the only HER-2/neu–targeted agent that is currently approved for use in the adjuvant setting. The FDA approved trastuzumab in November 2006 for use as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for treatment of HER-2/neu–positive, node-positive breast cancer.167,168 Subsequently, the BCIRG 006 study reported that giving trastuzumab concurrently with docetaxel and carboplatin appeared as effective as giving trastuzumab following an anthracycline containing regimen.169,170 Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB) Women with stage IIIA and IIIB breast cancer have advanced local-regional breast cancer but have no clinically detected distant metastases (Fig. 17-30).233 In an effort to provide optimal local-regional disease-free survival as well as distant diseasefree survival for these women, surgery is integrated with radiation therapy and chemotherapy (Fig. 17-31). However, it should VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 541 CHAPTER 17 The Breast have revolutionized management of the axilla and changed practice such that selected patients with axillary metastasis can now avoid ALND if they have clinical and pathologic features similar to those patients enrolled on Z0011. However, there have been some concerns raised about the Z0011 study which include the fact that the study only recruited about half of the intended patients and that there was no standardization of whether or not patients received irradiation to the low axilla when the radiation oncologist irradiated the breast. These issues have thus far limited the uptake of the results of Z0011 by some centers. The International Breast Cancer Study Group (IBCSG) 23-01 trial was similar in design to Z0011 but enrolled only patients with micrometastases in the SLNs. Patients with SLN micrometastases were randomized to ALND vs. no further surgery. Unlike Z0011, the 23-01 trial did not exclude patients treated with mastectomy. Approximately 9% of patients randomized to each study arm underwent mastectomy. The investigators published the primary and secondary endpoints of the trial showing no differences in OS or local-regional recurrence between the study arms.229 However, as with the Z0011 trial, some concerns have been raised regarding the 23-01 study. For example, in the statistics on the primary endpoint, local recurrence included contralateral breast cancer and other tumor types as events. No hypothesis was presented as to why the difference in axillary surgery should impact on either of these events. Including these events therefore reduced the power of the study to show a statistical difference between treatment arms. There is also concern that the study appears underpowered to show a meaningful difference in overall survival. Most pathology laboratories perform a more detailed analysis of the SLN than is routinely done for axillary nodes recovered from a level I and II dissection. This can include examining thin sections of the node with step sectioning at multiple levels through the paraffin blocks or performing immunohistochemical staining of the SLN for cytokeratin or a combination of these techniques. The results of ACOSOG Z0010 and NSABP B-32 showed no clinically meaningful difference in survival based on detection of occult metastases in the SLNs using immunohistochemical staining and do not support the routine use in SLN processing. The type of intraoperative assessment of SLNs also varies for different clinicians and pathology laboratories. Some centers prefer to use touch preparation cytologic analysis of the SLNs, whereas others use frozen-section analysis, and the sensitivity and specificity of these assays vary considerably. The GeneSearch Breast Lymph Node Assay is a real-time reversetranscriptase polymerase chain reaction assay that detects breast tumor cell metastasis in lymph nodes through the identification of the gene expression markers mammaglobin and cytokeratin 19. These markers are present in higher levels in breast tissue and not in nodal tissue (cell type-specific messenger RNA). The GeneSearch assay generates expression data for genes of interest, which are then evaluated against predetermined criteria to provide a qualitative (positive/negative) result. The assay is designed to detect foci that correspond to metastases which are seen with examination by standard hematoxylin and eosin staining and measure >0.2 mm. The GeneSearch assay results have been compared with permanent-section histologic analysis and frozen-section analysis of sentinel nodes in a prospective trial, and the assay was recently approved by the FDA for the intraoperative assessment of sentinel nodes.230 When a positive node is identified intraoperatively by touch preparation, frozen-section analysis, or GeneSearch assay, the surgeon can proceed with 542 UNIT II PART SPECIFIC CONSIDERATIONS A B Figure 17-30. Locally advanced breast cancer. A. Mammography of the right breast reveals a large tumor with enlarged axillary lymph nodes. B. Imaging of the left breast is normal. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) be noted that most of these patients will already have distant metastasis which is often highlighted by radiological evidence when bone scans, PET &/or CT scans are performed. Even when they are negative, elevated serum tumor markers may be another indicator that distant spread has already occurred. The paradigm therefore which is appropriate for small screen detected cancers where cure can be expected in >90% of patients, often by local treatment alone is not the same clinical scenario as with locally advanced disease. Indeed, a previous randomized study of neoadjuvant therapy followed by modified radical mastectomy, post-operative radiotherapy and endocrine therapy vs. primary endocrine therapy followed by sequential therapy on progression of disease showed no difference in either overall survival or uncontrolled local disease at death.234 Preoperative (also known as neoadjuvant) chemotherapy should be considered in the initial management of patients with locally advanced stage III breast cancer, especially those with estrogen receptor negative tumors. For selected clinically indolent, Figure 17-31. Treatment pathways for stage IIIA and stage IIIB breast cancer. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ estrogen receptor positive, locally advanced tumors, primary endocrine therapy may be considered, especially if the patient has other co-morbid conditions. A series of 195 patients with ER-positive locally advanced breast cancer treated by endocrine therapy—median age 69 years, median tumor size 6 cm, median follow-up 61 months—reported a five year overall survival of 76%, a breast cancer specific survival of 86%, and a metastasis free survival of 77%. The median time to an alternative treatment was 48 months.235 Given that this was a 20-year series, the number of such patients is small but should be considered when the clinician is discussing treatment options. Surgical therapy for women with stage III disease is usually a modified radical mastectomy, followed by adjuvant radiation therapy. Chemotherapy is used to maximize distant disease-free survival, whereas radiation therapy is used to maximize local-regional control and disease-free survival. In selected patients with stage IIIA cancer, preoperative chemotherapy can reduce the size of the primary cancer and permit breast-conserving surgery. Investigators from the MD Anderson Cancer Center reported that low localregional failure rates could be achieved in selected patients with stage III disease treated with preoperative chemotherapy followed by breast-conserving surgery and radiation.236 The 5-year actuarial ipsilateral breast tumor recurrence-free survival rates in this study were 95%. They noted that the ipsilateral breast tumor recurrence rates increased when patients had clinical N2 or N3 disease, >2 cm of residual disease in the breast at surgery, a pattern of multifocal residual disease in the breast at surgery, and lymphovascular space invasion in the primary tumor. This study demonstrates that breast-conserving surgery can be used for appropriately selected patients with locally advanced breast cancer who achieve a good response with preoperative chemotherapy. However, the Oxford overview of all randomized studies of neoadjuvant therapy (vs. adjuvant therapy) reported a hazard ratio of 1.5 (i.e., 50% increase) in local recurrence rates. A meta-analysis reported a hazard ratio of 1.3.237 These findings are important in view of the previous findings that the avoidance of recurrence in a conserved breast avoids about one breast cancer death over the next 15 years for every four such recurrences avoided.12 Furthermore, the German Breast Cancer Group recently reported their local recurrence rate in 5,535 patients in seven studies. With a median of 46 months (range 1–127) follow-up the local recurrence rates ranged from 7.6% to 19.5% for T1-T4 tumors and from 6.4%–17.9% for N0-N3 tumors treated with neoadjuvant therapy.238 Therefore, this is an important issue which needs to be addressed in future locally advanced and neoadjuvant studies. For patients with stage IIIA disease who experience minimal response to chemotherapy and for patients with stage IIIB breast cancer, preoperative chemotherapy can decrease the local-regional cancer burden enough to permit subsequent modified radical mastectomy to establish local-regional control. In both stage IIIA and IIIB disease, surgery is followed by adjuvant radiation therapy. However there is a small percentage of patients who experience progression of disease during neoadjuvant therapy and therefore the surgeon should review patients with the oncologist at regular points during the neoadjuvant regimen. internal mammary lymph node radiation therapy in women who are at increased risk for occult involvement (cancers involving the medial aspect of the breast, axillary lymph node involvement) but who show no signs of internal mammary lymph node involvement. Systemic chemotherapy and radiation therapy are indicated in the treatment of grossly involved internal mammary lymph nodes. Internal Mammary Lymph Nodes Women with local-regional recurrence of breast cancer may be separated into two groups: those who have had mastectomy and those who have had lumpectomy. Women treated previously with mastectomy undergo surgical resection of the local-regional recurrence and appropriate reconstruction. Distant Metastases (Stage IV) Treatment for stage IV breast cancer is not curative but may prolong survival and enhance a woman’s quality of life.239 Endocrine therapies that are associated with minimal toxicity are preferred to cytotoxic chemotherapy in estrogen receptor positive disease. Appropriate candidates for initial endocrine therapy include women with hormone receptor-positive cancers who do not have immediately life threatening disease (or ‘visceral crisis’). This includes not only women with bone or soft tissue metastases but also women with limited visceral metastases. Symptoms per se (e.g., breathlessness) are not in themselves an indication for chemotherapy. For example, breathlessness due to a pleural effusion can be treated with percutaneous drainage and if the breathlessness is relieved the patient should be commenced on endocrine therapy whereas if the breathlessness is due to lymphangitic spread then chemotherapy would be the treatment of choice. The same approach should be taken to other symptoms such as pain. Systemic chemotherapy is indicated for women with hormone receptor-negative cancers, ‘visceral crisis’, and hormone-refractory metastases. Women with stage IV breast cancer may develop anatomically localized problems that will benefit from individualized surgical or radiation treatment, such as brain metastases, pleural effusion, pericardial effusion, biliary obstruction, ureteral obstruction, impending or existing pathologic fracture of a long bone, spinal cord compression, and painful bone or soft tissue metastases. Bisphosphonates, which may be given in addition to chemotherapy or endocrine therapy, should be considered in women with bone metastases. Whether to perform surgical resection of the local-regional disease in women with stage IV breast cancer has been debated after several reports have suggested that women who undergo resection of the primary tumor have improved survival over those who do not. Khan and associates used the National Cancer Data Base to identify patterns of treatment in women with metastatic breast cancer and found that those who had surgical resection with negative margins had a better prognosis than those women who did not have surgical therapy.240 Gnerlich et al reported similar findings using the SEER database, and there have been several reports subsequent to this study from single institutions that have confirmed these findings.241 Some have suggested that the finding of improved survival is due to selection bias and that local therapy should be reserved for palliation of symptoms. A randomized trial is currently underway through ECOG to address this question. In the meantime, surgical management of patients with stage IV disease should be addressed by obtaining multidisciplinary input and by considering the treatment goals of each individual patient and the patient’s treating physicians. Local-Regional Recurrence VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast Metastatic disease to internal mammary lymph nodes may be occult, may be evident on chest radiograph or CT scan, or may present as a painless parasternal mass with or without skin involvement. There is no consensus regarding the need for 543 544 Chemotherapy and antiestrogen therapy are considered, and adjuvant radiation therapy is given if the chest wall has not previously received radiation therapy or if the radiation oncologist feels that given the time from previous treatment there is scope for further radiation therapy, particularly if this is palliative. Women treated previously with a breast conservation procedure undergo a mastectomy and appropriate reconstruction. Chemotherapy and antiestrogen therapy are considered. Breast Cancer Prognosis UNIT II PART SPECIFIC CONSIDERATIONS Survival rates for women diagnosed with breast cancer in the United States can be obtained from the SEER Program of the National Cancer Institute. Data have been collected since 1973 and is updated at regular intervals. The overall 5-year relative survival for breast cancer patients from the time period of 2003–2009 from 18 SEER geographic areas was 89.2%. The 5-year relative survival by race was reported to be 90.4% for white women and 78.7% for black women. The 5-year survival rate for patients with localized disease (61% of patients) is 98.6%; for patients with regional disease (32% of patients), 84.4%; and for patients with distant metastatic disease (5% of patients), 24.3%. Breast cancer survival has significantly increased over the past two decades due to improvements in screening and local and systemic therapies. Data from the American College of Surgeons National Cancer Data Base can also be accessed and reports survival based on stage of disease at presentation using the AJCC staging system. SURGICAL TECHNIQUES IN BREAST CANCER THERAPY Excisional Biopsy with Needle Localization Excisional biopsy implies complete removal of a breast lesion with a margin of normal-appearing breast tissue. In the past, surgeons would obtain prior consent from the patient allowing mastectomy if the initial biopsy results confirmed cancer. Today it is A important to consider the options for local therapy (lumpectomy vs. mastectomy with or without reconstruction) and the need for nodal assessment with SLN dissection. Needle core biopsy is the preferred diagnostic method and excisional biopsy should be reserved for those cases where the needle biopsy results are discordant with the imaging findings or clinical examination (Fig. 17-32). In general circumareolar incisions can be used to access lesions which are subareolar or within a short distance of the nipple-areolar complex. Elsewhere in the breast, incisions should be placed which are in the lines of tension in the skin that are generally concentric with the nipple-areola complex. In the lower half of the breast, the use of radial incisions typically provides the best outcome. When the tumor is quite distant from the central breast, the biopsy incision can be excised separately from the primary mastectomy incision, should a mastectomy be required. Radial incisions in the upper half of the breast are not recommended because of possible scar contracture resulting in displacement of the ipsilateral nipple-areola complex. Similarly, curvilinear incisions in the lower half of the breast may displace the nipple-areolar complex downward. After excision of a suspicious breast lesion, the specimen should be x-rayed to confirm the lesion has been excised with appropriate margins. The biopsy tissue specimen is orientated for the pathologist using sutures, clips, or dyes. Additional margins (superior, inferior, medial, lateral, superficial, and deep) may be taken from the surgical bed if the specimen x-ray shows the lesion is close to one or more margins. Some surgeons also take additional shavings from the margins as one approach to confirm complete excision of the suspicious lesion. Electrocautery or absorbable ligatures are used to achieve wound hemostasis. Cosmesis may be facilitated by approximation of the surgical defect using 3-0 absorbable sutures. A running subcuticular closure of the skin using 4-0 or 5-0 absorbable monofilament sutures is performed. Wound drainage is usually not required. Excisional biopsy with needle localization requires a preoperative visit to the mammography suite for placement of a Figure 17-32. Lesion to be targeted to excisional biopsy. A. Craniocaudal view of the left breast demonstrating 2 lesions (arrows) to be targeted for needle localization and excision. B. Oblique view demonstrating target lesions. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) B VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 545 CHAPTER 17 The Breast A B Figure 17-33. Wire localization procedure. Mammographic images of hookwire in place targeting lesions for excision in the left breast (A) and the right breast (B). (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) localization wire or a radiolabeled seed that can be detected intraoperatively with a handheld probe. The lesion can also be targeted by sonography in the imaging suite or in the operating room. The lesion to be excised is accurately localized by mammography, and the tip of a thin wire hook is positioned close to the lesion (Fig. 17-33). Using the wire hook as a guide, the surgeon subsequently excises the suspicious breast lesion while removing a margin of normal-appearing breast tissue. Before the patient leaves the operating room, specimen radiography is performed to confirm complete excision of the suspicious lesion (Fig. 17-34). Sentinel Lymph Node Dissection Sentinel lymph node (SLN) dissection is primarily used to assess the regional lymph nodes in women with early breast cancers who are clinically node negative by physical examination and imaging studies.242-250 This method also is accurate in 9 women with larger tumors (T3 N0), but nearly 75% of these women will prove to have axillary lymph node metastases on histologic examination and wherever possible it is better to identify them preoperatively as this will allow a definitive procedure for known axillary disease. SLN dissection has also been reported to be accurate for staging of the axilla after chemotherapy in women with clinically node-negative disease at initial presentation.251,252 Tan et al in a review and meta-analysis of 449 cases of SLN biopsy in clinically lymph node negative disease reported a sensitivity of 93% giving a false negative rate of 7% with a negative predictive value of 94% and an overall accuracy of 95%.253 Clinical situations where SLN dissection is not recommended include patients with inflammatory breast cancers, those with palpable axillary lymphadenopathy and biopsy proven metastasis, DCIS without mastectomy, or prior axillary surgery. Although limited data are available, SLN dissection appears to be safe in pregnancy when performed with radioisotope alone. Evidence from large prospective studies suggests that the combination of intraoperative gamma probe detection of radioactive colloid and intraoperative visualization of blue dye (isosulfan blue dye or methylene blue) is more accurate for identification of SLNs than the use of either agent alone. Some surgeons use preoperative lymphoscintigraphy, although it is not required for identification of the SLNs. On the day before surgery, or the day of surgery, the radioactive colloid is injected either in the breast parenchyma around the primary tumor or prior biopsy site, into the subareolar region, or subdermally in proximity to the primary tumor site. With a 25-gauge needle, 0.5 mCi of 0.2-μm technetium 99m–labeled sulfur colloid is injected for same-day surgery or a higher dose of 2.5 mCi of technetium-labeled sulfur colloid is administered when the isotope is to be injected on the day before surgery. Subdermal injections are given in proximity to the cancer site or in the subareolar location. Later, in the operating room, 3 to 5 mL of blue dye is injected either in the breast parenchyma or in the subareolar location. It is not recommended that the blue dye be used in a subdermal injection because this can result in tattooing of the skin (isosulfan blue dye) or skin necrosis (methylene blue). For nonpalpable cancers, the injection of the technetiumlabeled sulfur colloid solution can be guided by ultrasound or by mammographic guidance. It is helpful for the radiologist to mark the skin overlying the breast cancer at the time of needle localization using an indelible marker. In women who have undergone previous excisional biopsy, the injections are made in the breast parenchyma around the biopsy cavity but not into the cavity itself. Women are told preoperatively that the isosulfan blue dye injection will cause a change in the color of their urine and that there is a very small risk of allergic reaction to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 546 UNIT II PART SPECIFIC CONSIDERATIONS A B C Figure 17-34. Specimen mammography. Specimen mammograms demonstrating excision of targeted (A) density, (B) calcifications, and (C) spiculated mass seen on preoperative imaging. (Photos used with permission of Dr. Anne Turnbull, Consultant Radiologist/ Director of Breast Screening, Royal Derby Hospital, Derby, UK.) the dye (1 in 10,000). Anaphylactic reactions have been documented and some groups administer a regimen of antihistamine, steroids, and a histamine H-2 receptor antagonist preoperatively as a prophylactic regimen to prevent allergic reactions. The use of radioactive colloid is safe, and radiation exposure is very low. Sentinel node dissection can be performed in pregnancy with the radioactive colloid without the use of blue dye. A hand-held gamma counter is used to transcutaneously identify the location of the SLN. This can help to guide placement of the incision. A 3- to 4-cm incision is made in line with that used for an axillary dissection, which is a curved transverse incision in the lower axilla just below the hairline. After dissecting through the subcutaneous tissue, the surgeon dissects through the axillary fascia, being mindful to identify blue lymphatic channels. Following these channels can lead directly to the SLN and limit the amount of dissection through the axillary tissues. The gamma probe is used to facilitate the dissection and to pinpoint the location of the SLN. As the dissection continues, the signal from the probe increases in intensity as the SLN is approached. The SLN also is identified by visualization of blue dye in the afferent lymph vessel and in the lymph node itself. Before the SLN is removed, a 10-second in vivo radioactivity count is obtained. After removal of the SLN, a 10-second ex vivo radioactive count is obtained, and the node is then sent to the pathology laboratory for either permanent- or frozen-section analysis. The lowest false-negative rates for SLN dissection have been obtained when all blue lymph nodes and all lymph nodes with counts >10% of the 10-second ex vivo count of the SLN are harvested (“10% rule”). Based on this, the gamma counter is used before closing the axillary wound to measure residual radioactivity in the surgical bed. A search is made for additional SLNs if the counts remain high. This procedure is repeated until residual radioactivity in the surgical bed is less than 10% of the 10-second ex vivo count of the most radioactive SLN and all blue nodes have been removed. Studies have demonstrated that 98% of all positive SLNs will be recovered with the removal of four SLNs, therefore it is not necessary to remove greater than four SLNs for accurate staging of the axilla. Results from the NSABP B-32 trial showed that the falsenegative rate for SLN dissection is influenced by tumor location, type of diagnostic biopsy, and number of SLNs removed at surgery.220 The authors reported that tumors located in the lateral breast were more likely to have a false-negative SLN. This may be explained by difficulty in discriminating the hot spot in the axilla when the radioisotope has been injected at the primary tumor site in the lateral breast. Those patients who had undergone an excisional biopsy before the SLN procedure were significantly more likely to have a false-negative SLN. This report further confirms that surgeons should use needle biopsy for diagnosis whenever possible and reserve excisional biopsy for the rare situations in which needle biopsy findings are nondiagnostic or discordant. Finally, removal of a larger number of SLNs at surgery appears to reduce the false-negative rate. In B-32, the false-negative rate was reduced from 17.7% to 10% when two SLNs were recovered and to 6.9% when three SLNs were removed. Yi and associates reported that the number of SLNs that need to be removed for accurate staging is influenced by individual patient and primary tumor factors.254 In the B-32 trial, SLNs were identified outside the level I and II axillary nodes in 1.4% of cases. This was significantly influenced by the site of radioisotope injection. When a subareolar or periareolar injection site was used, there were no instances VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Breast Conservation Breast conservation involves resection of the primary breast cancer with a margin of normal-appearing breast tissue, adjuvant radiation therapy, and assessment of regional lymph node status.256,257 Resection of the primary breast cancer is alternatively called segmental mastectomy, lumpectomy, partial mastectomy, wide local excision, and tylectomy. For many women with stage I or II breast cancer, breast-conserving therapy (BCT) is preferable to total mastectomy because BCT produces survival rates equivalent to those after total mastectomy while preserving the breast.258 Six prospective randomized trials have shown that overall and disease-free survival rates are similar with BCT and mastectomy, however three of the studies showed higher local-regional failure rates in patients undergoing BCT. In two of these studies, there were no clear criteria for histologically negative margins.12,256-258 Data from the EBCTCG meta-analysis revealed that the addition of radiation reduces recurrence by half and improves survival at year 15 by about a sixth.259 When all of this information is taken together, BCT is considered to be oncologically equivalent to mastectomy. In addition to being equivalent to mastectomy in terms of oncologic safety, BCT appears to offer advantages over mastectomy with regard to quality of life and aesthetic outcomes. BCT allows for preservation of breast shape and skin as well as preservation of sensation, and provides an overall psychologic advantage associated with breast preservation. Breast conservation surgery is currently the standard treatment for women with stage 0, I, or II invasive breast cancer. Women with DCIS require only resection of the primary cancer and adjuvant radiation therapy without assessment of regional lymph nodes. When a lumpectomy is performed, a curvilinear incision lying concentric to the nipple-areola complex is made in the skin overlying the breast cancer when the tumor is in the upper aspect of the breast. Radial incisions are preferred when the tumor is in the lower aspect of the breast. Skin excision is not necessary unless there is direct involvement of the overlying skin by the primary tumor. The breast cancer is removed with an envelope of normal-appearing breast tissue that is adequate to achieve a cancer-free margin. Significant controversy exists on the appropriate margin width for BCT.260 Specimen x-ray should routinely be performed to confirm the lesion has been excised and that there appears to be an appropriate margin. Specimen orientation is performed by the surgeon. Additional margins from the surgical bed are taken as needed to provide a histologically negative margin. Requests for determination of ER, PR, and HER-2 status are conveyed to the pathologist. It is the surgeon’s responsibility to ensure complete removal of cancer in the breast. Ensuring surgical margins that are free of breast cancer will minimize the chances of local recurrence and will enhance cure rates. Local recurrence of breast cancer after conservation surgery is determined primarily by the adequacy of surgical margins. Cancer size and the extent of skin excision are not significant factors in this regard. It is the practice of many North American and European surgeons to undertake re-excision when residual cancer within 2 mm of a surgical margin is determined by histopathologic examination. If clear margins are not obtainable with re-excision, mastectomy is required. SLN is performed before removal of the primary breast tumor. When indicated, intraoperative assessment of the sentinel node can proceed while the segmental mastectomy is being performed. The use of oncoplastic surgery can be entertained at the time of segmental mastectomy or at a later time to improve the overall aesthetic outcome. The use of oncoplastic techniques range from a simple re-shaping of breast tissue to local tissue rearrangement to the use of pedicled flaps or breast reduction techniques. The overall goal is to achieve the best possible aesthetic result. In determining which patients are candidates for oncoplastic breast surgery, several factors should be considered, including the extent of the resection of breast tissue necessary to achieve negative margins, the location of the primary tumor within the breast, and the size of the patient’s breast and body habitus. Oncoplastic techniques are of prime consideration when: (a) a significant area of breast skin will need to be resected with the specimen to achieve negative margins; (b) a large volume of breast parenchyma will be resected resulting in a significant defect; (c) the tumor is located between the nipple and the inframammary fold, an area often associated with unfavorable cosmetic outcomes; or (d) excision of the tumor and closure of the breast may result in malpositioning of the nipple. Mastectomy and Axillary Dissection A skin-sparing mastectomy removes all breast tissue, the nipple-areola complex, and scars from any prior biopsy procedures.261,262 There is a recurrence rate of less than 6% to 8%, comparable to the long-term recurrence rates reported with standard mastectomy, when skin-sparing mastectomy is used for patients with Tis to T3 cancers. A total (simple) mastectomy without skin sparing removes all breast tissue, the nipple-areola complex, and skin. An extended simple mastectomy removes all breast tissue, the nipple-areola complex, skin, and the level I axillary lymph nodes. A modified radical (‘Patey’) mastectomy removes all breast tissue, the nipple-areola complex, skin, and the levels I, II and III axillary lymph nodes: the pectoralis minor which was divided and removed by Patey may be simply divided, giving improved access to level III nodes, and then left in-situ or occasionally the axillary clearance can be performed without dividing pectoralis minor. The Halsted radical mastectomy removes all breast tissue and skin, the nipple-areola complex, the pectoralis major and pectoralis minor muscles, and the level I, II, and III axillary lymph nodes. The use of systemic chemotherapy and hormonal therapy as well as adjuvant radiation therapy for breast cancer have nearly eliminated the need for the radical mastectomy. Nipple-areolar sparing mastectomy has been popularized over the last decade especially for risk-reducing mastectomy in high risk women. For those patients with a cancer diagnosis, many consider the following factors for eligibility: tumor located more than 2–3 cm from the border of the areola, smaller breast size, minimal ptosis, no prior breast surgeries with VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 547 CHAPTER 17 The Breast of SLNs identified outside the level I or II axilla, compared with a rate of 20% when a peritumoral injection was used. This supports the overall concept that the SLN is the first site of drainage from the lymphatic vessels of the primary tumor. Although many patients will have similar drainage patterns from injections given at the primary tumor site and at the subareolar plexus, some patients will have extra-axillary drainage, either alone or in combination with axillary node drainage, and this is best assessed with a peritumoral injection of the radioisotope. Kong et al reported that internal mammary node drainage on preoperative lymphoscintigraphy was associated with worse distant disease-free survival in early-stage breast cancer patients.255 548 UNIT II PART SPECIFIC CONSIDERATIONS Figure 17-35. Modified radical mastectomy: elevation of skin flaps. Skin flaps are 7 to 8 mm in thickness, inclusive of the skin and telasubcutanea. (Visual Art: © 2012. The University of Texas MD Anderson Cancer Center.) periareolar incisions, body mass index less than 40 kg/m2, no active tobacco use, no prior breast irradiation, and no evidence of collagen vascular disease. For a variety of biologic, economic, and psychosocial reasons, some women desire mastectomy rather than breast conservation. Women who are less concerned about cosmesis may view mastectomy as the most expeditious and desirable therapeutic option because it avoids the cost and inconvenience of radiation therapy. Some women whose primary breast cancers cannot be excised with a reasonable cosmetic result or those who have extensive microcalcifications are best treated with mastectomy. Similarly women with large cancers that occupy the subareolar and central portions of the breast and women with multicentric primary cancers also undergo mastectomy. Modified Radical Mastectomy A modified radical mastectomy preserves the pectoralis major muscle with removal of level I, II, and III (apical) axillary lymph nodes.261 The operation was first described by David Patey, a surgeon at St Bartholomew’s Hospital London, who reported a series of cases where he had removed the pectoralis minor muscle allowing complete dissection of the level III axillary lymph nodes while preserving the pectoralis major and the lateral pectoral nerve. A modified radical mastectomy permits preservation of the medial (anterior thoracic) pectoral nerve, which courses in the lateral neurovascular bundle of the axilla and usually penetrates the pectoralis minor to supply the lateral border of the pectoralis major. Anatomic boundaries of the modified radical mastectomy are the anterior margin of the latissimus dorsi muscle laterally, the midline of the sternum medially, the subclavius muscle superiorly, and the caudal extension of the breast 2 to 3 cm inferior to the inframammary fold inferiorly. Skin-flap thickness varies with body habitus but ideally is 7 to 8 mm inclusive of skin and telasubcutanea (Fig. 17-35). Once the skin flaps are fully developed, the fascia of the pectoralis major muscle and the overlying breast tissue are elevated off the underlying musculature, which allows for the complete removal of the breast (Fig. 17-36). Subsequently, an axillary lymph node dissection is performed. The most lateral extent of the axillary vein is identified and the areolar tissue of the lateral axillary space is elevated as the vein is cleared on its anterior and inferior surfaces. The areolar tissues at the junction of the axillary vein and the anterior edge of the latissimus dorsi muscle, which include the lateral and subscapular lymph node groups (level I), are cleared. Care is taken to preserve the thoracodorsal neurovascular bundle. Figure 17-36. Modified radical mastectomy after resection of breast tissue. The pectoralis major muscle is cleared of its fascia as the overlying breast is elevated. The latissimus dorsi muscle is the lateral boundary of the dissection. (Visual Art: © 2012.The University of Texas MD Anderson Cancer Center.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 549 CHAPTER 17 The Breast Figure 17-37. Modified radical mastectomy (Patey): axillary lymph node dissection. The dissection proceeds from lateral to medial, with complete visualization of the anterior and inferior aspects of the axillary vein. Loose areolar tissue at the junction of the axillary vein and the anterior margin of the latissimus dorsi muscle is swept inferomedially inclusive of the lateral (axillary) lymph node group (level I). Care is taken to preserve the thoracodorsal artery, vein, and nerve in the deep axillary space. The lateral lymph node group is resected in continuity with the subscapular lymph node group (level I) and the external mammary lymph node group (level I). Dissection anterior to the axillary vein allows removal of the central lymph node group (level II) and the apical (subclavicular) lymph node group (level III). The superomedial limit of this dissection is the clavipectoral fascia (Halsted’s ligament). Inset depicts division of the insertion of the pectoralis minor muscle at the coracoid process. The surgeon’s finger shields the underlying brachial plexus. (Reproduced with permission from Bland KI, et al. Modified radical mastectomy and total (simple) mastectomy. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: Saunders, 2009. Copyright Elsevier.) The dissection then continues medially with clearance of the central axillary lymph node group (level II). The long thoracic nerve of Bell is identified and preserved as it travels in the investing fascia of the serratus anterior muscle. Every effort is made to preserve this nerve, because permanent disability with a winged scapula and shoulder weakness will follow denervation of the serratus anterior muscle. Patey divided the pectoralis minor and removed it to allow access right up to the apex of the axilla. The pectoralis minor muscle is usually divided at the tendinous portion near its insertion onto the coracoid process (Fig. 17-37 inset), which allows dissection of the axillary vein medially to the costoclavicular (Halsted’s) ligament. Finally, the breast and axillary contents are removed from the surgical bed and are sent for pathologic assessment. In Patey’s modified radical mastectomy he removed the pectoralis minor muscle. Many surgeons now divide only the tendon of the pectoralis minor muscle at its insertion onto the coracoid process while leaving the rest of the muscle intact, which still provides good access to the apex of the axilla. Seromas beneath the skin flaps or in the axilla represent the most frequent complication of mastectomy and axillary lymph node dissection, reportedly occurring in as many as 30% of cases. The use of closed-system suction drainage reduces the incidence of this complication. Catheters are retained in the wound until drainage diminishes to <30 mL per day. Wound infections occur infrequently after a mastectomy and the majority are a result of skin-flap necrosis. Cultures of specimens taken from the infected wound for aerobic and anaerobic organisms, débridement, and antibiotic therapy are effective management. Moderate or severe hemorrhage in the postoperative period is rare and is best managed with early wound exploration for control of hemorrhage and re-establishment of closed-system suction drainage. The incidence of functionally significant lymphedema after a modified radical mastectomy is approximately 20% but can be as high as 50% to 60% when postoperative radiation is employed. Extensive axillary lymph node dissection, the delivery of radiation therapy, the presence of pathologic lymph nodes, and obesity are predisposing factors. Patients should be referred to physical therapy at the earliest signs of lymphedema to prevent progression to the later stages. The use of individually fitted compressive sleeves and complex decongestive therapy may be necessary. Reconstruction of the Breast and Chest Wall The goals of reconstructive surgery after a mastectomy for breast cancer are wound closure and breast reconstruction, which is either immediate or delayed.263 In most cases, wound closure after mastectomy is accomplished with simple approximation of the wound edges. However, if a more radical removal of skin and subcutaneous tissue is necessary, a pedicled myocutaneous flap from the latissimus dorsi muscle is generally the best approach for wound coverage. A skin graft provides functional coverage that will tolerate adjuvant radiation therapy; however, this is not preferred, because poor graft adherence may delay delivery of radiation therapy. Breast reconstruction after riskreducing mastectomy or after mastectomy for early-stage breast cancer may be performed at the same time as the mastectomy. This allows for a skin-sparing mastectomy to be performed, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 550 UNIT II PART SPECIFIC CONSIDERATIONS which offers the best overall cosmetic outcomes. Reconstruction can proceed with an expander/implant reconstruction or with autologous tissue such as a pedicled myocutaneous flap or a free flap using microvascular techniques. In patients with locally advanced breast cancer, reconstruction is often delayed until after completion of adjuvant radiation therapy to ensure that local-regional control of disease is obtained. The expected use of postmastectomy radiotherapy should also be considered as a reason for delayed reconstruction as radiotherapy to a reconstructed breast has been reported to result in inferior cosmetic outcomes. Consideration can be made for placement of a tissue expander to allow for skin-sparing but this should be discussed with the radiation oncologist and other members of the treatment team. If chest wall coverage is needed to replace a large skin or soft tissue defect, many different types of myocutaneous flaps are employed, but the latissimus dorsi and the rectus abdominis myocutaneous flaps are most frequently used. The latissimus dorsi myocutaneous flap consists of a skin paddle based on the underlying latissimus dorsi muscle, which is supplied by the thoracodorsal artery with contributions from the posterior intercostal arteries. A transverse rectus abdominis myocutaneous (TRAM) flap consists of a skin paddle based on the underlying rectus abdominis muscle, which is supplied by vessels from the deep inferior epigastric artery. The free TRAM flap uses microvascular anastomoses to establish blood supply to the flap. When the bony chest wall is involved with cancer, resection of a portion of the bony chest wall is indicated. If only one or two ribs are resected and soft tissue coverage is provided, reconstruction of the bony defect is usually not necessary, because scar tissue will stabilize the chest wall. If more than two ribs are sacrificed, it is advisable to stabilize the chest wall with prosthetic material, which is then covered with soft tissue by using a latissimus dorsi or TRAM flap. NONSURGICAL BREAST CANCER THERAPIES Radiation Therapy Radiation therapy is used for all stages of breast cancer depending on whether the patient is undergoing BCT or mastectomy.264-270 Adjuvant radiation for patients with DCIS and early-stage breast cancer are described above. Those women treated with mastectomy who have cancer at the surgical margins are at sufficiently high risk for local recurrence to warrant the use of adjuvant radiation therapy to the chest wall postoperatively. Women with metastatic disease involving four or more axillary lymph nodes and premenopausal women with metastatic disease involving one to three lymph nodes also are at increased risk for recurrence and are candidates for the use of chest wall and supraclavicular lymph node radiation therapy. In advanced local-regional breast cancer (stage IIIA or IIIB), women are at high risk for recurrent disease after surgical therapy, and adjuvant radiation therapy is used to reduce the risk of recurrence. Current recommendations for stages IIIA and IIIB breast cancer are: (a) adjuvant radiation therapy to the breast and supraclavicular lymph nodes after neoadjuvant chemotherapy and segmental mastectomy with or without axillary lymph node dissection, (b) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after neoadjuvant chemotherapy and mastectomy with or without axillary lymph node dissection, and (c) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after segmental mastectomy or mastectomy with axillary lymph node dissection and adjuvant chemotherapy. The use of partial breast irradiation (APBI) for patients treated with breast-conserving surgery is also described above. APBI can be delivered via brachytherapy, external beam radiation therapy using three-dimensional conformal radiation, or intensity-modulated radiation therapy. Although initial results are promising in highly selected low-risk populations, APBI should be used in the clinical setting only as part of a prospective trial. Chemotherapy Adjuvant Chemotherapy. The Early Breast Cancer Trialists’ Collaborative Group overview analysis of adjuvant chemotherapy demonstrated reductions in the odds of recurrence and of death in women ≤70 years of age with stage I, IIA, or IIB breast cancer.118,271-275 For those ≥70 years of age, the lack of definitive clinical trial data regarding adjuvant chemotherapy prevented definitive recommendations. Adjuvant chemotherapy is of minimal benefit to women with negative nodes and cancers ≤0.5 cm in size and is not recommended. Women with negative nodes and cancers 0.6 to 1.0 cm are divided into those with a low risk of recurrence and those with unfavorable prognostic features that portend a higher risk of recurrence and a need for adjuvant chemotherapy. Adverse prognostic factors include blood vessel or lymph vessel invasion, high nuclear grade, high histologic grade, HER-2/neu overexpression, and negative hormone receptor status. Adjuvant chemotherapy is recommended by the NCCN guidelines for women with these unfavorable prognostic features. Table 17-14 lists the frequently used chemotherapy regimens for breast cancer. For women with hormone receptor-negative cancers that are >1 cm in size, adjuvant chemotherapy is appropriate. However, women with node-negative hormone receptor–positive cancers and T1 tumors are candidates for antiestrogen therapy with or without chemotherapy. Assessment of overall risk using known prognostic factors or additional testing such as the 21-gene recurrence score assay can help to guide decision making regarding chemotherapy in patients with node-negative ER-positive breast cancer. For special-type cancers (tubular, mucinous, medullary, etc), which are usually strongly estrogen receptor positive, adjuvant antiestrogen therapy should be advised for cancers >1 cm. For women with node-positive tumors or with a special-type cancer that is >3 cm, the use of chemotherapy is appropriate: those with hormone receptorpositive tumors should receive antiestrogen therapy. For stage IIIA breast cancer preoperative chemotherapy with an anthracycline-containing or taxane-containing regimen followed by either a modified radical mastectomy or segmental mastectomy with axillary dissection followed by adjuvant radiation therapy should be considered, especially for estrogen receptor negative disease. While the same regimen may be considered for estrogen receptor positive disease it is known that these tumors respond less well to chemotherapy with <10% pCR rate overall and <3% pCR rate for lobular cancers. Other options such as neoadjuvant endocrine therapy followed by localregional treatment or in a minority of cases primary endocrine therapy may be considered depending on other tumor characteristics and the patient’s co-morbid conditions and preference. Neoadjuvant (Preoperative) Chemotherapy. In the early 1970s, the National Cancer Institute in Milan, Italy, initiated VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 17-14 Adjuvant chemotherapy regimens for breast cancer HER-2/neu Positive (Trastuzumab-Containing Regimens) FAC/CAF AC → T + concurrent trastuzumab (T = paclitaxel) FEC/CEF Docetaxel + trastuzumab → FEC AC or EC TCH (docetaxel, carboplatin, trastuzumab) TAC (T = docetaxel) Chemotherapy followed by trastuzumab sequentially A → CMF AC → docetaxel + trastuzumab E → CMF CMF AC × 4 A → T → C (T = paclitaxel) FEC → T (T = docetaxel) TC (T = docetaxel) A = Adriamycin (doxorubicin); C = cyclophosphamide; E = epirubicin; F = 5-fluorouracil; M = methotrexate; T = Taxane (docetaxel or paclitaxel); → = followed by. Source: Adapted from Carlson RW, et al: Breast cancer, in NCCN Practice Guidelines in Oncology. Fort Washington, PA: National Comprehensive Cancer Network, 2006. two prospective randomized multimodality clinical trials for women with T3 or T4 breast cancer.276 The best results were achieved when surgery was interposed between chemotherapy courses, with 82% local-regional control and 25% having a 5-year disease-free survival. The NSABP B-18 trial evaluated the role of neoadjuvant chemotherapy in women with operable stage II and III breast cancer.188 Women entered into this study were randomly assigned to receive either surgery followed by chemotherapy or neoadjuvant chemotherapy followed by surgery. There was no difference in the 5-year disease-free survival rates for the two groups, but after neoadjuvant chemotherapy there was an increase in the number of lumpectomies performed and a decreased incidence of node positivity. It was suggested that neoadjuvant chemotherapy be considered for the initial management of breast cancers judged too large for initial lumpectomy. Several prospective clinical trials have evaluated the neoadjuvant approach and two meta-analyses have been performed each showing that neoadjuvant vs. adjuvant chemotherapy are equivalent in terms of OS.237,277 These analyses also evaluated local-regional recurrence (LRR) and found that there was an increase in LRR rates for patients receiving neoadjuvant chemotherapy when radiation therapy was used alone without surgery after completion of chemotherapy. Mittendorf and colleagues evaluated a contemporary series of almost 3000 patients treated with breast conserving surgery and radiation therapy who received either neoadjuvant or adjuvant chemotherapy for breast Nodal Evaluation in Patients Receiving Neoadjuvant Chemotherapy The management of the axilla after neoadjuvant chemotherapy has not been specifically addressed in randomized trials. Standard practice has been to perform an axillary lymph node dissection after chemotherapy or to perform a sentinel lymph node dissection before chemotherapy for nodal staging before chemotherapy is initiated. A number of small single-institution studies, one multicenter study, and a recent meta-analysis have explored the use of SLN dissection at the completion of chemotherapy. The published results from these studies have demonstrated the feasibility of SLN dissection in breast cancer patients after neoadjuvant chemotherapy. Review of 14 studies with 818 patients showed a false negative rate of 11% with an overall accuracy of 94%.251,252,282 Although the issue has not been specifically addressed in the published trials, the presence of suspected or documented axillary metastases at initial presentation generally is considered a contraindication to SLN VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 551 CHAPTER 17 The Breast HER-2/neu Negative (Non– Trastuzumab-Containing Regimens) cancer.278 They found that the risk of LRR was driven by biologic factors and disease stage and was not impacted by the timing of chemotherapy delivery. These data highlight the impor10 tance of the multidisciplinary management of patients with breast cancer in achieving the best outcomes. The use of neoadjuvant chemotherapy offers the opportunity to observe the response of the intact primary tumor and any regional nodal metastases to a specific chemotherapy regimen.279 For patients whose tumors remain stable in size or even progress with the initial neoadjuvant chemotherapy regimen, a new regimen may be considered that uses another class of agents, although there is no randomized data confirming this will improve outcome. After treatment with neoadjuvant chemotherapy, patients are assessed for clinical and pathologic response to the regimen. Patients whose tumors achieve a pathologic complete response to neoadjuvant chemotherapy have been shown to have statistically improved survival outcomes to those of patients whose tumors demonstrate only a partial response, remain stable, or progress on treatment. Patients who experience progression of disease during neoadjuvant chemotherapy have the poorest survival.280,281 This means that while patients who achieve a pCR will have a better outlook based on their response to neoadjuvant chemotherapy. Equally other patients will have a poorer outlook compared to when they started neoadjuvant therapy based on the non-response to treatment. The FDA is now proposing to use the neoadjuvant platform and pathologic response rates as a mechanism of accelerated approval for new agents although the short term endpoints (i.e., pCR) have not yet been shown to correlate with long-term outcomes (i.e., disease free survival and overall survival). Current NCCN recommendations for treatment of operable advanced local-regional breast cancer are neoadjuvant chemotherapy with an anthracycline-containing or taxane-containing regimen or both, followed by mastectomy or lumpectomy with axillary lymph node dissection if necessary, followed by adjuvant radiation therapy. For patients with HER-2-positive breast cancer, trastuzumab can be combined with chemotherapy in the preoperative setting to increase pathologic complete response rates. For inoperable stage IIIA and for stage IIIB breast cancer, neoadjuvant chemotherapy is used to decrease the local-regional cancer burden. This may then permit subsequent modified radical or radical mastectomy, which is followed by adjuvant radiation therapy. 552 dissection after neoadjuvant chemotherapy, and these patients usually undergo axillary lymph node dissection after completion of chemotherapy. Neoadjuvant Endocrine Therapy. There is little random- UNIT II PART SPECIFIC CONSIDERATIONS ized data on neoadjuvant endocrine therapy and virtually none which reports local recurrence rates. Neoadjuvant endocrine therapy has not been based on randomized controlled trials. It has most commonly been used in elderly women who were deemed poor candidates for surgery or cytotoxic chemotherapy. As clinicians have gained experience with neoadjuvant treatment strategies, it is now clear from examination of predictors of complete pathologic response that ER-positive tumors do not shrink in response to chemotherapy as readily as ERnegative tumors.283 Indeed the pCR rate in estrogen receptor negative tumors is approximately three times that of estrogen receptor positive tumors. Fisher et al examined the results of the NSABP B-14 and B-20 trials and found that, as age increased, women obtained less benefit from chemotherapy. They recommended that factors194 including tumor estrogen receptor concentration, nuclear grade, histologic grade, tumor type, and markers of proliferation should be considered in these patients before choosing between the use of chemotherapy and hormonal therapy. If in fact the tumor is estrogen receptor rich, these patients may benefit more from endocrine therapy in the neoadjuvant setting than they might if they received standard chemotherapy. Neoadjuvant endocrine therapy has been shown to shrink tumors, enabling breast-conserving surgery in women with hormone receptor-positive disease who otherwise would have to be treated with mastectomy although long-term recurrence rates have not been reported.284 With the use of neoadjuvant chemotherapy or endocrine therapy, observation of the response of the intact tumor and/ or nodal metastases to a specific regimen could ultimately help to define which patients will benefit from specific therapies in the adjuvant setting. In adjuvant trials the primary endpoint is typically survival, whereas in neoadjuvant trials the endpoints have more often been clinical or pathologic response rates. However, with the reported increase in local recurrence and the link between local recurrence and survival by the Early Breast Cancer Trialists’ Collaborative Group, surgeons need to become more focused on local recurrence as a primary endpoint of neoadjuvant therapies. There are a number of clinical trials underway comparing neoadjuvant chemotherapy and endocrine therapy regimens with pretreatment and posttreatment biopsy samples obtained from the primary tumors in all of the participants. These samples are being subjected to intensive genomic and proteomic analyses that may help to define a more personalized or individualized approach to breast cancer treatment in the future. Antiestrogen Therapy Tamoxifen. Within the cytosol of breast cancer cells are specific proteins (receptors) that bind and transfer steroid moieties into the cell nucleus to exert specific hormonal effects.274,285-289 The most widely studied hormone receptors are the estrogen receptor and progesterone receptor. Hormone receptors are detectable in >90% of well-differentiated ductal and lobular invasive cancers. Although the receptor status may remain the same between the primary cancer and metastatic disease in the same patient in the vast majority of cases, there are instances where the status is changed in the metastatic focus and therefore biopsy of newly diagnosed metastatic disease should be considered for assessment of hormone receptor and HER-2 status. After binding to estrogen receptors in the cytosol, tamoxifen blocks the uptake of estrogen by breast tissue. Clinical responses to antiestrogen are evident in >60% of women with hormone receptor-positive breast cancers but in <10% of women with hormone receptor-negative breast cancers. A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group showed that adjuvant therapy with tamoxifen for 5 years reduced breast cancer mortality by about a third through the first 15 years of follow-up.290 This mortality benefit continues to be statistically significant in the second and third 5-year periods (i.e., years 5–9 and 10–15) when the patients are no longer receiving endocrine treatment—the so called ‘carry-over effect’. The analysis also showed a 39% reduction in the risk of cancer in the contralateral breast. The antiestrogens do have defined toxicity, including bone pain, hot flashes, nausea, vomiting, and fluid retention. Thrombotic events occur in <3% of treated women. Cataract surgery is more frequently performed in patients receiving tamoxifen. A long-term risk of tamoxifen use is endometrial cancer. Tamoxifen therapy usually is discontinued after 5 years although recent data from randomized trials suggest a survival benefit for 10 years of tamoxifen therapy over 5 years. However, somewhat surprisingly the benefit is not seen in the second five years (i.e., years 5–9) while the patients are on treatment but only from years 10–15. In high risk patients who have received 5 years of adjuvant tamoxifen extended adjuvant therapy with at least 3 years of an aromatase inhibitor has been shown to provide a significant benefit in terms of disease outcome.291 Tamoxifen therapy is also considered for women with DCIS that is found to be estrogen receptor positive on immunohistochemical studies. The goals of such therapy are to decrease the risk of an ipsilateral recurrence after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event. This approach has not been universally accepted. Aromatase inhibitors. In postmenopausal women, aromatase inhibitors are now considered first-line therapy in the adjuvant setting or as a secondary agent after 1 to 2 years of adjuvant tamoxifen therapy. The nonsteroidal third generation aromatase inhibitors, anastrozole and letrozole, have both been shown to result in significantly fewer local and distant recurrences.292,293 While neither trial on its own has shown a significant survival advantage, an overview of all the studies of adjuvant aromatase inhibitors has reported a survival advantage to the use of aromatase inhibitors The HR is about 0.80 for 5 years of an aromatase inhibitor vs. 5 years of tamoxifen and this is irrespective of absolute risk. This has led some to suggest a switch policy—2 years of tamoxifen followed by 3 years of an aromatase inhibitor—for low risk patients where the absolute benefits may be small and the cost of an aromatase inhibitor may be significant for some individuals. As aromatase inhibitors come off patent, the cost issue should decrease and even for small benefits the additional cost of an aromatase inhibitor should become costeffective. Whether 10 years of an aromatase inhibitor will be better than 5 years is currently the subject of a randomised trial by the NSABP (B-42). For patients who have completed 5 years of adjuvant endocrine therapy and are 6–20 years from presentation, the question of whether reintroducing endocrine therapy VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Ablative Endocrine Therapy In the past, oophorectomy, adrenalectomy, and/or hypophysectomy were the primary endocrine modalities used to treat metastatic breast cancer, but today they are rarely used. Oophorectomy was used in premenopausal breast cancer patients. In contrast, pharmacologic doses of exogenous estrogens were given to postmenopausal women with similar recurrences. For both groups, the response rates were nearly 30%. Adrenalectomy and hypophysectomy were effective in individuals who had previously responded to either oophorectomy or exogenous estrogen therapy, and the response to these additional procedures was nearly 30%. Aminoglutethimide blocks enzymatic conversion of cholesterol to γ-5-pregnenolone and inhibits the conversion of androstenedione to estrogen in peripheral tissues. Dose-dependent and transient side effects include ataxia, dizziness, and lethargy. After treatment with this agent (medical adrenalectomy), adrenal suppression necessitates glucocorticoid therapy. Neither permanent adrenal insufficiency nor acute crises have been observed. Because the adrenal glands are the major site for production of endogenous estrogens after menopause, treatment with aminoglutethimide has been compared prospectively with surgical adrenalectomy and hypophysectomy in postmenopausal women and is equally efficacious. Anti–HER-2/neu Therapy The determination of tumor HER-2/neu expression or gene amplification for all newly diagnosed patients with breast cancer is now recommended.297-300 It is used to assist in the selection of adjuvant chemotherapy in both node-negative and nodepositive patients. Patients with HER-2-positive disease appear to have better outcomes with anthracycline-based adjuvant chemotherapy regimens. Patients with HER-2-positive tumors benefit if trastuzumab is added to paclitaxel chemotherapy. Cardiotoxicity may develop if trastuzumab is delivered concurrently with anthracycline-based chemotherapy. Trastuzumab was initially approved for the treatment of HER-2/neu–positive breast cancer in patients with metastatic disease. Once efficacy was demonstrated for patients with metastatic disease, the NSABP and the North Central Cancer Treatment Group conducted phase III trials evaluating the impact of adjuvant trastuzumab therapy in patients with earlystage breast cancer. After approval from the FDA, these groups amended their adjuvant trastuzumab trials (B-31 and N9831, respectively), to provide for a joint efficacy analysis. The first joint interim efficacy analysis demonstrated an improvement in 3-year disease-free survival from 75% in the control arm to 87% in the trastuzumab arm (hazard ratio = 0.48, P<.0001). There was an accompanying 33% reduction in mortality in the patients who received trastuzumab (hazard ratio = 0.67, P = 0.015). The magnitude of reduction in hazard for disease-free survival events crossed prespecified early reporting boundaries, so the data-monitoring committees for both groups recommended that randomized accrual to the trials be ended, and the results were subsequently published.167 Buzdar and colleagues reported the results of a randomized neoadjuvant trial of trastuzumab in combination with sequential paclitaxel followed by FEC-75 (5-fluorouracil, epirubicin, cyclophosphamide) vs. the same chemotherapy regimen without trastuzumab in 42 women with early-stage operable breast cancer. The pathologic complete response rates in this trial increased from 25 to 66.7% when chemotherapy was given concurrently with trastuzumab. None of the patients receiving the concurrent trastuzumab and FEC regimen developed symptoms of congestive heart failure. However, given the small sample size in this report, the 95% confidence interval for developing heart failure was 0% to 14.8%.301 A subsequent report which included additional patients treated with concurrent chemotherapy and trastuzumab further confirmed the high pathologic complete response rates and continued to show that cardiac function was preserved.302 This regimen was tested in a phase III multicenter trial (ACOSOG Z1041) which recently completed accrual. Several new agents have been approved for the treatment of women with metastatic HER-2-positive breast cancers. Lapatinib is a dual tyrosine kinase inhibitor that targets both HER-2 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 553 CHAPTER 17 The Breast might decrease long term recurrence rates is being addressed by the later study which randomizes patients to 5 years of letrozole or placebo. The aromatase inhibitors are less likely than tamoxifen to cause endometrial cancer but do lead to changes in bone mineral density that may result in osteoporosis and an increased rate of fractures in postmenopausal women. The risk of osteoporosis can be averted by treatment with bisphosphonates. Joint pains are a side effect which affects a significant number of patients. Node-negative and node-positive breast cancer patients whose tumors express hormone receptors should be considered for endocrine therapy in the adjuvant setting. Women with hormone receptor-positive cancers achieve significant reduction in risk of recurrence and mortality due to breast cancer through the use of endocrine therapies. For women with stage IV breast cancer, a third generation non-steroidal aromatase inhibitor is the preferred initial therapy. For postmenopausal women with prior aromatase inhibitor exposure, recommended second-line endocrine therapies include the pure anti-estrogen fulvestrant (at the 500-mg dose) or tamoxifen followed by progestins, high-dose estrogen, and androgens. For postmenopausal patients who received tamoxifen as prior endocrine therapy, subsequent endocrine therapies would be an aromatase inhibitor or fulvestrant (500 mg) followed by progestins, high dose estrogens, and androgens. In premenopausal patients with stage IV breast cancer either tamoxifen or oophorectomy (medical, surgical, or radioablative) could be used alone with the other then being added in on progression. An overview of four randomized trials suggested combining oophorectomy and tamoxifen would be the initial treatment options. If a tumor progresses while a premenopausal patient is on ovarian ablation plus tamoxifen then the tamoxifen can be stopped and an aromatase inhibitor added to the ovarian ablation. Subsequent therapies if the patient’s tumor is still deemed to be potentially hormone responsive can include ovarian ablation plus fulvestrant, ovarian ablation plus exemestane, and then progestins followed by high dose estrogens. Women whose tumors respond to an endocrine therapy with either shrinkage of their breast cancer (objective response) or long-term stabilization of disease (stable disease) are together consider to represent ‘clinical benefit’ and should receive additional endocrine therapy at the time of progression since their chances of a further response remain high.294-296 Patients whose tumors progress de-novo on an endocrine agent have a low rate of clinical benefit (<20%) to subsequent endocrine therapy; the choice of endocrine or chemotherapy should be considered based on the disease site and extent as well as the patient’s general condition and treatment preference.294 554 UNIT II PART and EGFR. It was approved for use with capecitabine in patients with HER-2-positive metastatic disease. Ado-trastuzumab (previously known as TDM1) was approved for patients who have previously received trastuzumab and a taxane either separately or in combination. Ado-trastuzumab binds to the HER-2 receptor and releases a cytotoxic agent into the cell that leads to apoptosis. The FDA has also approved pertuzumab, which also targets the HER-2 receptor, in combination with trastuzumab and docetaxel for treatment of metastatic HER-2-positive breast cancer. There is significant interest in dual targeting of HER-2 and multiple trials are ongoing in the metastatic and neoadjvuant settings. SPECIAL CLINICAL SITUATIONS SPECIFIC CONSIDERATIONS Nipple Discharge Unilateral Nipple Discharge Nipple discharge is a finding that can be seen in a number of clinical situations. It may be suggestive of cancer if it is spontaneous, unilateral, localized to a single duct, present in women ≥40 years of age, bloody, or associated with a mass. A trigger point on the breast may be present so that pressure around the nipple-areolar complex induces discharge from a single duct. In this circumstance, mammography and ultrasound are indicated for further evaluation. A ductogram also can be useful and is performed by cannulating a single discharging duct with a small nylon catheter or needle and injecting 1.0 mL of water-soluble contrast solution. Nipple discharge associated with a cancer may be clear, bloody, or serous. Testing for the presence of hemoglobin is helpful, but hemoglobin may also be detected when nipple discharge is secondary to an intraductal papilloma or duct ectasia. Definitive diagnosis depends on excisional biopsy of the offending duct and any associated mass lesion. A 3.0 lacrimal duct probe can be used to identify the duct that requires excision. Another approach is to inject methylene blue dye within the duct after ductography. The nipple must be sealed with collodion or a similar material so that the blue dye does not discharge through the nipple but remains within the distended duct facilitating its localization. Needle localization biopsy is performed when there is an associated mass that lies >2.0 to 3.0 cm from the nipple. Bilateral Nipple Discharge Nipple discharge is suggestive of a benign condition if it is bilateral and multiductal in origin, occurs in women ≤39 years of age, or is milky or blue-green. Prolactin-secreting pituitary adenomas are responsible for bilateral nipple discharge in <2% of cases. If serum prolactin levels are repeatedly elevated, plain radiographs of the sellaturcica are indicated and thin section CT scan is required. Optical nerve compression, visual field loss, and infertility are associated with large pituitary adenomas. Axillary Lymph Node Metastases in the Setting of an Unknown Primary Cancer A woman who presents with an axillary lymph node metastasis that is consistent with a breast cancer metastasis has a 90% probability of harboring an occult breast cancer.303 However, axillary lymphadenopathy is the initial presenting sign in only 1% of breast cancer patients. Fine-needle aspiration biopsy or core-needle biopsy can be used to establish the diagnosis when an enlarged axillary lymph node is identified. When metastatic cancer is found, immunohistochemical analysis may classify the cancer as epithelial, melanocytic, or lymphoid in origin. The presence of hormone receptors (estrogen or progesterone receptors) suggests metastasis from a breast cancer but is not diagnostic. The search for a primary cancer includes careful examination of the thyroid, breast, and pelvis, including the rectum. The breast should be examined with diagnostic mammography, ultrasonography, and MRI to evaluate for an occult primary lesion. Further radiologic and laboratory studies should include chest radiography and liver function studies. Additional imaging of the chest, abdomen, and skeleton may be indicated if the extent of nodal involvement is consistent with stage III breast cancer. Suspicious findings on mammography, ultrasonography, or MRI necessitate breast biopsy. When a breast cancer is found, treatment consists of an axillary lymph node dissection with a mastectomy or preservation of the breast followed by whole-breast radiation therapy. Chemotherapy and endocrine therapy should be considered. Breast Cancer During Pregnancy Breast cancer occurs in 1 of every 3000 pregnant women, and axillary lymph node metastases are present in up to 75% of these women.304 The average age of the pregnant woman with breast cancer is 34 years. Fewer than 25% of the breast nodules developing during pregnancy and lactation will be cancerous. Ultrasonography and needle biopsy specimens are used in the diagnosis of these nodules. Mammography is rarely indicated because of its decreased sensitivity during pregnancy and lactation; however, the fetus can be shielded if mammography is needed. Approximately 30% of the benign conditions encountered will be unique to pregnancy and lactation (galactoceles, lobular hyperplasia, lactating adenoma, and mastitis or abscess). Once a breast cancer is diagnosed, complete blood count, chest radiography (with shielding of the abdomen), and liver function studies are performed. Because of the potential deleterious effects of radiation therapy on the fetus, radiation cannot be considered until the fetus is delivered. A modified radical mastectomy can be performed during the first and second trimesters of pregnancy, even though there is an increased risk of spontaneous abortion after first-trimester anesthesia. During the third trimester, lumpectomy with axillary node dissection can be considered if adjuvant radiation therapy is deferred until after delivery. Lactation is suppressed. Chemotherapy administered during the first trimester carries a risk of spontaneous abortion and a 12% risk of birth defects. There is no evidence of teratogenicity resulting from administration of chemotherapeutic agents in the second and third trimesters. For this reason, many clinicians now consider the optimal strategy to be delivery of chemotherapy in the second and third trimesters as a neoadjuvant approach, which allows local therapy decisions to be made after the delivery of the baby. Pregnant women with breast cancer often present at a later stage of disease because breast tissue changes that occur in the hormone-rich environment of pregnancy obscure early cancers. However, pregnant women with breast cancer have a prognosis, stage by stage, that is similar to that of nonpregnant women with breast cancer. Male Breast Cancer Fewer than 1% of all breast cancers occur in men.305,306 The incidence appears to be highest among North Americans and the British, in whom breast cancer constitutes as much as 1.5% of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 555 A Phyllodes Tumors The nomenclature, presentation, and diagnosis of phyllodes tumors (including cystosarcoma phyllodes) have posed many problems for surgeons.307 These tumors are classified as benign, borderline, or malignant. Borderline tumors have a greater potential for local recurrence. Mammographic evidence of calcifications and morphologic evidence of necrosis do not distinguish between benign, borderline, and malignant phyllodes tumors. Consequently, it is difficult to differentiate benign phyllodes tumors from the malignant variant and from fibroadenomas. Phyllodes tumors are usually sharply demarcated from the surrounding breast tissue, which is compressed and distorted. Connective tissue composes the bulk of these tumors, which have mixed gelatinous, solid, and cystic areas. Cystic areas represent sites of infarction and necrosis. These gross alterations give the gross cut tumor surface its classical leaf-like (phyllodes) appearance. The stroma of a phyllodes tumor generally has greater cellular activity than that of a fibroadenoma. After microdissection to harvest clusters of stromal cells from fibroadenomas and from phyllodes tumors, molecular biology techniques have shown the stromal cells of fibroadenomas to be either polyclonal or monoclonal (derived from a single progenitor cell), whereas those of phyllodes tumors are always monoclonal. Most malignant phyllodes tumors (Fig. 17-38) contain liposarcomatous or rhabdomyosarcomatous elements rather than fibrosarcomatous elements. Evaluation of the number of mitoses and the presence or absence of invasive foci at the tumor margins may help to identify a malignant tumor. Small phyllodes tumors are excised with a margin of normal-appearing breast tissue. When the diagnosis of a phyllodes tumor with suspicious malignant elements is made, reexcision of the biopsy specimen site to ensure complete excision of the tumor with a 1-cm margin of normal-appearing breast tissue is indicated. B Figure 17-38. A. Malignant phyllodes tumor (cystosarcomaphyllodes). B. Histologic features of a malignant phyllodes tumor (hematoxylin and eosin stain, ×100). Large phyllodes tumors may require mastectomy. Axillary dissection is not recommended because axillary lymph node metastases rarely occur. Inflammatory Breast Carcinoma Inflammatory breast carcinoma (stage IIIB) accounts for <3% of breast cancers. This cancer is characterized by the skin changes of brawny induration, erythema with a raised edge, and edema (peaud’orange).308 Permeation of the dermal lymph vessels by cancer cells is seen in skin biopsy specimens. There may be an associated breast mass (Fig. 17-39). The clinical differentiation of inflammatory breast cancer may be extremely difficult, especially when a locally advanced scirrhous carcinoma invades dermal lymph vessels in the skin to produce peaud’orange and lymphangitis (Table 17-15). Inflammatory breast cancer also may be mistaken for a bacterial infection of the breast. More than 75% of women who have inflammatory breast cancer present with palpable axillary lymphadenopathy, and distant metastases also are frequently present. A positron emission VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 17 The Breast all male cancers. Jewish and African American males have the highest incidence. Male breast cancer is preceded by gynecomastia in 20% of men. It is associated with radiation exposure, estrogen therapy, testicular feminizing syndromes, and Klinefelter’s syndrome (XXY). Breast cancer is rarely seen in young males and has a peak incidence in the sixth decade of life. A firm, nontender mass in the male breast requires investigation. Skin or chest wall fixation is particularly worrisome. DCIS makes up <15% of male breast cancer, whereas infiltrating ductal carcinoma makes up >85%. Special-type cancers, including infiltrating lobular carcinoma, have occasionally been reported. Male breast cancer is staged in the same way as female breast cancer, and stage by stage, men with breast cancer have the same survival rate as women. Overall, men do worse because of the more advanced stage of their cancer (stage II, III or IV) at the time of diagnosis. The treatment of male breast cancer is surgical, with the most common procedure being a modified radical mastectomy. SLN dissection has been shown to be feasible and accurate for nodal assessment in men presenting with a clinically node-negative axilla. Adjuvant radiation therapy is appropriate in cases in which there is a high risk for local-regional recurrence. Approximately 80% of male breast cancers are hormone receptor positive, and adjuvant tamoxifen is considered. Systemic chemotherapy is considered for men with hormone receptor-negative cancers and for men with large primary tumors, multiple positive nodes, and locally advanced disease. Surgery alone and surgery with adjuvant radiation therapy have produced disappointing results in women with inflammatory breast cancer. However, neoadjuvant chemotherapy with ananthracycline-containing regimen may affect dramatic regressions in up to 75% of cases. Tumor should be assessed for HER-2 and hormone receptors with treatment dictated based on receptor status. Modified radical mastectomy is performed after demonstrated response to systemic therapy to remove residual cancer from the chest wall and axilla. Adjuvant chemotherapy may be indicated depending on final pathologic assessment of the breast and regional nodes. Finally, the chest wall and the supraclavicular, internal mammary, and axillary lymph node basins receive adjuvant radiation therapy. This multimodal approach results in 5-year survival rates that approach 30%. Patients with inflammatory breast cancer should be encouraged to participate in clinical trials. 556 UNIT II PART SPECIFIC CONSIDERATIONS Rare Breast Cancers Squamous Cell (Epidermoid) Carcinoma. Squamous Figure 17-39. Inflammatory breast carcinoma. Stage IIIB cancer of the breast with erythema, skin edema (peaud’orange), nipple retraction, and satellite skin nodules. tomography (PET)-computed tomography (CT) scan should be considered at the time of diagnosis to rule out concurrent metastatic disease. A report of the SEER program described distant metastases at diagnosis in 25% of white women with inflammatory breast carcinoma. Table 17-15 Inflammatory vs. noninflammatory breast cancer Inflammatory Noninflammatory Dermal lymph vessel invasion is present with or without inflammatory changes. Inflammatory changes are present without dermal lymph vessel invasion. Cancer is not sharply delineated. Cancer is better delineated. Erythema and edema frequently involve >33% of the skin over the breast. Erythema is usually confined to the lesion, and edema is less extensive. Lymph node involvement is present in >75% of cases. Lymph nodes are involved in approximately 50% of the cases. Distant metastases are present Distant metastases are less in 25% of cases. common at presentation. Distant metastases are more common at initial presentation. Source: Modified with permission from Chittoor SR, et al: Locally advanced breast cancer: Role of medical oncology, in Bland KI, et al (eds): The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders;1998;1281. Copyright Elsevier. cell (epidermoid) carcinoma is a rare cancer that arises from metaplasia within the duct system and generally is devoid of distinctive clinical or radiographic characteristics.309 Regional metastases occur in 25% of patients, whereas distant metastases are rare. Adenoid Cystic Carcinoma. Adenoid cystic carcinoma is very rare, accounting for <0.1% of all breast cancers. It is typically indistinguishable from adenoid cystic carcinoma arising in salivary tissues. These cancers are generally 1 to 3 cm in diameter at presentation and are well circumscribed. Axillary lymph node metastases are rare, but deaths from pulmonary metastases have been reported. Apocrine Carcinomas. Apocrine carcinomas are welldifferentiated cancers that have rounded vesicular nuclei and prominent nucleoli. There is a very low mitotic rate and little variation in cellular features. However, apocrine carcinomas may display an aggressive growth pattern. Sarcomas. Sarcomas of the breast are histologically similar to soft tissue sarcomas at other anatomic sites. This diverse group includes fibrosarcoma, malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, malignant schwannoma, rhabdomyosarcoma, osteogenic sarcoma, and chondrosarcoma. The clinical presentation is typically that of a large, painless breast mass with rapid growth. Diagnosis is by core-needle biopsy or by open incisional biopsy. Sarcomas are graded based on cellularity, degree of differentiation, nuclear atypia, and mitotic activity. Primary treatment is wide local excision, which may necessitate mastectomy. Axillary dissection is not indicated unless there is biopsy proven lymph node involvement. Angiosarcomas are classified as de novo, as postradiation, or as arising in association with postmastectomy lymphedema. In 1948, Stewart and Treves described lymphangiosarcoma of the upper extremity in women with ipsilateral lymphedema after radical mastectomy.310 Angiosarcoma is now the preferred name. The average interval between modified radical or radical mastectomy and the development of an angiosarcoma is 7 to 10 years. Sixty percent of women developing this cancer have a history of adjuvant radiation therapy. 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Evaluation of HER-2/ neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol. 2002;20:3095-3105. 300. Volpi A, De Paola F, Nanni O, et al. Prognostic significance of biologic markers in node-negative breast cancer patients: a prospective study. Breast Cancer Res Treat. 63:181-192. 301. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005; 23:3676-3685. 302. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007;13:228-233. 303. Tench DW. The unknown primary presenting with axillary lymphadenopathy. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders;1998:1447. 304. Robinson DS, Sundaram M, et al. Carcinoma of the breast in pregnancy and lactation. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders;1998:1433. 305. Giordano SH, Buzdar AU, Hortobagyi GN: Breast cancer in men. Ann Intern Med. 2002;137:678-687. 306. Wilhelm MC. Cancer of the male breast. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders; 1998:1416. 307. Khan SA, Badve S. Phyllodes tumors of the breast. Curr Treat Options Oncol. 2001;2:139-147. 308. Chittoor SR, Swain SM. Locally advanced breast cancer: Role of medical oncology. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders;1998:1403. 309. Mies C. Mammary sarcoma and lymphoma. In: Bland KI, Copeland EMI, eds. The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders;1998:307. 310. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema; a report of six cases in elephantiasis chirurgica. Cancer. 1948;1:64-81. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 18 chapter A Complex Region Benign Conditions of the Head and Neck 565 565 Ear Infections / 565 Sinus Inflammatory Disease / 567 Pharyngeal and Adenotonsillar Disease / 570 Benign Conditions of the Larynx / 572 Vascular Lesions / 574 Trauma of the Head and Neck Tumors of the Head and Neck 575 578 Disorders of the Head and Neck Richard O. Wein, Rakesh K. Chandra, C. René Leemans, and Randal S. Weber Etiology and Epidemiology / 578 Anatomy and Histopathology / 579 Carcinogenesis / 580 Second Primary Tumors in the Head and Neck / 580 Staging / 580 Upper Aerodigestive Tract / 580 Nose and Paranasal Sinuses / 592 Nasopharynx / 593 Ear and Temporal Bone / 594 Neck / 595 Salivary Gland Tumors / 599 A COMPLEX REGION The head and neck constitute a complex anatomic region where different pathologies may affect an individual’s ability to see, smell, hear, speak, obtain nutrition and hydration, or breathe. The use of a multidisciplinary approach to many of the disorders in this region is essential in an attempt to achieve the best functional results with care. This chapter reviews many of the common diagnoses encountered in the field of otolaryngology– head and neck surgery—and aims to provide an overview that clinicians can use as a foundation for understanding of this region. As is the case with every field of surgery, care for patients with disorders of the head and neck is constantly changing as issues of quality of life and the economics of medicine continue to evolve. BENIGN CONDITIONS OF THE HEAD AND NECK Ear Infections Infections may involve the external, middle, and/or internal ear. In each of these scenarios, the infection may follow an acute or chronic course and may be associated with both otologic and intracranial complications. Otitis externa typically refers to infection of the skin of the external auditory canal.1 Acute otitis externa is commonly known as swimmer’s ear, because moisture that persists within the canal after swimming often initiates the process and leads to skin maceration and itching. Typically, the patient subsequently traumatizes the canal skin by scratching (i.e., with a cotton swab or fingernail), thus eroding the normally protective skin/cerumen barrier. Because the environment within the external ear canal is already dark, warm, and humid, it then becomes susceptible to rapid microbial proliferation and tissue cellulitis. The most common organism responsible is Pseudomonas aeruginosa, although other bacteria and fungi may also be implicated. Symptoms and signs of otitis Reconstruction in Head and Neck Surgery 600 Skin Grafts / 600 Local Flaps / 600 Regional Flaps / 600 Free-Tissue Transfer / 601 Tracheostomy Long-Term Management and ­Rehabilitation 602 602 Palliative Care / 602 Follow-Up Care / 602 externa include itching during the initial phases and pain with swelling of the canal soft tissues as the infection progresses. Infected, desquamated debris accumulates within the canal. In the chronic inflammatory stage of the infection, the pain subsides, but profound itching occurs for prolonged periods with gradual thickening of the external canal skin. Standard treatment requires removal of debris under otomicroscopy and application of appropriate topical antimicrobials, such as neomycin/polymyxin or quinolone-containing eardrops, which often include topical steroid such as hydrocortisone or dexamethasone to nonspecifically decrease pain and swelling. Nonantibiotic antimicrobial preparations, such as 2% acetic acid, may also have a role, particularly for mixed bacterial/fungal infections. For this reason, the patient should also be instructed to keep the ear dry. Systemic antibiotics are reserved for those with severe infections, diabetics, and immunosuppressed patients. Diabetic, elderly, and immunodeficient patients are susceptible to a condition called malignant otitis externa, a fulminant necrotizing infection of the otologic soft tissues combined with osteomyelitis of the temporal bone. In addition to the previously mentioned findings, cranial neuropathies may be observed. The classic physical finding is granulation tissue along the floor of the external auditory canal (EAC). Symptoms include persistent otalgia for longer than 1 month and purulent otorrhea for several weeks. These patients require aggressive medical therapy; including IV antibiotics covering Pseudomonas.2 Other gram-negative bacteria and fungi are occasionally implicated, necessitating culture-directed therapy in those cases. Patients who do not respond to medical management require surgical debridement. This condition may progress to involvement of the adjacent skull base and soft tissues, meningitis, brain abscess, and death. In its acute phase, otitis media typically implies a bacterial infection of the middle ear. This diagnosis accounts for 25% of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 5 566 Patients with obstructive sleep apnea require evaluation to determine the specific anatomic site(s) of involvement. Long-term cardiovascular problems are a significant concern in these patients. Repair of traumatic soft tissue injuries requires precise ­re-alignment of anatomic landmarks such as the grey line and vermilion border. The key principle in the surgical repair of facial fractures is immobilization, which may require plates, screws, wires, and/ or intermaxillary fixation. Concurrent abuse of tobacco and alcohol are synergistic in increasing the risk of developing head and neck cancer Monomodality therapy (surgery or radiation) is used for early stage (I/II) head and neck cancer, whereas combination 6 7 8 s­ urgery and chemoradiation is utilized with advanced stage (III/IV) malignancies. Infectious conditions of the head and neck may present with life-threatening sequelae such as loss of airway or intracranial extension. Disorders of the head and neck can cause significant cosmetic and functional impairment. The practitioner must be empathetic to the effect of these morbidities on quality of life. Hoarseness, odynophagia, referred otalgia, nonhealing oral ulceration and/or cervical lymphadenopathy present for >2 weeks duration require consideration for subspecialty consultation for evaluation. pediatric antibiotic prescriptions and is the most common bacterial infection of childhood. Most cases occur before 2 years of age and are secondary to immaturity of the Eustachian tube. Contributing factors include upper respiratory viral infection and day-care attendance, as well as craniofacial conditions affecting Eustachian tube function, such as cleft palate. It is also possible that social factors such as day-care attendance and the inappropriate prescribing of antibiotics have led to antibiotic resistance. Classification of the infection as acute is based upon the duration of the process being less than 3 weeks. In this phase, otalgia and fever are the most common symptoms and physical exam reveals a bulging, opaque tympanic membrane (Fig. 18-1). The most common organisms responsible are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. If the process lasts 3 to 8 weeks, it is deemed subacute. Chronic otitis media, lasting more than 8 weeks, usually results from an unresolved acute otitis media. About 20% of patients demonstrate a persistent middle ear effusion 8 weeks after resolution of the acute phase. Rather than a purely infectious process, however, it represents chronic inflammation and hypersecretion by the middle ear mucosa associated with ­Eustachiantube dysfunction, viruses, allergy, ciliary d­ ysfunction, and other factors. The bacteriology is variable, but often includes those found in acute otitis media and may be polymicrobial. The exact role of bacteria in the pathophysiology is controversial. The patient experiences otalgia, ear fullness, and conductive hearing loss. Physical examination reveals a retracted tympanic membrane that may exhibit an opaque character or an air-fluid level. Bubbles may be seen behind the retracted membrane. Treatment for uncomplicated otitis media is oral antibiotic therapy. However, penicillin resistance of the commonly implicated organisms is rising such that almost 100% of Moraxella, 50% to 70% of Haemophilus, and up to 40% of pneumococcal strains are resistant.3 Beta-lactamase-resistant combinations, cephalosporins, and macrolides are often required, although amoxicillin and sulfas are still considered first-line drugs. Chronic otitis media is frequently treated with myringotomy and tube placement (Fig. 18-2). This is indicated for frequent acute episodes, chronic effusions persisting beyond 3 months, and those associated with significant conductive hearing loss. The purpose of this procedure is to remove the effusion and provide a route for middle ear ventilation. Tympanic membrane perforation during acute otitis media frequently results in resolution of severe pain and provides for drainage of purulent Figure 18-1. Acute otitis media. Figure 18-2. Myringotomy and tube. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ complications include epidural abscess, subdural abscess, brain abscess, otitic hydrocephalus (pseudotumor), and sigmoid sinus thrombophlebitis. In these cases, the otogenic source must be urgently treated with antibiotics and myringotomy tube placement. Mastoidectomy and neurosurgical consultation may be necessary. Bell’s palsy, or idiopathic facial paralysis, may be considered within the spectrum of otologic disease given the facial nerve’s course through the temporal bone. This entity is the most common etiology of facial nerve paralysis and is clinically distinct from that occurring as a complication of otitis media in that the otologic exam is normal. Historically, Bell’s palsy was synonymous with “idiopathic” facial paralysis. It is now accepted, however, that the majority of these cases represent a viral neuropathy caused by herpes simplex. Treatment includes oral steroids plus antiviral therapy (i.e., valacyclovir). Complete recovery is the norm, but does not occur universally, and selected cases may benefit from surgical decompression of the nerve within its bony canal. Electrophysiologic testing has been used to identify those patients in whom surgery might be indicated.6 The procedure involves decompression of the nerve via exposure in the mastoid and middle cranial fossa. Varicella zoster virus may also cause facial nerve paralysis when the virus reactivates from dormancy in the nerve. This condition, known as Ramsay Hunt syndrome, is characterized by severe otalgia followed by the eruption of vesicles of the external ear. Treatment is similar to Bell’s palsy, but full recovery is only seen in approximately two-thirds of cases. Traumatic facial nerve injuries may occur secondary to accidental trauma or surgical injury. Iatrogenic facial nerve trauma most often occurs during mastoidectomy.7 When the facial nerve is injured during an operative procedure, it is explored. Injury to >50% of the neural diameter of the facial nerve is addressed either with primary re-anastomosis or reconstructed with the use a nerve graft. Complete recovery of nerve function is uncommon in these cases. Sinus Inflammatory Disease Sinusitis is a clinical diagnosis based on patient signs and symptoms.8 The Task Force on Rhinosinusitis (sponsored by the American Academy of Otolaryngology–Head and Neck Surgery) has established criteria to define “a history consistent with sinusitis.” To establish the diagnosis a patient must exhibit at least two major factors or one major and two minor factors. The classification of sinusitis as acute vs. subacute or chronic is primarily based on the time course over which those criteria have been met. If signs and symptoms are present for at least 7 to 10 days, but for less than 4 weeks, the process is designated acute sinusitis. Subacute sinusitis is present for 4 to 12 weeks and chronic sinusitis is diagnosed when the patient has had signs and symptoms for at least 12 weeks. In addition, the diagnosis of chronic sinusitis requires some objective demonstration of mucosal inflammatory disease. This may be accomplished by endoscopic or radiologic examination (i.e., CT scan). Acute sinusitis typically follows a viral upper respiratory infection whereby sinonasal mucosal inflammation results in closure of the sinus ostium. This results in stasis of secretions, tissue hypoxia, and ciliary dysfunction. These conditions promote bacterial proliferation and acute inflammation. The mainstay of treatment is the use of antibiotics that are empirically directed toward the three most common organisms S. pneumoniae, H. influenzae, and M. catarrhalis. As with otitis media, antibiotic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 567 CHAPTER 18 DISORDERS OF THE HEAD AND NECK fluid and middle ear ventilation. These perforations will heal spontaneously after the infection has resolved in the majority of cases. Chronic otitis media, however, may be associated with nonhealing tympanic membrane perforations. Patients may have persistent otorrhea, which is treated with topical drops. Preparations containing aminoglycoside are avoided, because this class of drugs is toxic to the inner ear. Solutions containing alcohol or acetic acid may be irritative or caustic to the middle ear, and are also avoided in the setting of a perforation. Nonhealing perforation requires surgical closure (tympanoplasty) after medical treatment of any residual acute infection. Chronic inflammation may also be associated with erosion of the ossicular chain, which can be reconstructed with ­various prostheses or autologous ossicular replacement techniques. Cholesteatoma is an epidermoid cyst of the middle ear and/or mastoid, which causes bone destruction secondary to its expansile nature and through enzymatic destruction. Cholesteatoma develops as a consequence of Eustachian tube dysfunction and chronic otitis media secondary to retraction of squamous elements of the tympanic membrane into the middle ear space. Squamous epithelium may also migrate into the middle ear via a perforation. Chronic mastoiditis that fails medical management or is associated with cholesteatoma is treated by mastoidectomy. Complications of otitis media may be grouped into two categories: intratemporal (otologic) and intracranial.4 Fortunately, complications are rare in the antibiotic era, but mounting antibiotic resistance necessitates an increased awareness of these conditions. Intratemporal complications include acute coalescent mastoiditis, petrositis, facial nerve paralysis, and labyrinthitis. In acute coalescing mastoiditis, destruction of the bony lamellae by an acute purulent process results in severe pain, fever, and swelling behind the ear. The mastoid air cells coalesce into one common space filled with pus. Mastoid infection may also spread to the petrous apex, causing retro-orbital pain and sixth-nerve palsy. These diagnoses are confirmed by computed tomographic (CT) scan. Facial nerve paralysis may also occur secondary to an acute inflammatory process in the middle ear or mastoid.5 Intratemporal complications are managed by myringotomy tube placement in addition to appropriate IV antibiotics. In acute coalescent mastoiditis, and petrositis, mastoidectomy is also performed as necessary to drain purulent foci. Labyrinthitis refers to inflammation of the inner ear. Most cases are idiopathic or are secondary to viral infections of the endolymphatic space. The patient experiences vertigo with sensorineural hearing loss and symptoms may smolder over several weeks. Labyrinthitis associated with middle ear infection may be serous or suppurative. In the former case, bacterial products and/or inflammatory mediators transudate into the inner ear via the round window membrane, establishing an inflammatory process therein. Total recovery is eventually possible after the middle ear is adequately treated. Suppurative labyrinthitis, however, is a much more toxic condition in which the acute purulent bacterial infection extends into the inner ear and causes marked destruction of the sensory hair cells and neurons of the eighth-nerve ganglion. This condition may hallmark impending meningitis and must be treated rapidly. The goal of management of inner ear infection, which occurs secondary to middle ear infection, is to “sterilize” the middle ear space with antibiotics and the placement of a myringotomy tube. Meningitis is the most common intracranial complication. Otologic meningitis in children is most commonly associated with a H. influenzae type B infection. Other intracranial 568 UNIT II PART SPECIFIC CONSIDERATIONS resistance is a mounting concern. Nosocomial acute sinusitis frequently involves Pseudomonas or S. aureus, both of which may also exhibit significant antibiotic resistance. Other treatments include topical and systemic decongestants, nasal saline spray, topical nasal steroids, and oral steroids in selected cases. In the acute setting, surgery is reserved for complications or pending complications, which may include extension to the eye (orbital cellulitis or abscess) or the intracranial space (meningitis, intracranial abscess). It should also be noted that, strictly speaking, a viral upper respiratory infection (common cold) is a form of acute sinusitis. The working definition outlined previously, however, attempts to exclude these cases by requiring that symptoms be present for at least 7 to 10 days, by which time the common cold should be in a resolution phase. Use of this working definition strives to avoid unnecessary antibiotic prescriptions and further promotion of resistance. Chronic sinusitis represents a heterogeneous group of patients with multifactorial etiologies contributing to ostial obstruction, ciliary dysfunction, and inflammation. Components of genetic predisposition, allergy, anatomic obstruction, bacteria, fungi, and environmental factors play various roles, depending on the individual patient.8 Diagnosis is suspected with clinical signs and symptoms persisting for at least 12 weeks. Chronic sinusitis may also be associated with the presence of nasal polyps, particularly when there is heavy eosinophilic inflammation. Mucosal inflammation in nonpolypoid chronic sinusitis is predominantly mediated by neutrophils, or is mixed in nature. Nasal endoscopy is a critical element of the diagnosis of chronic sinusitis. Anatomic abnormalities, such as septal deviation, nasal polyps, and purulence may be observed (Fig. 18-3 and 18-4). The finding of purulence or polypoid change by nasal endoscopy is supportive of the diagnosis of chronic sinusitis, if symptoms persist for at least 12 weeks. In this setting, purulence may represent an acute exacerbation of chronic sinusitis. Pus found on endoscopic exam may be cultured, and subsequent antibiotic therapy can be directed accordingly. Further, the spectrum of bacteria found in chronic sinusitis is highly variable and includes higher prevalence of polymicrobial infections and antibiotic-resistant organisms. Overall, S. aureus, coagulasenegative staphylococci, gram-negative bacilli, and streptococci are isolated, in addition to the typical pathogens of acute sinusitis. Thus, the increased prevalence of community acquired methicillin resistant S. aureus is a mounting concern.9 The diagnosis of chronic sinusitis can be confirmed by CT scan, which demonstrates mucosal thickening and/or sinus opacification. It should be underscored, however, that CT scan is not the positive gold standard because many asymptomatic patients will demonstrate findings on a sinus CT scan, and many patients with presumed sinusitis will have negative findings. CT scan has excellent negative predictive value when performed in the setting of active symptoms. Thus, if a patient complains of sinusitis-like symptoms but has no specific physical (endoscopic) findings, and the scan is negative, other diagnoses (e.g., allergies, migraines, tension headaches) should be sought. This has led to the utility of point-of-care CT (POC-CT) scan that can be performed in the physician’s office. POC-CT utilizes cone beam technology10, which acquires the equivalent of >100 axial slices in approximately 1 minute at an effective resolution of 0.3 mm or less. The equipment occupies a room of 8' × 10' and can thus be accommodated in almost any office setting (Fig. 18-5). Perhaps most important, the radiation dosing for Figure 18-3. Endoscopic view of purulence within a surgically opened maxillary sinus cavity. Figure 18-5. POC-CT system. All components can be fit within an 8' × 10' room in an outpatient office setting. Figure 18-4. Endoscopic image of a nasal polyp. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 569 even the most sophisticated protocol is 0.17 mSv, which is <10% the dose of a conventional head CT and equivalent to approximately 20 days of background radiation. One theoretical shortcoming of this technology is that it does not permit soft tissue imaging. This is seldom a concern in sinonasal evaluation, as this is typically undertaken in bone windows. The acquired data are immediately formatted into triplanar (axial, sagittal, coronal) reconstructions and is also compatible with devices used for intraoperative stereotactic navigation, which can be used to confirm relationships between the disease process, medial orbital wall, and skull base during surgery (Fig. 18-6 and 18-7). Variations of this and other technologies have also been adapted for intraoperative use to ensure completeness of resection and to update anatomic relationships for further intraoperative stereotaxis.Notably, imaging of the temporal bone for evaluation of middle ear structures can be performed via POC-CT as well. Medical management of chronic sinusitis includes a prolonged course of oral antibiotics for 3 to 6 weeks, nasal and/or oral steroids, and nasal irrigations with saline or antibiotic solutions.8 Underlying allergic disease may be managed with antihistamines and possible allergy immunotherapy. Although the role of these treatments in resolving chronic sinusitis remains questionable, they may be considered in patients with comorbid allergic rhinitis or as part of empirical management before consideration of surgery. The use of oral steroids may also be selected empirically, particularly in patients with comorbid chronic airway inflammatory diseases such as nasal polyps, allergic rhinitis, or asthma. The decision to use oral steroids must be individualized with consideration of the risks and side effects of these medications. As yet, there is no ­consensus regarding what constitutes a “maximum” course of medical therapy that should be attempted before consideration of s­ urgery for chronic sinusitis. It should be noted that unless there is suspicion of neoplasm or pending complication of sinusitis, the decision to proceed with surgery is highly individualized. This is because surgery for uncomplicated chronic sinusitis is elective, and patients who “fail” medical management will exhibit significant variability in symptoms, physical signs, and CT findings. More aggressive medical and surgical management may be necessary in patients with comorbid chronic inflammatory disease of the airways such as allergic rhinitis, nasal polyposis, and asthma. Surgery is typically preformed endoscopically where the goals are to remove polyps, enlarge the natural sinus ostia (see Fig. 18-3), and to remove chronically infected bone to promote both ventilation and drainage of the sinus cavities. Inspissated mucin or pus is drained and cultured. Eventual resolution of the chronic inflammatory process can be attained with a combination of meticulous surgery and directed medical therapy, although the patient must understand that surgery may not alter the underlying immunologic pathophysiology. In cases where resection of inflammatory tissue and polyps are not required, recent trends have also included use of angioplasty-type balloons to dilate sinus ostia. The exact role for this technology is unclear, but appears to have promise in outpatient office management of patients with focal or limited obstructive pathology. The role of fungi in sinusitis is an area of active investigation. Fungal sinusitis may take on both noninvasive and invasive forms. The noninvasive forms include intracavitary fungal ball and allergic fungal sinusitis, both of which occur in immunocompetent patients. A fungal ball is typically seen in individuals with chronic (or recurrent acute) symptoms that are often VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK Figure 18-6. Triplanar imaging revealing proximity to critical structures such as the orbital wall and skull base. This can be used for diagnosis of sinus opacification as well as stereotactic intraoperative navigation, where endoscope view (lower right) can be radiologically correlated with location in the 3 cardinal planes. This case reflects classic allergic fungal sinusitis where the opacified sinuses are filled with heterogeneous whitish material on CT images. Polyps in the ethmoid cavity are seen on the endoscope image. 570 UNIT II PART SPECIFIC CONSIDERATIONS Figure 18-7. Sphenoid sinus fungal ball. The sinus has been opened revealing cheesy material during this intraoperative endoscopic view (lower right). The crosshairs stereotactically confirm location within the sphenoid sinus radiologically in the cardinal planes. subtle and limited to a single sinus. Patients may complain about the perception of a foul odor and occasionally report e­ xpelling crusty debris upon nose blowing. Fungus balls represent a ­significant proportion of isolated sphenoid sinus pathology (Fig. 18-7). The most common scenario, however, is surgery to remove the debris and re-establish sinus ventilation, which is almost always curative. Classic allergic fungal sinusitis is thought to involve direct stimulation of eosinophils by a subset of helper T cells (TH2) primed by fungal antigens. Patients often present with chronic sinusitis that has been especially refractory to medical management. CT scan has characteristic features, and endoscopic evaluation reveals florid polyposis and inspissated mucin containing fungal debris and products of eosinophil breakdown. The implicated organisms are usually those of the Dematiaceae family, but Aspergillus species are also seen.11 Treatment includes systemic steroids, surgery, and nasal irrigations. Oral antifungal therapy is sometimes indicated as well. Immunocompetent patients may occasionally develop an indolent form of invasive fungal sinusitis, but more commonly, invasive fungal sinusitis affects immunocompromised patients, diabetics, or the elderly.11 Fungal invasion of the microvasculature causes ischemic necrosis and black eschar of the sinonasal mucosa. Aspergillus and fungi of the Mucoraceae family are often implicated with the latter more common in diabetic patients. Treatment requires aggressive surgical debridement and IV antifungals, but the prognosis is dismal.12 Pharyngeal and Adenotonsillar Disease The pharyngeal mucosa contains significant concentrations of lymphoid tissue, predisposing this area to reactive inflammatory changes. Lymphoid tissue of various pharyngeal subsites forms the so-called Waldeyer’s ring, consisting of the palatine tonsils (“the tonsils”), lingual tonsil (lymphoid tissue accumulation within the tongue base), and adenoid. The mucosa of the posterior and lateral pharyngeal walls is also rich with lymphoid cells. Infection, immune-mediated inflammatory disease, or local stressors, such as radiation or acid reflux, may initiate lymphoid reactivity and associated symptoms. Chronic or recurrent adenotonsillitis and adenotonsillar hypertrophy are the most common disorders affecting these structures. In the vast majority of cases, infectious pharyngitis is viral rather than bacterial in origin. Most cases resolve without complication from supportive care and possibly antibiotics. Patients with tonsillitis typically present with sore throat, dysphagia, and fever. The mucosa is inflamed. Tonsillar exudates and cervical adenitis may be seen, especially when the etiology is bacterial. If adenoiditis is present, symptoms may be similar to those of sinusitis. Objective evaluation of the adenoid requires endoscopy and/or radiographic imaging (lateral neck soft-tissue X-ray). Tonsillitis and adenoiditis may follow acute, recurrent acute, and chronic temporal patterns. It should be noted, however, that clinical diagnosis often is inaccurate for determining whether the process is bacterially induced. When the patient also has hoarseness, rhinorrhea, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Occasionally, pharyngeal biopsy specimen or cervical lymph node biopsy specimen is required to establish the diagnosis. Noninfectious causes of pharyngitis must also be considered. These include mucositis from chemoradiation therapy, which may be associated with fungal superinfection. Pharyngitis may also be seen in immune-mediated conditions such as erythema multiforme, bullous pemphigoid, and pemphigus vulgaris. In addition, reflux is being increasingly identified as a cause of both laryngitis and pharyngitis, particularly when the symptoms are chronic. A 24-hour pH probe is the gold standard diagnostic test, and treatment is usually successful with lifestyle modification, although proton pump inhibitors are often prescribed.14 Obstructive adenotonsillar hypertrophy may present with nasal obstruction, rhinorrhea, voice changes, dysphagia, and sleep-disordered breathing or OSA depending on the particular foci of lymphoid tissue involved. Tonsillectomy and adenoidectomy are indicated for chronic or recurrent acute infection and for obstructive hypertrophy.15 The American Academy of Otolaryngology–Head and Neck Surgery Clinical Indicators Compendium suggests tonsillectomy after three or more infections per year despite adequate medical therapy. Tonsillectomy has also been advocated in children who miss 2 or more weeks of school annually secondary to recurrent tonsil infection. Multiple techniques have been described, including electrocautery, sharp dissection, laser, and radiofrequency ablation. There is no consensus as to the best method. In cases of chronic or recurrent infection, surgery is considered only after failure of medical therapy. Patients with recurrent peritonsillar abscess should undergo tonsillectomy when the acute inflammatory changes have resolved. Selected cases, however, require tonsillectomy in the acute setting for the management of severe inflammation, systemic toxicity, or impending airway compromise. Adenoidectomy, in conjunction with myringotomy and tube placement, may be beneficial for children with chronic or recurrent otitis media.16 This is because the adenoid appears to function as a bacterial reservoir that seeds the middle ear via the Eustachian tube. Adenoidectomy is also the first line of surgical management for children with chronic sinusitis. In addition to acting as a bacterial reservoir, an obstructive adenoid impairs mucociliary clearance from the sinonasal tract into the pharynx. The primary complications of tonsillectomy include perioperative bleeding, airway obstruction, death, and readmission for dehydration secondary to postoperative dysphagia.17 Complications of adenoidectomy also include hemorrhage, as well as nasopharyngeal stenosis. In both procedures, there is risk of velopharyngeal insufficiency. In the latter condition, nasal regurgitation of liquids and hypernasal speech are experienced. Patients with significant airway obstruction secondary to adenotonsillar hypertrophy are also at risk for postobstructive pulmonary edema syndrome, once the obstruction is relieved by adenotonsillectomy. Overall, bleeding is the most prevalent risk and may require a return trip to the operating room for control. With the exception of bleeding, which is observed in 3% to 5% of patients, most of these complications are rare or self-limiting. It deserves special notation that adenotonsillectomy in a child with Down syndrome requires attention to the cervical spine. Patients with this syndrome may exhibit atlantoaxial instability, resulting in cervical spine injury if the neck is extended for the procedure. Baseline radiographs, with appropriate orthopedic or neurosurgical consultation, are indicated preoperatively. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 571 CHAPTER 18 DISORDERS OF THE HEAD AND NECK cough, and no evidence of exudates or adenitis, an upper respiratory viral infection can be presumed. When a bacterial cause is suspected antibiotics should be initiated to cover the usual organisms: group A beta-hemolytic streptococci (Streptococcus pyogenes), S. pneumoniae, and group C and G streptococci.13 H. influenzae and anaerobes also have been implicated. It is particularly important to identify group A beta-hemolytic streptococci in pediatric patients to initiate timely antibiotic therapy, given the risk of rheumatic fever, which may occur in up to 3% of cases if antibiotics are not used. Historically, if bacterial pharyngitis was suspected in a child, oropharyngeal swab with culture was performed to identify group A beta-hemolytic streptococci. Currently, rapid antigen assays are available with sensitivity and specificity of approximately 85% and 90%, respectively. Some experts advocate culture only when these are negative. Unnecessary antibiotic therapy for patients who are unlikely to have a bacterial etiology should be avoided, given the already mounting antibiotic resistance problem. When suspicion for a bacterial process is high, or with positive culture/antigen assay results, treatment may include penicillin, cephalosporin, or macrolide antibiotics in penicillin-allergic patients. Complications of S. pyogenes pharyngitis may be systemic, including rheumatic fever, poststreptococcal glomerulonephritis, and scarlet fever. The incidence of glomerulonephritis is not influenced by antibiotic therapy. Scarlet fever results from production of erythrogenic toxins by streptococci. This causes a punctate rash, first appearing on the trunk and then spreading distally, sparing the palms and soles. The so-called strawberry tongue also is seen. Locoregional complications include peritonsillar abscess and, rarely, deep-neck space abscess. Peritonsillar abscess is typically drained with transoral technique under local anesthesia, as is the authors’ practice, but some suggest that needle aspiration without incision is sufficient.13 Deep neck space abscess, which more commonly is odontogenic in origin, usually requires operative incision and drainage via a transcervical approach. Candida albicans is the most common fungal organism to cause pharyngitis. This organism is a normal component of the oral flora, but under conditions of immunosuppression, broad-spectrum antibacterial therapy, poor oral hygiene, or vitamin deficiency, it may become pathogenic. Whitish-cheesy or creamy mucosal patches are observed with underlying erythema. Diagnosis is easily established by Gram’s stain of this material, revealing budding yeast and pseudohyphae. Oral (-azole) and topical (nystatin) antifungals are usually effective, and immunosuppressed patients may require prophylactic therapy. Atypical cases of pharyngitis may be caused by Corynebacterium diphtheriae, Bordetella pertussis (whooping cough), Neisseria gonorrhoeae, and secondary syphilis. Diphtheria and pertussis are fortunately rare in developed countries as a result of pediatric vaccination. Atypical viral causes include herpes simplex virus, Epstein-Barr virus (EBV), cytomegalovirus, and HIV are associated with pharyngitis. Systemic EBV infection represents clinical mononucleosis, although syphilis, cytomegalovirus, and HIV are known to cause mononucleosis-like syndromes. These conditions, particularly EBV, may exhibit an exudative pharyngotonsillitis that may be confused with a bacterial etiology. Progression of the clinical picture reveals lymphadenopathy, splenomegaly, and hepatitis. Diagnosis is established based on the detection of heterophile antibodies or atypical lymphocytes in the peripheral blood. 572 UNIT II PART SPECIFIC CONSIDERATIONS Sleep disorders represent a continuum from simple snoring to upper airway resistance syndrome to obstructive sleep apnea (OSA).18 Upper airway resistance syndrome and OSA are associated with snoring, excessive daytime somnolence, fatigue, and frequent sleep arousals. In OSA, polysom1 nogram demonstrates at least 10 episodes of apnea or hypopnea per hour of sleep. The average number of apneas and hypopneas per hour can be used to calculate a respiratory disturbance index, which, along with oxygen saturation, can be used to grade the severity of OSA. These episodes occur as a result of collapse of the pharyngeal soft tissues during sleep. In adults, it should be noted that in addition to tonsil size, factors such as tongue size and body mass index (especially >35 kg/m2) are significant predictors of OSA. Other anatomic findings associated with OSA include obese neck, retrognathia, low hyoid bone, and enlarged soft palate. Surgery should be considered after failure of more conservative measures, such as weight loss, elimination of alcohol use, use of oral appliances to open the airway during sleep, and continuous positive airway pressure (CPAP). Recent trends have also included the use of oral appliances to prevent base of tongue retro-prolapsed and subsequent narrowing of the pharyngeal airway during sleep. Oral appliances are useful to avert simple snoring and mild OSA, but their role in more advanced cases is unclear. It is well accepted that CPAP is much more efficacious than an oral appliance, while the latter is associated with improved patient compliance. Those failing conservative therapies may elect a surgical procedure should be tailored to the particular patient’s pattern of obstruction. In children, surgical management typically involves tonsillectomy and/or adenoidectomy, because the disorder is usually caused, at least in part, by hypertrophy or collapse of these structures. In any individual patient, the anatomy must be carefully evaluated to determine whether the site of airway collapse is in the retropalatal region, retrolingual area, or both. In adults, uvulopalatoplasty is frequently performed to alleviate soft-palate collapse and is the most common operation performed for sleep-disordered breathing. The goal of this procedure is to remove redundant tissue from the uvula and soft palate, along with obstructive tonsillar tissue. This can be accomplished with cold steel, laser, and/or cautery. Adults with significant nasal obstruction may benefit from adenoidectomy, septoplasty, reduction in size of the inferior turbinates, and possibly external nasal surgery. Patients with a significant component of retrolingual obstruction may be candidates for tongue base reduction, tongue base advancement, or hyoid suspension. Additionally, a variety of maxillomandibular advancement procedures also have been described to enlarge the anterior-posterior dimension of the retrolingual airway. Patients with moderate to severe sleep apnea frequently manifest involvement of the tongue base. However, management of this subgroup may be difficult, as procedures addressing the retrolingual airway can involve difficult recovery, significant morbidity, and limited success. These patients often continue to require continuous positive airway pressure despite performance of multilevel surgical procedures. Patients with severe OSA (respiratory disturbance index >40, lowest nocturnal oxygen saturation <70%) and unfavorable anatomy or comorbid cardiopulmonary disease may require tracheotomy,19 which is the only surgical “cure” for OSA. Tracheotomy should be offered in patients with evidence of right heart failure (cor ­pulmonale), which is a potential sequela of severe OSA or undertreated cases of moderate OSA. On the opposite end of the spectrum, many patients present with snoring but fail to exhibit OSA according to polysomnographic criteria. These “social snorers” may pursue elective procedures that stiffen the uvula and soft palate. This may be accomplished by the application of radiofrequency energy or cautery to induce submucosal scar, or by palatal implants. Elective uvulopharyngoplasty may also be a consideration in this population. Benign Conditions of the Larynx Disorders of voice may affect a wide array of patients with respect to age, gender, and socioeconomic status. The principal symptom of these disorders, at least when a mass lesion is present, is hoarseness. Other vocal manifestations include hypophonia or aphonia, breathiness, and pitch breaks. Benign laryngeal disorders may also be associated with airway obstruction, dysphagia, and reflux.20 Smoking may also be a risk factor for benign disease, but this element of the history should raise the index of suspicion for malignancy. Recurrent respiratory papillomatosis (RRP) reflects involvement of human papillomavirus (HPV) within the mucosal epithelium of the upper aerodigestive tract. The larynx is the most frequently involved site, and subtypes 6 and 11 are the most often implicated. The disorder typically presents in early childhood, secondary to viral acquisition during vaginal delivery. Many cases resolve after puberty, but the disorder may progress into adulthood. Adult-onset RRP typically occurs in the third or fourth decade of life, is usually less severe, and is more likely to involve extralaryngeal sites of the upper aerodigestive tract. With laryngeal involvement, RRP is most likely to present with hoarseness, although airway compromise may be observed. The diagnosis can be established with office endoscopy. Currently, there is no “cure” for RRP. Treatment involves operative microlaryngoscopy with excision or laser ablation, and the natural history is eventual recurrence. Therefore, surgery has an ongoing role for palliation of the disease. Multiple procedures are typically required over the patient’s lifetime. Several medical therapies, including intralesional cidofovir injection and oral indole-3-carbinol, are being investigated to determine their abilities to retard recurrence. Additionally, the advent of HPV vaccines has suggested a role for this therapy in prevention of RRP.21 Laryngeal granulomas typically occur in the posterior larynx on the arytenoid mucosa (Fig. 18-8). These lesions are Figure 18-8. Laryngeal granuloma. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 573 Figure 18-9. Large cyst of vocal cord. as the supraglottic larynx. Occasionally, they derive from minor salivary glands, and congenital cysts may persist as remnants of the branchial arch. Cysts may present in a variety of ways depending on the size and site of origin (Fig. 18-9). Cysts of the vocal cord may be difficult to distinguish from vocal polyps, and video stroboscopic laryngoscopy may be necessary to help establish the diagnosis. Cysts observed in children can be quite large, thus compromising the airway. Lesions of the true vocal cord usually present with hoarseness. Treatment again depends on the size and site of the cyst. Large cysts of the supraglottic larynx are treated by marsupialization with cold steel or a CO2 laser. Those of the vocal cord itself require careful microsurgical technique for complete removal of the cyst while preserving the overlying mucosa. Leukoplakia of the vocal fold represents a white patch (which cannot be wiped off ) on the mucosal surface, usually on the superior surface of the true vocal cord. Rather than a diagnosis per se, the term leukoplakia describes a finding on laryngoscopic examination. The significance of this finding is that it may represent squamous hyperplasia, dysplasia, and/or carcinoma. Lesions exhibiting hyperplasia have a 1% to 3% risk of progression to malignancy. In contrast, that risk is 10% to 30% for those demonstrating dysplasia. Furthermore, leukoplakia may be observed in association with inflammatory and reactive pathologies, including polyps, nodules, cysts, granulomas, and papillomas. The wide, differential diagnosis for leukoplakia necessitates sound clinical judgment when selecting lesions that require operative direct laryngoscopy with biopsy specimen for histopathologic analysis. Features of ulceration and erythroplasia are particularly suggestive of possible malignancy. A history of smoking and alcohol abuse should also prompt a malignancy work-up. In the absence of suspected malignancy, conservative measures are used for 1 month. These include reduction of caffeine and alcohol, which are dehydrating and promote laryngopharyngeal reflux, proper hydration, and elimination of vocal abuse behaviors. Antireflux therapy, including proton pump inhibitors, may be prescribed. Investigational therapies, including retinoids, also have been attempted. Any lesions that progress, persist, or recur should be considered for excisional biopsy specimen. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK typically secondary to multiple factors,22 including reflux, voice abuse, chronic throat clearing, endotracheal intubation, and vocal fold paralysis. Effective management requires identification of the underlying cause(s). Patients report pain (often with swallowing) more commonly than vocal changes. In addition to fiber-optic laryngoscopy, work-up may include voice analysis, laryngeal electromyography (EMG), and pH probe testing.23 Treatment is individualized, depending on the contributing factors identified. First-line modalities that may be used include voice rest, voice retraining therapy, and anti-reflux therapy. The management of vocal cord paresis/paralysis is discussed later in this section. It is notable that the majority of cases demonstrate a component of reflux and when maximal medical therapy has failed, fundoplication may be indicated. The role of surgical excision is somewhat controversial, because it does not address the underlying etiology and is frequently associated with recurrence. Nonetheless, excision is indicated when carcinoma is suspected or when the patient has airway obstruction. Surgery may also be indicated in selected cases when a granuloma has matured into a fibroepithelial polyp, or when the patient (e.g., a performing artist) requires prompt removal for voice restoration. Surgical excision is optimally performed under jet ventilation so as to avoid endotracheal intubation. During surgery, it is important to preserve the arytenoid perichondrium to promote epithelialization postoperatively. Edema in the superficial lamina propria of the vocal cord is known as polypoid corditis, polypoid laryngitis, polypoid degeneration of the vocal cord, or Reinke’s edema. The superficial lamina propria just underlies the vibratory epithelial surface. Edema is thought to arise from injury to the capillaries that exist in this layer, with subsequent extravasation of fluid. Patients report progressive development of a rough, lowpitched voice. Females more commonly present for medical attention because the lowered vocal frequency is more evident, given the higher fundamental frequency of the female voice. The etiology is also multifactorial and may involve smoking, laryngopharyngeal reflux, hypothyroidism, and vocal hyperfunction. Most of these patients are heavy smokers and findings are typically bilateral.24 Focal, unilateral hemorrhagic vocal cord polyps are more common in men. These occur secondary to capillary rupture within the mucosa by shearing forces during voice abuse. Use of anticoagulant or antiplatelet drugs may be a risk factor. As with laryngeal granulomas, treatment of polypoid corditis and vocal cord polyps requires addressing the underlying factors. Conservative management includes absolute discontinuance of smoking, reflux management, and voice therapy. Notably, topical and systemic steroids are ineffective for these conditions. For polypoid corditis, elective surgery may be performed under microlaryngoscopy to evacuate the gelatinous matrix within the superficial lamina propria and trim excess mucosa. Focal polyps may be excised superficially under microlaryngoscopy. Surgery, particularly for polypoid corditis, will be less effective in patients who continue to smoke, although it should be noted that because of their heavy smoking history, surgery might be necessary to rule out occult malignancy. Surgery for polypoid corditis and hemorrhagic polyps may be accomplished either with cold steel or by using the carbon dioxide (CO2) laser. Postoperative voice therapy is usually indicated. Vocal cord cysts may occur under the laryngeal mucosa, particularly in regions containing mucous-secreting glands, such 574 UNIT II PART SPECIFIC CONSIDERATIONS Unilateral vocal cord paralysis is typically iatrogenic in origin,25 following surgery to the thyroid, parathyroid, carotid, or cardiothoracic structures. Vocal cord paralysis may also be secondary to malignant processes in the lungs, thoracic cavity, skull base, or neck. In the pediatric population up to one fourth of cases may be neurologic in origin, with Arnold-Chiari malformation being the most common. Overall, the left vocal cord is more commonly involved secondary to the longer course of the recurrent laryngeal nerve (RLN) on that side, which extends into the thoracic cavity. When anterior approaches to the cervical spine are performed, however, the right RLN is at an increased risk, because it courses more laterally to the tracheoesophageal complex. Neurotoxic medications, trauma, intubation injury, and atypical infections are less common causes of vocal cord paralysis. The cause remains idiopathic in up to 20% of adults and 35% of children. These cases should prompt an imaging work-up to examine the course of the vagal/RLN in question: from the skull base to the aortic arch on the left, and from skull base to the subclavian on the right. “Idiopathic” left true vocal cord paralysis may be a presenting sign of malignancy involving the lung, thyroid, or esophagus. Adults typically present with hoarseness and the voice may be breathy if the contralateral vocal cord has not compensated to close the glottic valve. If the proximal vagus nerve or the superior laryngeal nerve is involved, the patient may demonstrate aspiration secondary to diminished supraglottic sensation. Stridor, weak cry, and respiratory distress are seen in children, but adults typically do not exhibit signs of airway compromise unless paralysis is bilateral. Flexible fiber-optic laryngoscopy usually confirms the diagnosis, but laryngeal EMG may be necessary to distinguish vocal cord paralysis from mechanical fixation secondary to scar tissue or cricoarytenoid joint fixation. The position of the paralyzed fold depends on the residual innervation, pattern of reinnervation, and the degrees of atrophy and fibrosis of the laryngeal musculature. In bilateral vocal cord paralysis, the cords are often paralyzed in a paramedian position, creating airway compromise that necessitates tracheotomy. Once an airway is secure, vocal cord lateralization or arytenoidectomy may be performed electively to provide an adequate airway. Treatment of unilateral vocal cord paralysis includes speech therapy, which promotes glottic closure to optimize the voice and prevent aspiration. Some patients do well with this modality alone. Surgical treatment to augment or medialize the paralyzed vocal fold is performed to provide a surface against which the contralateral normal fold may make contact. Injection laryngoplasty may be performed under office or operative laryngoscopy with a variety of autologous (fat, collagen) or alloplastic (hydroxyapatite, hyaluronic acid, micronized cadaveric human collagen) compounds. Teflon injection is of historical significance only secondary to the incidence of severe foreign body inflammatory reactions. Injection of the vocal fold increases its bulk to optimize closure with the contralateral normal fold. This technique also is useful for vocal cord atrophy, which may occur with aging. Laryngeal framework surgery involves the implantation of cartilage, hydroxyapatite, Gore-Tex, or silicone under the musculomembranous fold via an external approach through a window in the thyroid cartilage (Fig. 18-10).26 This may be combined with procedures to adduct the vocal process of the arytenoids. Laryngeal reinnervation (with the ansa cervicalis to the RLN transfer) and pacing have also been attempted with various success. Figure 18-10. Cross-section of the larynx demonstrating the principle of medialization laryngoplasty. An implant is used to push the paralyzed vocal cord toward the midline. Vascular Lesions Vascular lesions can be broadly classified into two groups: hemangiomas and vascular malformations.27 Hemangiomas are the most common vascular lesions present in infancy and childhood. These lesions are present at birth in up to 30% of cases, but usually become apparent in the first few weeks of life. The lesions proliferate in size over the first year before beginning involution, which subsequently occurs over the next 2 to 12 years. While 40% of cases will resolve completely, the remainder will require intervention. Once the proliferative phase has ended, the lesion should be observed every 3 months for involution, and surgery should be considered for those that have not significantly involuted by 3 to 4 years of age. Surgical treatment of proliferating hemangiomas is reserved for lesions associated with severe functional or cosmetic problems, such as those involving the nasal tip or periorbital region. Treatment is performed with either the flashlamp-pumped pulsed-dye laser (FPDL), the potassium titanyl phosphate (KTP) laser, or the neodymium yttrium-aluminum garnet (Nd:YAG) laser, repeated every 4 to 6 weeks until the lesion disappears. Systemic steroids may be used to halt rapidly proliferating lesions until the child reaches 12 to 18 months, after which growth should stabilize or involution begin. Subcutaneous interferon-α-2a may also be used for this purpose. This treatment, however, is associated with neurologic side effects and should be used with caution.27,28 There have also been recent trends of using propranolol to inhibit hemangioma growth, and this practice is gaining popularity in complicated cases. Vascular malformations, in contrast, are almost always present at birth and slowly enlarge without proliferation.29 These may arise from capillaries, venules, veins, arteriovenous channels, and/or lymphatics. Capillary malformations usually involve the midline neck or forehead, and may fade with age. Venular malformations are also known as port-wine stains. These lesions often follow facial dermatomes and usually thicken with age. Venous malformations are composed of ectatic veins within the lips, tongue, or buccal area. These may present as purple masses or subcutaneous/submucosal nodules. Arteriovenous malformations are rare malformations of arteriovenous channels that failed to regress during development. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Lymphatic malformations or lymphangiomas of the head and neck usually involve the cervical area, in which case they are more commonly macrocystic and well demarcated. Those arising above the hyoid bone tend to be microcystic and have an infiltrative quality. Lymphangiomas may become secondarily infected and may rapidly enlarge, causing airway compromise. These lesions may also be associated with feeding difficulties and failure to thrive. Capillary hemangiomas and superficial port-wine stains are effectively treated by FPDL. The KTP or Nd:YAG laser is used for deeper port-wine stains. Venous malformations may be treated with laser, sclerotherapy, and/or surgical excision, depending on the depth, size, and location. Superficial lesions are treated with the Nd:YAG laser, which has deeper penetration than either the FPDL or KTP laser. Deeper venous malformations may benefit from Nd:YAG therapy of the superficial component followed by meticulous surgical excision of the deeper component. Sclerotherapy should be undertaken with extreme caution in the head and neck, because the valveless quality of the veins in this region introduces significant risk of cavernous sinus thrombosis. Arteriovenous malformations require formal surgical resection with negative margins. Preoperative angiographic embolization is frequently used to facilitate surgery. Microvascular reconstruction may be necessary, depending on the extent of the resection required. Surgical excision is also required for lymphatic malformations, although superficial lesions are sometimes treatable with the CO2 laser. This often is difficult for microcystic cases given the infiltrative nature. Sclerotherapy with OK-432 is effective in macrocystic lymphangiomas, and multiple other sclerosing agents, including bleomycin, have been explored.30 575 CHAPTER 18 DISORDERS OF THE HEAD AND NECK TRAUMA OF THE HEAD AND NECK Management of head and neck soft-tissue trauma follows general surgical principles, with several salient features. In the acute setting, patients should be managed with head-of-bed elevation to decrease tissue edema. Most lacerations without significant tissue loss can be closed primarily, which is preferred where possible. Head and neck soft tissues have the benefit of a robust blood supply. Thus, nearly devitalized soft tissues often survive, such that any tissue debridement should be very conservative. Closure of trapdoor lacerations requires conservative undermining of surrounding tissue and good approximation of subdermal levels prior to epidermal closure. A pressure dressing is also applied. These measures are employed to avoid a pincushion deformity (Fig. 18-11). Typically, when repairing facial lacerations, subdermal layers are approximated with an absorbable 3-0 or 4-0 suture such as, Vicryl or polydioxanone, and the skin is closed using 5-0 or 6-0 monofilament nylon or Prolene. Sutures are removed after 4 to 5 days, but may be removed earlier in thin-skinned areas. Systemic antibiotics are reserved for through-and-through mucosal lacerations, contaminated wounds, bite injuries, and when delayed closure is performed (>72 hours). The chosen antibiotic should cover S. aureus. After skin injuries, the patient is instructed to avoid sunlight, because this can cause pigmentary abnormalities in the abrasion or scar line, which matures over a 6- to 12-month period. Wound closure must be understood in the context of the cosmetic and functional anatomic landmarks of the head and neck. Management of injuries to the eyelid requires identification of the orbicularis oculi, which is closed in a separate layer. The gray line (conjunctival margin; Fig. 18-12) must Figure 18-11. Trap door laceration (A) healed with a “pin cushion” deformity (B) soft-tissue layers must be meticulously approximated (C) to avoid this complication. Figure 18-12. Alignment of the gray line is the key step in the repair of eyelid lacerations. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 576 2% 36% 3% 3% UNIT II PART 20% 14% 21% SPECIFIC CONSIDERATIONS Figure 18-14. Sites of common mandible fractures. Figure 18-13. Approximation of the vermilion border is the key step in the repair of lip lacerations. be carefully approximated to avoid lid notching or height mismatch. Management of lip injuries follows the same principle. The orbicularis oris must be closed, and the vermilion bor2 der carefully approximated (Fig. 18-13). Injuries involving one-fourth the width of the eyelid or one third the width of the lip may be closed primarily; otherwise, flap or grafting procedures may be required. With laceration of the auricle, key structures such as the helical rim and antihelix must be carefully aligned. These injuries must be repaired so that the cartilage is covered. The principles of auricular repair are predicated on the fact that the cartilage has no intrinsic blood supply and is thus susceptible to ischemic necrosis following trauma. The suture should be passed through the perichondrium, while placement through the cartilage itself should be avoided. Auricular hematomas should be drained promptly, with placement of a bolster as a pressure dressing. A pressure dressing is frequently advocated after closure of an ear laceration. It also deserves note that the surgeon must avoid the temptation to perform aggressive debridement after injuries to the eyelid or auricle. Given the rich vascular supply to the face and neck, many soft-tissue components that appear devitalized will indeed survive. Most traumatic facial nerve injuries are secondary to temporal bone trauma, which is discussed later in this section. Softtissue injuries occurring in the midface may involve distal facial nerve branches. Those injured anterior to a vertical line dropped from the lateral cantus do not require repair secondary to collateral innervation in the anterior midface. Posterior to this line, the nerve should be repaired, primarily if possible, using 8-0 to 10-0 monofilament suture to approximate the e­ pineurium under microscopic visualization. If neural segments are missing, cable grafting is performed using either the greater auricular (provides 7 to 8 cm) or sural nerve (up to 30 cm) as a donor. Injuries to the buccal branch should alert the examiner to a possible parotid duct injury. This structure lies along an imaginary line drawn from the tragus to the midline upper lip, running along with the buccal branch of the facial nerve. The duct should be repaired over a 22-gauge stent or marsupialized into the oral cavity. Facial bone fractures most commonly involve the mandible. Fractures most often involve the angle, body, or condyle, and in most cases, two or more sites are almost always involved (Fig. 18-14). Fractures are described as either favorable or unfavorable, depending on whether or not the masticatory musculature tends to pull the fracture into reduction or distraction. Vertically favorable fractures are brought into reduction by the masseter, while horizontally favorable fractures are brought into reduction by the pterygoid musculature. The fracture is usually evaluated by radiographic exam using a Panorex, but specialized plain film views, and occasionally CT scan, are necessary in selected cases. Classical management of mandible fractures dictated closed reduction and a 4- to 6-week period of intermaxillary fixation (IMF) with arch bars applied via circumdental wiring. Comminuted, displaced, or unfavorable fractures underwent open reduction and wire fixation in addition to IMF. Currently, arch bars and IMF are performed to establish occlusion. The fracture is then exposed and reduced, using transoral approaches where possible. Transcervical approaches are required to address fractures of the ramus or posterior body, with careful attention given to preserving the marginal mandibular branch of the facial nerve. Rigid fixation is then accomplished by the application of plates and screws. Selected fractures, such as those of the body, 3 benefit from dynamic compression plating, which applies pressure toward the fracture line. With rigid fixation, IMF is required to establish occlusion, and may not be necessary for a full 6 postoperative weeks. This is preferable because IMF is associated with gingival and dental disease, as well as with significant weight loss and malnutrition, during the fixation period. New techniques have included the 4-point fixation technique, where the maxilla and mandible are held in occlusion by wires attached to intraoral cortical bone screws, with two screws above and below the occlusal line anteriorly. In edentulous patients, determining the baseline occlusion is of less VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 577 Frontal bar II Lateral zygomaticomaxillary buttresses I Medial nasomaxillary buttresses Figure 18-15. Major buttresses of the midface. Figure 18-16. Classic Le Fort fracture patterns. significance because dentures may be refashioned once healing is complete. If IMF is required to aid in immobilization of the fracture in an edentulous patient, interosseous wiring and/or the fabrication of custom-made splints is required. Midface fractures are classically described in three patterns: Le Fort I, II, and III. A full understanding of midface structure is first necessary (Fig. 18-15). Three vertical buttresses support the midface: the nasofrontal-maxillary, the frontozygomaticomaxillary, and pterygomaxillary.31 The five horizontal buttresses include the frontal bone, nasal bones, upper alveolus, zygomatic arches, and the infraorbital region. Classical signs of midface fractures in general include subconjunctival hemorrhage; malocclusion; midface numbness or hypesthesia (maxillary division of the trigeminal nerve); facial ecchymoses/ hematoma; ocular signs/symptoms; and mobility of the maxillary complex. Le Fort I fractures occur transversely across the alveolus, above the level of the teeth apices. In a pure Le Fort I fracture, the palatal vault is mobile while the nasal pyramid and orbital rims are stable. The Le Fort II fracture extends through the nasofrontal buttress, medial wall of the orbit, across the infraorbital rim, and through the zygomaticomaxillary articulation. The nasal dorsum, palate, and medial part of the infraorbital rim are mobile. The Le Fort III fracture is also known as craniofacial disjunction. The frontozygomaticomaxillary, frontomaxillary, and frontonasal suture lines are disrupted. The entire face is mobile from the cranium. It is convenient to conceptualize complex midface fractures according to these patterns (Fig. 18-16); however, in reality, fractures reflect a combination of these three types. Also, the fracture pattern may vary between the left and right sides of the midface. Lateral blows to the cheek may be associated with isolated zygoma fractures. The zygoma is typically displaced inferiorly and medially with disruption of the suture lines between the temporal, frontal, and maxillary bones and the zygoma. Disruption of the latter articulation may be associated with depression into the maxillary sinus and blood in the sinus cavity. Fractures of the midface and/or zygoma may be associated with an orbital blowout, whereas the orbital floor is disrupted and orbital soft tissues subsequently herniate into the maxillary sinus (Fig. 18-17). The mechanism of orbital blowout may involve propagation of adjacent fracture lines or may be the result of a sudden increase in intraorbital pressure during the injury. This may be associated with enophthalmos or entrapment of the inferior oblique muscle. The latter results in diplopia upon upward gaze. Entrapment is confirmed by forced duction testing, where, under topical or general anesthesia, the muscular attachment of the inferior oblique is grasped with forceps and manipulated to determine passive ocular mobility. Fractures of the midface, zygoma, and orbital floor are best evaluated using CT scan, and repair requires a combination of transoral and external approaches to achieve at least two points of fixation for each fractured segment.32 Significant areas of bone loss can be reconstructed with commercially available hydroxyapatite Figure 18-17. Coronal computed tomography demonstrating an orbital blowout fracture with herniation of orbital contents into the maxillary sinus. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK III 578 UNIT II PART SPECIFIC CONSIDERATIONS bone cements, an osteoconductive calcium-phosphate matrix. Blowout fractures demonstrating significant entrapment or enophthalmos are treated by orbital exploration and reinforcement of the floor with mesh or bone grafting. Temporal bone fractures occur in approximately one fifth of skull fractures. As with fractures of the mandible and midface, blunt trauma (from motor vehicle accident or assault) usually is implicated. Unfortunately, the incidence of temporal bone fracture from gunshot wounds to the head is rising. Fractures are divided into two patterns (Fig. 18-18), longitudinal and transverse, based on the clinical picture and CT imaging. In practice, most fractures are oblique. By classical descriptions, longitudinal fractures constitute 80% and are associated with lateral skull trauma. Signs and symptoms include conductive hearing loss, ossicular injury, bloody otorrhea, and labyrinthine concussion. The facial nerve is injured in approximately 20% of cases. In contrast, the transverse pattern constitute only 20% of temporal bone fractures and occurs secondary to fronto-occipital trauma. The facial nerve is injured in 50% of cases. These injuries frequently involve the otic capsule to cause sensorineural hearing loss and loss of vestibular function. Hemotympanum may be observed. A cerebrospinal fluid (CSF) leak must be suspected in temporal bone trauma. This resolves with conservative measures in most cases. The most significant consideration in the management of temporal bone injuries is the status of the facial nerve. Delayed or partial paralysis will almost always resolve with conservative management. However, immediate paralysis that does not recover within 1 week should be considered for nerve decompression. Electroneurography and EMG have been used to help determine which patients with delayed-onset complete paralysis will benefit from surgical decompression. The finding of >90% degeneration more than 72 hours after the onset of complete paralysis is considered an indication for surgery.33 Multiple approaches have been described for facial nerve decompression, some of which require the sacrifice of hearing. These patients may have severe intracranial or vascular injuries such that the decision to operate must also be made in the context of the patient’s overall medical stability. It is of paramount importance to protect the eye in patients with facial nerve paralysis of any etiology, because absence of an intact blink reflex will predispose to corneal drying and abrasion. This requires the placement of artificial tears throughout the day with lubricant ointment, eye taping, and/or a humidity chamber at night.34,35 TUMORS OF THE HEAD AND NECK When a discussion of neoplasms of the head and neck is initiated, the conversation frequently focuses on squamous cell carcinoma. This is because the majority of malignancies of this region are represented by this pathology. The diagnosis and treatment of lesions spanning from the lips and oral cavity to the larynx and hypopharynx requires a similar methodic approach. The selection of treatment protocols varies for each site within the upper aerodigestive tract. The importance of multidisciplinary management cannot be underestimated. Presentation of cases before a tumor board allowing review of a patient’s history, physical examination findings, imaging, and prior pathology specimens allows for confirmation of the patient’s status. Additionally, it should encourage discussion from multiple points of view concerning the most appropriate treatment options available. Participation in the discussion with representatives of radiation oncology, medical oncology, surgical oncology, oral maxillofacial surgery/dental medicine, along with radiologists and pathologists specializing in upper aerodigestive tract disorders benefits not only the patient but also represents an excellent teaching opportunity for all disciplines. The development of organ preservation protocol and the evolution of free tissue reconstructive techniques are some of the most significant advances made within the field during the last two decades. The future of the treatment of head and neck cancer lies within the field of molecular biology. As more is understood about the genetics of cancer, tailoring treatment options to a particular tumor mutation has the capacity to maximize survival while achieving the highest quality of life. Etiology and Epidemiology Figure 18-18. View of cranial surface of skull base. Longitudinal (left) and transverse (right) temporal bone fractures. It should come as no surprise that abuse of tobacco and alcohol are the most common preventable risk factors associated with the development of head and neck cancers. This relationship is 4 synergistic rather than additive. Smoking confers a 1.9-fold increased risk to males and a threefold increased risk to females for developing a head and neck carcinoma, compared to nonsmokers. The risk increases as the number of years smoking and number of cigarettes smoked per day increases. Alcohol alone confers a 1.7-fold increased risk to males drinking one to two drinks per day, compared to nondrinkers. This increased risk rises to > threefold for heavy drinkers. Individuals who both smoke (two packs per day) and drink (four units of alcohol VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Although evidence linking HIV infection to squamous cell carcinoma of the head and neck is lacking, several AIDS-defining malignancies, including Kaposi’s sarcoma, and non-Hodgkin’s lymphoma may require the care of an otolaryngologist. 579 Anatomy and Histopathology The upper aerodigestive tract is divided into several distinct sites that include the oral cavity, pharynx, larynx, and nasal cavity/paranasal sinuses. Within these sites are individual subsites with specific anatomic relationships that affect diagnosis, tumor spread, and selection of treatment options. The spread of a tumor from one site to another is determined by the course of the nerves, blood vessels, lymphatic pathways, and fascial planes. The fascial planes serve as barriers to the direct invasion of tumor and facilitate the pattern of spread to regional lymph nodes. The oral cavity extends from the vermilion border of the lip to the hard-palate/soft-palate junction superiorly, to circumvallate papillae inferiorly, and to the anterior tonsillar pillars laterally (Fig. 18-19). It is divided into seven subsites: lips, alveolar ridges, oral tongue, retromolar trigone, floor of mouth, buccal mucosa, and hard palate. Advanced oral cavity lesions may present with mandibular and/or maxillary involvement requiring special consideration at the time of resection and reconstruction. Regional metastatic spread of lesions of the oral cavity is to the lymphatics of the submandibular and the upper jugular region (e.g., levels I, II, and III). The pharynx is divided into three regions: nasopharynx, oropharynx, and hypopharynx. The nasopharynx extends from the posterior nasal septum and choana to the skull base and includes the fossa of Rosenmüller and torus tubarius of the Eustachian tubes laterally. The inferior margin of the nasopharynx is the superior surface of the soft palate. The adenoids, typically involuted in adults, are located with the posterior aspect of this site. Given the midline location of the nasopharynx, bilateral regional metastatic spread is common in these lesions. Lymphadenopathy of the posterior triangle (level V) of the neck should provoke consideration for a nasopharyngeal primary. The major sites within the oropharynx are the tonsillar region, base of tongue, soft palate, and posterolateral pharyngeal walls. Regional lymphatic drainage for oropharyngeal lesions Vermilion Buccal mucosa Hard palate Palatine raphe Soft palate Retromolar trigone Palatine tonsil Circumvallate papillae Lower gingiva Figure 18-19. Oral cavity landmarks. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK per day) had a 35-fold increased risk for the development of a ­carcinoma compared to controls.36 Users of smokeless tobacco have a four times increased risk of oral cavity carcinoma compared to nonusers. Tobacco is the leading preventable cause of death in the United States and is responsible for one of every five deaths.37Approximately one fourth of U.S. adults habitually use tobacco products, with recent trends demonstrating an increase in the use of tobacco products by women. The evidence supporting the need for head and neck cancer patients to pursue smoking cessation after treatment is compelling. In a study by Moore, 40% of patients who continued to smoke after definitive treatment for an oral cavity malignancy went on to recur or develop a second head and neck malignancy.38 For patients who stopped smoking after treatment, only 6% went on to develop a recurrence. Induction of specific p53 mutations within upper aerodigestive tract tumors has been noted in patients with histories of tobacco and alcohol use.39,40 When smokers who develop head and neck squamous cell carcinomas are compared to nonsmokers, differences between the two populations emerge. Koch and associates41 noted that nonsmokers were represented by a disproportionate number of women and were more frequently at the extremes of age (<30 or >85 years of age). Tumors from nonsmokers presented more frequently in the oral cavity, specifically within the oral tongue, buccal mucosa, and alveolar ridge. Smokers presented more frequently with tumors of the larynx, hypopharynx, and floor of mouth. Former smokers, defined as those individuals who had quit >10 years prior, demonstrated a profile more consistent with nonsmokers. In India and Southeast Asia, the product of the areca catechu tree, known as a betel nut, is chewed in a habitual manner and acts as a mild stimulant similar to that of coffee. The nut is chewed in combination with lime and cured tobacco as a mixture known as a quid. The long-term use of the betel nut quid can be destructive to oral mucosa and dentition and is highly carcinogenic.42 Another habit associated with oral malignancy is that of reverse smoking, where the lighted portion of the tobacco product is within the mouth during inhalation. The risk of hard palate carcinoma is 47 times greater in reverse smokers compared to nonsmokers. HPV is an epitheliotropic virus that has been detected to various degrees within samples of oral cavity squamous cell carcinoma. Infection alone is not considered sufficient for malignant conversion; however, results of multiple studies suggest a role of HPV in a subset of head and neck squamous cell carcinoma. Multiple reports reflect that up to 40% to 60% of current diagnoses of tonsillar carcinoma demonstrate evidence of HPV types 16 or 18. Environmental ultraviolet light exposure has been associated with the development of lip cancer. The projection of the lower lip, as it relates to this solar exposure, has been used to explain why the majority of squamous cell carcinomas arise along the vermilion border of the lower lip. In addition, pipe smoking also has been associated with the development of lip carcinoma. Factors such as mechanical irritation, thermal injury, and chemical exposure have been described as an explanation for this finding. Other entities associated with oral malignancy include Plummer-Vinson syndrome (achlorhydria, iron-deficiency anemia, mucosal atrophy of mouth, pharynx, and esophagus), chronic infection with syphilis, and immunocompromised status (30-fold increase with renal transplant). 580 UNIT II PART SPECIFIC CONSIDERATIONS frequently occurs to the upper and lower cervical lymphatics (e.g., levels II, III, IV). Retropharyngeal metastatic lymphatic spread may occur with oropharyngeal lesions. The hypopharynx extends from the vallecula to the lower border of the cricoid posterior and lateral to the larynx. The subsites of this region include the pyriform fossa, the postcricoid space, and posterior pharyngeal wall. Regional lymphatic spread is frequently bilateral and to the mid- and lower cervical lymph nodes (e.g., levels III, IV). The larynx is divided into three regions: the supraglottis, glottis, and subglottis. The supraglottic larynx includes the epiglottis, false vocal cords, medial surface of the aryepiglottic folds, and the roof of the laryngeal ventricles. The glottis includes the true vocal cords, anterior and posterior commissure, and the floor of the laryngeal ventricle. The subglottis extends from below the true vocal cords to the cephalic border of the cricoid within the airway. The supraglottis has a rich lymphatic network, which accounts for the high rate of bilateral spread of metastatic disease that is not typically seen with the glottis. Glottic and subglottic lesions, in addition to potential spread to the cervical chain lymph nodes, may also spread to the paralaryngeal and paratracheal lymphatics and require attention to prevent lower central neck recurrence. Carcinogenesis Development of a tumor represents the loss of cellular signaling mechanisms involved in the regulation of growth. Following malignant transformation, the processes of replication (mitosis), programmed cell death (apoptosis), and the interaction of a cell with its surrounding environment are altered. Advances in molecular biology have allowed for the identification of many of the mutations associated with this transformation. Overexpression of mutant p53 is associated with carcinogenesis at multiple sites within the body. Point mutations in p53 have been reported in up to 45% of head and neck carcinomas. Koch et al noted that p53 mutation is a key event in the malignant transformation of >50% of head and neck squamous cell carcinomas in smokers.41 Carcinogenesis has long been explained as a two-hit process, involving DNA damage and the progression of mutated cells through the cell cycle. These two events also are known as initiation and promotion. It has been proposed that approximately 6 to 10 independent genetic mutations are required for the development of a malignancy. Overexpression of mitogenic receptors, loss of tumor-suppressor proteins, expression of oncogene-derived proteins that inhibit apoptosis, and overexpression of proteins that drive the cell cycle can allow for unregulated cell growth. Genetic mutations may occur as a result of environmental exposure (e.g., radiation or carcinogen exposure), viral infection, or spontaneous mutation (deletions, translocations, frame shifts). Common genetic alterations, such as loss of heterozygosity at 3p, 4q, and 11q13, and the overall number of chromosomal microsatellite losses are found more frequently in the tumors of smokers than in the tumors of nonsmokers.41 Second Primary Tumors in the Head and Neck Patients diagnosed with a head and neck cancer are predisposed to the development of a second tumor within the aerodigestive tract. The overall rate of second primary tumors is approximately 14%. A second primary tumor detected within 6 months of the diagnosis of the initial primary lesion is defined as a synchronous neoplasm. The prevalence of synchronous tumors is approximately 3% to 4%. The detection of a second primary lesion more than 6 months after the initial diagnosis is referred to as metachronous tumor. About 80% of second primaries are metachronous and at least half of these lesions develop within 2 years of the diagnosis of the original primary. The incidence and site of the second primary tumor vary and depend on the site and the inciting factors associated with the initial primary tumor. The importance of advocating smoking cessation and addressing alcoholism in these patients cannot be overemphasized. Patients with a primary malignancy of the oral cavity or pharynx are most likely to develop a second lesion within the cervical esophagus, whereas patients with a carcinoma of the larynx are at risk for developing a neoplasm in the lung. As such, the presentation of a new-onset dysphagia, unexplained weight loss, or chronic cough/hemoptysis must be assessed thoroughly in patients with a history of prior treatment for a head and neck cancer. A staging examination is recommended at the initial evaluation of all patients with primary cancers of the upper aerodigestive tract. This may involve a direct laryngoscopy, rigid/flexible esophagoscopy, and rigid/flexible bronchoscopy also known as “panendoscopy.” Some surgeons argue against the use of bronchoscopy because of the low yield of the examination in asymptomatic patients with a normal chest X-ray. Additionally, barium swallow has been used instead of esophagoscopy as a preoperative evaluation. Staging Staging for upper aerodigestive tract malignancies is defined by the American Joint Committee on Cancer and follows the TNM (primary tumor, regional nodal metastases, distant metastasis) staging format43. The T staging criteria for each site varies depending upon the relevant anatomy (e.g., vocal cord immobility is seen with T3 lesions). Table 18-1 demonstrates TNM staging for oral cavity lesions. The N classification system is uniform for all head and neck sites except for the nasopharynx. Upper Aerodigestive Tract Lip. The lips represent a transition from external skin to internal mucous membrane that occurs at the vermilion border. The underlying musculature of the orbicularis oris creates a circumferential ring that allows the mouth to have a sphincter-like function. Cancer of the lip is most commonly seen in white men from the ages of 50 to 70 years, but can be seen in younger patients, particularly those with fair complexions. Risk factors include prolonged exposure to sunlight, fair complexion, immunosuppression, and tobacco use. The majority of lip malignancies are diagnosed on the lower lip (88%–98%), followed by the upper lip (2%–7%) and oral commissure (1%). The histology of lip cancers is predominantly squamous cell carcinoma; however, other tumors, such as keratoacanthoma, verrucous carcinoma, basal cell carcinoma, malignant melanoma, minor salivary gland malignancies, and tumors of mesenchymal origin (e.g., malignant fibrous histiocytoma, leiomyosarcoma, and rhabdomyosarcoma), may also present in this location. Basal cell carcinoma presents more frequently on the upper lip than lower. Clinical findings in lip cancer include an ulcerated lesion on the vermilion or cutaneous surface. Careful palpation is important in determining the actual size and extent of these lesions. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 581 Table 18-1 TNM staging for oral cavity carcinoma Primary Tumor Unable to assess primary tumor T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor is < 2 cm in greatest dimension T2 Tumor > 2 cm and < 4 cm in greatest dimension T3 Tumor > 4 cm in greatest dimension T4 (lip) Primary tumor invading cortical bone, inferior alveolar nerve, floor of mouth, or skin of face (e.g., nose or chin) T4a (oral) Tumor invades adjacent structures (e.g., cortical bone, into deep tongue musculature, maxillary sinus) or skin of face T4b (oral) Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery CHAPTER 18 DISORDERS OF THE HEAD AND NECK TX Regional lymphadenopathy NX Unable to assess regional lymph nodes N0 No evidence of regional metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2a Metastasis in single ipsilateral lymph node, >3 cm and < 6 cm N2b Metastasis in multiple ipsilateral lymph nodes, all nodes < 6 cm N2c Metastasis in bilateral or contralateral lymph nodes, all nodes < 6 cm N3 Metastasis in a lymph node > 6 cm in greatest dimension Distant metastases MX Unable to assess for distant metastases M0 No distant metastases M1 Distant metastases TMN Staging Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1-3 N1 M0 T4a N0 M0 T4a N1 M0 T1-4a N2 M0 Any T N3 M0 T4b Any N M0 Any T Any N M1 Stage IVa Stage IVb Stage IVc Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source of the material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 582 Preauricular node UNIT II PART Infraparotid node SPECIFIC CONSIDERATIONS Submental nodes Submandibular nodes Upper deep cervical node Figure 18-20. Lymphatics of the lip. The presence of paresthesia in the area adjacent to the lesion may indicate mental nerve involvement. Characteristics of lip primaries that negatively affect prognosis include perineural invasion, involvement of the underlying maxilla/mandible, presentation on the upper lip or commissure, regional lymphatic metastasis, and age younger than 40 years at onset. Lip cancer results in fewer than 200 patient deaths annually and is stage dependent. Early diagnosis coupled with adequate treatment results in a high likelihood of disease control. The selection of treatment for any given lip cancer is determined by the overall health of the patient, size of the primary lesion, and the presence of regional metastases. Small primary lesions may be treated with surgery or radiation with equal success and acceptable cosmetic results. However, surgical excision with histologic confirmation of tumor-free margins is the preferred treatment modality. Lymph node metastasis occurs in fewer than 10% of patients with lip cancer (Fig. 18-20). The primary echelon of nodes at risk is in the submandibular and submental regions. In the presence of clinically evident neck metastasis, neck dissection is indicated. The overall 5-year cure rate of lip cancer approximates 90% and drops to 50% in the presence of neck metastases. Postoperative radiation is administered to the primary site and neck for patients with close or positive margins, lymph node metastases, when tumor thickness is >4mm or in the setting of perineural invasion.44 The reconstruction of lip defects after tumor excision requires innovative techniques to provide oral competence, maintenance of dynamic function, and acceptable cosmesis. The typical lip length is 6 to 7 cm. This simple fact is important because the reconstructive algorithms available to the head and neck surgeon are based on the proportion of lip resected. Realignment of the vermilion border during the reconstruction and preservation of the oral commissure (when possible) are important principles in attempting to attain an acceptable cosmetic result. Resection with primary closure is possible with a defect of up to one third of the lip (Fig. 18-21). When the Figure 18-21. Wedge resection of lower lip squamous cell ­carcinoma. resection includes one third to one half of the lip, rectangular excisions can be closed using Burow’s triangles in combination with advancement flaps and releasing incisions in the mental crease.45 Rotational transposition of tissue from the upper lip can repair other medium-size defects. For larger defects of up to 75%, the Karapandzic flap uses a sensate, neuromuscular flap that includes the remaining orbicularis oris muscle, conserving its blood supply from branches of the labial artery (Fig. 18-22). The lip-switch (Abbe-Estlander) flap or a stair-step advancement technique can be used to repair defects of either the upper or lower lip. Microstomia is a potential complication with these types of lip reconstruction. For very large defects, Webster or Bernard types of repair using lateral nasolabial flaps with buccal advancement have also been described.46 Oral Cavity. As previously mentioned in Anatomy and Histopathology, the oral cavity is composed of several sites with different anatomic relationships. The majority of tumors in the oral cavity are squamous cell carcinomas (>90%). Each site is briefly reviewed with emphasis placed on anatomy, diagnosis, and treatment options. Oral Tongue. The oral tongue is a muscular structure with overlying nonkeratinizing squamous epithelium. The posterior limit of the oral tongue is the circumvallate papillae, whereas its ventral portion is contiguous with the anterior floor of mouth. The tongue is composed of four intrinsic and four extrinsic muscles separated at the midline by the median fibrous septum. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 583 CHAPTER 18 DISORDERS OF THE HEAD AND NECK Figure 18-22. A-C. Karapandzic labiaplasty for lower lip carcinoma. Tumors of the tongue begin in the stratified epithelium of the surface and eventually invade into the deeper muscular structures. The tumors may present as ulcerations or as exophytic masses (Fig. 18-23).47 The regional lymphatics of the oral cavity are to the submandibular space and the upper cervical lymph nodes (Fig. 18-24). The lingual nerve and the hypoglossal nerve may be directly invaded by locally extensive tumors (Fig. 18-25). Involvement can result in ipsilateral paresthesias and deviation of the tongue on protrusion with fasciculations and eventual atrophy. Tumors on the tongue may occur on any surface, but are most commonly seen on the lateral and ventral surfaces.48 Primary tumors of the mesenchymal components of the tongue include leiomyomas, leiomyosarcomas, rhabdomyosarcomas, and neurofibromas. Surgical treatment of small (T1–T2) primary tumors is wide local excision with either primary closure or healing by secondary intention. The CO2 laser may be used for excision Figure 18-23. Oral tongue squamous cell carcinoma. Retrovascular Periparotid Prevascular Preglandular Subparotid Jugulodigastric Jugulocarotid Submental Juguloomohyoid Figure 18-24. Primary lymphatics for regional spread of oral cavity malignancies. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 584 Stylopharyngeus, stylohyoid and styloglossus mm. Submandibular gland Lingual n. Hypoglossal n. Digastric muscle (posterior belly) UNIT II PART Digastric m. (anterior belly) Myohyoid m. Hyoid bone SPECIFIC CONSIDERATIONS A Deep lingual a. Lingual n. Dorsal lingual a. Styloid process Genioglossus m. Hypoglossal n. Middle constrictor m. Geniohyoid m. Sublingual a. External carotid a. Hyoglossus m. Hyoid bone Figure 18-25. A and B. Anatomy of the floor of mouth and submandibular space. a. = artery; m. = muscle; n. = nerve. B of early tongue cancers or for ablation of premalignant lesions. A partial glossectomy, which removes a significant portion of the lateral oral tongue, still permits reasonably effective postoperative function. Resection of larger tumors of the tongue that invade deeply can result in significant functional impairment. If lingual contact with the palate, lip, and teeth is decreased, it will result in impaired articulation. The use of soft, pliable fasciocutaneous free flaps can provide intraoral bulk and preservation of tongue mobility. Prosthetic augmentation can allow for contact between the remaining tongue tissue and the palate, improving a patient’s ability to speak and swallow. Treatment of the regional lymphatics is typically performed with the same modality used to address the primary site. When the primary site is addressed surgically, modified radical neck dissection (MRND) or selective neck dissection (SND) is performed. Depth of invasion of the primary tumor can direct the need for elective lymph node dissection with early stage lesions.49 Floor of Mouth. The floor of mouth is a mucosal covered semilunar area that extends from the anterior tonsillar pillar posteriorly to the frenulum anteriorly, and from the inner surface of the mandible to the ventral surface of the oral tongue. The ostia of the submaxillary and sublingual glands are contained in the anterior floor of mouth. The muscular floor of mouth is composed of the sling-like genioglossus, mylohyoid, and hyoglossus muscles, which serve as a barrier to spread of disease. Invasion into these muscles can result in decreased tongue mobility and poor articulation. Another pathway for spread of tumor is along the salivary ducts, which can result in direct extension into the sublingual space. Anterior or lateral extension to the mandibular periosteum is of primary importance in the preoperative assessment for these lesions. Imaging studies of the mandible, including CT scan, magnetic resonance imaging (MRI), and Panorex radiography, are helpful for ascertaining bone invasion. A careful clinical evaluation, which includes bimanual palpation to assess adherence or fixation to adjacent bone, is also essential (Fig. 18-26). The absence of fixation of the lesion to the inner mandibular cortex indicates that a mandible-sparing procedure is feasible.50 Deep invasion into the intrinsic musculature of the tongue causes fixation and mandates a partial glossectomy in conjunction with resection of the floor of mouth. Lesions in the anterior floor of mouth may invade the sublingual gland or submandibular duct and require resection of either of these structures in continuity with the primary lesion. Direct extension of tumors into or through the sublingual space and into the submaxillary space may necessitate the need for removal of the primary tumor with the neck dissection specimen in continuity. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 585 Tissue excised A Figure 18-26. A and B. Differences in the transoral resection of a floor of mouth and alveolar ridge lesion. B The resection of large tumors of the floor of mouth may require a lip-splitting incision (Fig. 18-27) and immediate reconstruction. The goals are to obtain watertight closure to avoid a salivary fistula and to avoid tongue tethering to maximize mobility. For small mucosal lesions, wide local excision can be followed by placement of a split-thickness skin graft over the Figure 18-27. Composite resection specimen of a T4 floor of mouth squamous cell carcinoma. muscular bed. Larger defects that require marginal or s­ egmental mandibulectomy require complex reconstruction with a fasciocutaneous or a vascularized osseous free flap. Alveolus/Gingiva. The alveolar mucosa overlies the bone of the mandible and maxilla. It extends from the gingivobuccal sulcus to the mucosa of the floor of mouth and hard palate. The posterior limits are the pterygopalatine arch and the ascending portion of the ramus of the mandible. Because of the tight attachment of the alveolar mucosa to the mandibular and maxillary periosteum, treatment of lesions of the alveolar mucosa frequently requires resection of the underlying bone. Marginal resection of the mandible can be performed for tumors of the alveolar surface that present with minimal bone invasion. Although access for such a procedure can be performed by using an anterior mandibulotomy (Fig. 18-28), use of transoral and pull-through procedures is preferred if a coronal or sagittal marginal mandibulotomy is performed. For more extensive tumors that invade into the medullary cavity, segmental mandibulectomy is necessary. Preoperative radiographic evaluation of the mandible plays an important role in determining the type of bone resection required. For radiographic evaluation of the mandible, Panorex views demonstrate gross cortical invasion. MRI is the best modality for demonstrating invasion of the medullary cavity of the mandible. Sectional CT scanning with bone settings is the optimum modality for imaging subtle cortical invasion. Gross bony invasion involvement at the mandibular symphysis negatively impacts locoregional control.51 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK Incision cheek may require through-and-through resection. Reconstruction aimed at providing both an internal and external lining may be accomplished with a folded fasciocutaneous free flap or a combination of pedicled and free tissue techniques. 586 Palate. The hard palate is defined as the semilunar area UNIT II PART SPECIFIC CONSIDERATIONS Figure 18-28. Anterior mandibulotomy with mandibular swing to approach a posterior lesion. Retromolar Trigone. The retromolar trigone is represented by tissue posterior to the posterior inferior alveolar ridge and ascends over the inner surface of the ramus of the mandible. Similar to alveolar lesions, early involvement of the mandible is common because of the lack of intervening soft tissue in the region. The clinical presentation of trismus represents involvement of the muscles of mastication and may indicate spread to the skull base. Tumors of the region may extend posteriorly into the oropharyngeal anatomy or laterally to invade the mandible. As a result, resection of retromolar trigone tumors usually requires a marginal or segmental mandibulectomy with a soft-tissue and/ or osseous reconstruction to maximize a patient’s postoperative ability for speech and swallowing. Ipsilateral neck dissection is performed because of the risk of metastasis to the regional lymphatics. Huang and associates demonstrated a 5-year, disease-free survival rate for T1 lesions of 76%, which declined to 54% for T4 disease. Patients with N0 disease had a 5-year survival rate of 69%.52 Buccal Mucosa. The buccal mucosa includes all of the mucosal lining from the inner surface of the lips to the line of attachment of mucosa of the alveolar ridges and pterygomandibular raphe. The etiologies of malignancies in the buccal area include lichen planus, chronic dental trauma, and the habitual use of tobacco and alcohol. Tumors in this area have a propensity to spread locally and to metastasize to regional lymphatics. Local intraoral spread may necessitate resection of the alveolar ridge of the mandible or maxilla. Lymphatic drainage is to the facial and the submandibular nodes (level I). Small lesions can be excised s­ urgically, but more advanced tumors require combined surgery and postoperative radiation.53 Deep invasion into the between the upper alveolar ridge and the mucous membrane covering the palatine process of the maxillary palatine bones. It extends from the inner surface of the superior alveolar ridge to the posterior edge of the palatine bone. Most squamous cell carcinomas of the hard palate are caused by habitual tobacco and alcohol use. Chronic irritation from ill-fitting dentures also may play a causal role. Inflammatory lesions arising on the palate may mimic malignancy and can be differentiated by biopsy specimen. Necrotizing sialometaplasia appears on the palate as a butterflyshaped ulcer that clinically appears similar to a neoplasm. Treatment is symptomatic and biopsy specimen confirms its benign nature. Torus palatini are bony outgrowths of the midline palate and do not specifically require surgical treatment unless symptomatic. Squamous cell carcinoma and minor salivary gland tumors are the most common malignancies of the palate.54 The latter include adenoid cystic carcinoma, mucoepidermoid carcinoma, adenocarcinoma, and polymorphous low-grade adenocarcinoma. Mucosal melanoma may occur on the palate and presents as a nonulcerated, pigmented plaque. Kaposi’s sarcoma of the palate is the most common intraoral site for this tumor. Tumors may present as either an ulcerative, exophytic, or submucosal mass. Minor salivary gland tumors tend to arise at the junction of the hard and soft palate. Direct infiltration of bone leads to extension into the floor of the nasal cavity and/or maxillary sinus. Squamous cell carcinoma of the hard palate is treated surgically. Adjuvant radiation is indicated for advanced staged tumors. Because the periosteum of the palate can act as a barrier to spread of tumor, mucosal excision may be adequate for very superficial lesions. Involvement of the periosteum requires removal of a portion of the bony palate. Partial palatectomy of infrastructure maxillectomy may be required for larger lesions involving the palate or maxillary antrum. Malignancies may extend along the greater palatine nerve making biopsy specimen important for identifying neurotropic spread. Throughand-through defects of the palate require a dental prosthesis for rehabilitation of swallowing and speech. Oropharynx. The oropharynx extends from the soft palate to the superior surface of the hyoid bone (or floor of the vallecula) and includes the base of tongue, the inferior surface of the soft palate and uvula, the anterior and posterior tonsillar pillars, the glossotonsillar sulci, tonsils, and the lateral and posterior pharyngeal walls. Laterally, the borders of this region are the pharyngeal constrictors and the medial aspect of the mandible. Direct extension of tumors from the oropharynx into these lateral tissues may involve spread into the parapharyngeal space. The ascending ramus of the mandible can be involved when tumors invade the medial pterygoid muscle. As was true of the oral cavity, the histology of the majority of tumors in this region is squamous cell carcinoma. Although less common, minor salivary gland tumors may present as submucosal masses in the tongue base and soft palate. Additionally, the tonsils and tongue base may be the presenting site for a lymphoma noted clinically as asymmetrical enlargement. Oropharyngeal cancer may present as an ulcerative lesion or an exophytic mass. Tumor fetor from necrosis is common. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 18-2 Head and neck squamous cell carcinoma patterns of presentation Variable HPV-positive HPV-negative Typical age 40 – 60 years over 60 years of age Primary site tongue base, tonsil entire UADT Prognosis with ASD favorable poor Risk factors oral sex, number of partners habitual tobacco and alcohol use Incidence increasing stable, decreasing (UADT – upper aerodigestive tract, ASD -advanced stage disease) found in levels III, IV, and V, in addition to the retropharyngeal and parapharyngeal lymph nodes. Approximately 50% of patients have metastases at the time of presentation and bilateral metastases are common from tumors arising in the tongue base and soft palate. The treatment goals for patients with oropharyngeal cancer include maximizing survival and preserving function. Management of squamous cell cancers of this region includes surgery alone, primary radiation alone, surgery with postoperative radiation, and combined chemotherapy with radiation therapy.56 Tumors of the oropharynx tend to be radiosensitive.57 Patients with early stage lesions may be candidates for monomodality radiation alone. Adequate treatment of the neck is important with oropharyngeal squamous cancer because of the high risk of regional metastasis. Concomitant chemoradiation is commonly utilized in patients with advanced stage (III, IV) oropharyn5 geal carcinoma.58 This approach has been effectively demonstrated to preserve function and is associated with survivorship comparable to surgery with postoperative radiation. In an effort to resect tumors of the oropharynx in a minimally invasive fashion, that might otherwise require a lipsplitting mandibulotomy approach with dissection through the floor of mouth, the transoral robotic surgical approach utilizing the da Vinci Surgical System has been utilized with favorable results. Dean et al reported on the use of robot-assisted primary and salvage surgery for 36 patients with T1 and T2 tumors of the oropharynx compared to traditional open salvage resection. Patients that underwent robot-assisted surgery had shorter lengths of stay and were less likely to be gastrostomy tube or tracheostomy dependent at 6 months.59 Of patients undergoing primary transoral robotic surgery to tonsillar carcinoma, 93% still required some form of postoperative adjuvant therapy.60 Advocates of the technique believe that initial surgical management of the oropharynx, a site typically treated with primary radiation or chemoradiation therapy, allows for a better long-term functional result with the potential for decreasing the intensity of adjuvant therapy to radiation alone as opposed to postoperative chemoradiation. Clinical trials and experience with the technique and continue evolve with the focus of use directed at early-stage oropharyngeal carcinomas. Extensive oropharyngeal cancers may require surgical resection and postoperative radiotherapy. Lesions that involve the mandible require composite resections, such as the classic jaw-neck resection or “commando” procedure. Surgical management of the tongue base may require total glossectomy for extensive lesions crossing the anatomic midline. The potential need for synchronous performance of total laryngectomy at the time of tongue base resection should be explained to the patient. Preservation of the larynx after total glossectomy is associated with a significant risk of postoperative dysphagia and aspiration.61 Swallowing rehabilitation in patients with oropharyngeal carcinoma is an important aspect of posttreatment care. For soft palate defects, palatal obturators may assist in providing a seal between the nasopharynx and the posterior pharyngeal wall. Nasal regurgitation of air and liquids can be decreased with use. Close cooperation between the head and neck surgeon and the maxillofacial prosthodontist is essential to provide patients with the optimum prosthetic rehabilitation. Preoperative planning can result in the creation of a defect that better tolerates obturation. For patients with postglossectomy defects, palatal augmentation prostheses can provide bulk extending inferiorly from VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 587 CHAPTER 18 DISORDERS OF THE HEAD AND NECK A muffled or “hot potato” voice is seen with large tongue base tumors. Dysphagia and weight loss are common symptoms. Referred otalgia, mediated by the tympanic branches of cranial nerve (CN) IX and CN X, is a common complaint. Trismus may indicate advanced disease and usually results from involvement of the pterygoid musculature. The incidence of regional metastases from cancers of the oropharynx is high. Consequently, ipsilateral or bilateral nontender cervical lymphadenopathy is a common presenting sign. The incidence of oropharyngeal squamous cell carcinoma has increased significantly over the last three decades. The etiology for this rise has been attributed to the HPV-16 related development of malignancy. HPV infection can induce the production of two viral oncoproteins, E6 and E7, which inactivate tumor suppressors p53 and Rb leading to tumor promotion. In a prospective clinical trial of patients enrolled in the Eastern Cooperative Group (ECOG) trial 2399, Fakhry et al reported on the survival benefit seen in oropharyngeal cancer patients that were HPV-positive. Patients were treated with sequential chemoradiation for advanced stage disease. HPV positivity was found in 57% of all oropharyngeal cancers in the study. HPV-positive cancers demonstrated a higher response rate to induction chemotherapy (82% vs. 55%) and improved 2-year survival (95% vs. 62%). Compared to patients with HPV-negative tumors, HPV-positive cancers presented in younger male patients and were associated with a history of higher lifetime number of sexual partners and oral sex.55 HPV-associated oropharyngeal carcinoma is considered to represents a distinct clinicopathologic entity different from the traditional squamous cell carcinoma of the head and neck associated with the long-term use of tobacco and alcohol (Table 18-2). Surprisingly, the rate of distant metastasis is similar in HPV-positive and HPV-negative patients indicating survival benefits are likely from improved locoregional control with treatment. Clinical trials are currently being performed to assess if therapy can be deintensified in the HPV patient population while obtaining the same locoregional and overall survival seen with standard treatment options. Imaging studies are important for adequate staging and should assess for extension to the larynx, parapharyngeal space, pterygoid musculature, mandible, and nasopharynx. Lymph node metastasis from oropharyngeal cancer most commonly occurs in the subdigastric area of level II. Metastases also are 588 the palate. The prosthesis decreases the volume of the oral cavity and allows the remaining tongue or soft tissue to articulate with the palate. It also facilitates posterior projection of the food bolus during the oral and pharyngeal phases of swallowing. Paratracheal nodes Adenoid Nasopharynx Figure 18-30. View of the hypopharynx demonstrating the potential pathways of spread of tumor and pertinent anatomy. Soft palate Palatine tonsil Epiglottis Oropharynx SPECIFIC CONSIDERATIONS Thyroid nodes Paraesophageal nodes Eustachian tube orifice Hyoid bone Larynx Cricoid cartilage Hypopharynx UNIT II PART ynx extends from the vallecula to the lower border of the cricoid cartilage and includes the pyriform sinuses, the lateral and posterior pharyngeal walls, and the postcricoid region (Fig. 18-29). Squamous cancers of the hypopharynx frequently present at an advanced stage. Clinical findings are similar to those of lower oropharyngeal lesions and include a neck mass, muffled or hoarse voice, referred otalgia, dysphagia, and weight loss. A common symptom is dysphagia, starting with solids and progressing to liquids, leaving patients malnourished at the time of presentation. Invasion of the larynx by direct extension can result in vocal cord paralysis and may lead to airway compromise. Routine office examination should include flexible fiberoptic laryngoscopy to properly assess the extent of tumor. During examination, the patient should be instructed to perform a Valsalva maneuver, which will result in passive opening of the pyriform sinuses and postcricoid regions, providing improved visualization. Decreased laryngeal mobility or fixation may indicate invasion of the prevertebral fascia and unresectability. Barium swallow can provide information regarding postcricoid and upper esophageal extension, potential multifocality within the esophagus, and document the presence of aspiration. CT and/or MRI imaging should be obtained through the neck Hypopharynx Hypopharynx and Cervical Esophagus. The hypophar- Thyroid gland Figure 18-29. Relationship of nasopharynx, oropharynx, and hypopharynx. and upper chest to assess for invasion of the laryngeal framework and to identify for regional metastases, with special attention given to the paratracheal and upper mediastinal lymph nodes (Fig. 18-30). Bilateral metastatic adenopathy in the paratracheal chain is common and the majority of patients present with nodal disease at the time of diagnosis. Tumors of the hypopharynx and cervical esophagus are associated with poorer survival rates than are other sites in the head and neck because of advanced stage and lymph node metastasis at presentation. Surgery with postoperative radiation therapy improves locoregional control compared to singlemodality therapy in the treatment of advanced stage tumors.62 Definitive radiation therapy may be effective for limited T1 tumors, whereas concomitant chemoradiation is generally used for T2 and T3 tumors.63 Surgical salvage after radiation failure has a success rate of less than 50% and can be associated with significant wound-healing complications. Larynx-preserving surgical procedures for tumors of the hypopharynx are possible for only a limited number of lesions. Tumors of the medial pyriform wall or pharyngo-epiglottic fold may be resected with partial laryngopharyngectomy. In this circumstance, the tumor must not involve the apex of the pyriform sinus, vocal cord mobility must be unimpaired, and the patient VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Larynx. Laryngeal carcinoma is a diagnosis typically entertained in individuals with prominent smoking histories and the complaint of a change in vocal quality (Fig. 18-31). The borders of the larynx span from the epiglottis superiorly to the cricoid Figure 18-31. Endoscopic view of a laryngeal squamous carcinoma. 589 Pre-epiglottic space Arytenoid cartilage Supraglottis Hyoid bone False cord Ventricle of Morgani Glottis Thyroid cartilage Larynx Subglottis Vocal cord Cricoid cartilage Figure 18-32. Sagittal view of the larynx with the divisions of the supraglottis, glottis, and subglottis demonstrated. cartilage inferiorly. The lateral limits of the larynx are the aryepiglottic folds. The larynx is composed of three regions: the supraglottis, the glottis, and the subglottic (Fig. 18-32). The supraglottic includes the epiglottis, aryepiglottic folds, arytenoids, and ventricular bands (false vocal folds). The inferior boundary of the supraglottic is a horizontal plane passing through the lateral margin of the ventricle. The glottis is composed of the true vocal cords (superior and inferior surfaces) and includes the anterior and posterior commissures. The subglottic extends from the inferior surface of the glottis to the lower margin of the cricoid cartilage. The soft-tissue compartments of the larynx are separated by fibroelastic membranes, which can act as barriers to the spread of cancer. These membranes thicken medially to form the false vocal fold and the vocal ligament (the true vocal cord). The supraglottic larynx contains pseudostratified, ciliated respiratory epithelium that covers the false vocal cords. The epiglottis and the vocal cords are lined by stratified, nonkeratinizing squamous epithelium. The subglottic mucosa is pseudostratified, ciliated respiratory epithelium. Minor salivary glands are also found in the supraglottic and subglottic. Tumor types that arise in the larynx are primarily squamous cell carcinoma but also include tumors of neuroendocrine origin, squamous papillomas, granular cell tumors, and tumors of salivary origin. Several histologic variants of squamous cell carcinoma exist and include verrucous, basaloid squamous cell, adenosquamous, and spindle cell carcinoma. Tumors of the laryngeal framework include synovial sarcoma, chondroma, and chondrosarcoma. The normal functions of the larynx are airway patency, protection of the tracheobronchial tree during swallowing, and phonation. Patients with tumors of the supraglottic larynx may present with symptoms of chronic sore throat, dysphonia VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK must have adequate pulmonary reserve. Given the increased risk for postoperative aspiration associated with various forms of partial laryngectomy, a history significant for pulmonary disease is a contraindication for performing the procedures. Because the majority of patients with tumors of the hypopharynx present with large lesions with significant submucosal spread, total laryngectomy often is required to achieve negative resection margins. Resection of the primary tumor and surrounding pharyngeal tissue is performed en bloc. Bilateral neck dissection is frequently indicated given the elevated risk of nodal metastases found with these lesions. When laryngopharyngectomy is performed for hypopharyngeal tumors the surgical defect is repaired by primary closure when possible. Generally, 4 cm or more of pharyngeal mucosa is necessary for primary closure to provide an adequate lumen for swallowing and to minimize the risk of stricture formation. Larger surgical defects require closure with the aid of pedicled myocutaneous flaps or microvascular reconstruction with radial forearm or jejunal free flap. When total laryngopharyngoesophagectomy is necessary, gastric pull-up is performed. Cervical esophageal cancer may be managed surgically or by concomitant chemoradiation. Preservation of the larynx is possible if the cricopharyngeus muscle demonstrates limited involvement. Unfortunately, this is not often the case and many patients with cervical esophageal cancer require laryngectomy. Total esophagectomy is performed because of the tendency for multiple primary tumors and skip lesions seen with esophageal cancers. Despite aggressive treatment strategies, the 5-year survival rate for cervical esophageal cancer is less than 20%. Given the presence of paratracheal lymphatic spread, surgical treatment for tumors of this area must include paratracheal lymph node dissection, in addition to treatment of the lateral cervical lymphatics. 590 UNIT II PART SPECIFIC CONSIDERATIONS (“hot potato” voice), dysphagia, or a neck mass secondary to regional metastasis. Supraglottic tumors may cause vocal cord fixation by inferior extension in the paraglottic space or direct invasion of the cricoarytenoid joint. Anterior extension of tumors arising on the laryngeal surface of the epiglottis into the preepiglottic space produces a muffled quality to the voice. Referred otalgia or odynophagia is encountered with advanced supraglottic cancers. Bulky tumors of the supraglottic may result in airway compromise. In contrast to most supraglottic lesions, hoarseness is an early symptom in patients with tumors of the glottis.64 Airway obstruction from a glottic tumor is usually a late symptom and is the result of tumor bulk or impaired vocal cord mobility. Decreased vocal cord mobility may be caused by direct muscle invasion or involvement of the RLN. Fixation of the vocal cord indicates invasion into the vocalis muscle, paraglottic space, or cricoarytenoid joint. Superficial tumors that are bulky may appear to cause cord fixation through mass effect. Subglottic cancers are relatively uncommon and typically present with vocal cord paralysis (usually unilateral) and/or airway compromise. The staging classification for squamous cell cancers of the larynx includes assessment of vocal cord mobility as well as local tumor extension. Accurate clinical staging of laryngeal tumors requires flexible fiber-optic endoscopy in the office and direct microlaryngoscopy under general anesthesia. Direct laryngoscopy, used to assess the extent of local spread, may be combined with esophagoscopy or bronchoscopy to adequately stage the primary tumor and to exclude the presence of a synchronous lesion. Key areas to note for tumor extension in supraglottic tumors are the vallecula, base of tongue, ventricle, arytenoid, and anterior commissure. For glottic cancers, it is important to determine extension to the false cords, anterior commissure, arytenoid, and subglottic. Radiographic imaging by CT and/or MRI provides important staging information and is crucial for identifying cartilage erosion or invasion and extension into the preepiglottic or paraglottic spaces. High quality, thin-section images through the larynx should be obtained in patients with laryngeal tumors and used with clinical assessment to arrive at a final disease pretreatment staging. Lymph node metastasis may be defined more readily with the use of imaging studies. Lymphatic drainage of the larynx is distinct for each subsite. Two major groups of laryngeal lymphatic pathways exist: those that drain areas superior to the ventricle, and those that drain areas inferior to it. Supraglottic drainage routes pierce the thyrohyoid membrane with the superior laryngeal artery, vein, and nerve, and drain mainly to the subdigastric and superior jugular nodes.64Those from the glottic and subglottic areas exit via the cricothyroid ligament and end in the prelaryngeal node (the delphian node), the paratracheal lymph nodes, and the deep cervical nodes along the inferior thyroid artery. Limited glottic cancers typically do not spread to regional lymphatics (1%–4%). However, there is a high incidence of lymphatic spread from supraglottic (30%–50%) and subglottic cancers (40%). When considering treatment for laryngeal tumors, it is useful to categorize them as a continuum from early tumors (those with a small area of involvement resulting in minimal functional impairment) to advanced tumors (those with significant airway compromise and local extension). For example, severe dysplasia and carcinoma in situ often can be treated successfully with CO2 laser resection or conservative surgical approaches. In contrast, more advanced tumors may require partial laryngectomy (Fig. 18-33) or even total laryngectomy (Fig. 18-34).65 Further complicating the Thyroid cartilage Unilateral lesion Perichondrium Figure 18-33. Example of the resection of a vertical partial laryngectomy for an early stage glottic carcinoma. Figure 18-34. Total laryngectomy specimen featuring a locally invasive advanced stage glottic squamous carcinoma. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ resection. Although using a CO2 laser can provide excellent hemostasis and minimize damage to the adjacent uninvolved tissue, scarring associated with its use is considered more significant than with conventional “cold” techniques. Microflap dissection, using a subepithelial infusion of a saline-epinephrine solution into Reinke’s space, allows for assessment of depth of invasion and the ability to resect the lesion as a single unit. Use of an operative microscope aids the precision of such dissections. Open laryngofissure and cordectomy may be reserved for more invasive tumors. For larger tumors of the glottis with impaired vocal cord mobility, a variety of partial resections exist that permit preservation of reasonable vocal quality. For lesions involving the anterior commissure with limited subglottic extension, an anterofrontal partial laryngectomy is indicated. For lateralized T2 or T3 glottic tumors without cartilage destruction, a vertical partial laryngectomy is feasible. In this circumstance, reconstruction is accomplished by means of a false vocal cord imbrication to simulate a true vocal cord on the side of the resection. For T3 glottic lesions not involving the preepiglottic space or cricoarytenoid joint, a supracricoid laryngectomy with cricohyoidopexy or cricohyoidoepiglottopexy (CHEP) are options.65 The supracricoid laryngectomy technique uses the remaining arytenoids as the phonatory structures, which come into apposition with epiglottic remnant in the CHEP, or with the tongue base in the cricohyoidopexy. Oncologic advantages of this procedure include the complete removal of the paraglottic spaces and thyroid cartilage. The supracricoid laryngectomy with CHEP is associated with excellent disease control and a high rate of tracheostomy decannulation. Favorable deglutition rates and a breathy vocal quality are seen postoperatively with this procedure. For lesions with involvement of the cricoarytenoid joint and/or extension to the level of the cricoid, total laryngectomy is required. The risk for aspiration is high following certain partial laryngectomies. Patient selection is vital to successful application of these techniques. Presurgical pulmonary assessment may be necessary. One simple measurement of functional reserve is to have the patient climb two flights of stairs. Those able to do so without stopping are more likely to be candidates for conservation surgical procedures. The approach to the treatment for patients with advanced tumors of the larynx and hypopharynx has evolved over time. Chemoradiation has demonstrated the ability for comparable locoregional disease control and overall survival similar to Figure 18-35. Pectoralis flap reconstruction of a laryngectomy patient requires soft-tissue augmentation for pharynx closure. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 591 CHAPTER 18 DISORDERS OF THE HEAD AND NECK treatment paradigm is the role of radiotherapy, with or without chemotherapy, with the goal of laryngeal preservation.66 Prognostic factors for patients with cancer of the larynx are tumor size, nodal metastasis, perineural invasion, and extracapsular spread of disease in cervical lymph nodes. Patient comorbidities are important to consider when arriving at a treatment plan for patients with laryngeal cancer. For severe dysplasia or carcinoma in situ of the vocal cord, complete removal of the involved mucosa with microlaryngoscopy is an effective treatment. Patients with limited involvement of the arytenoid or anterior commissure are the best candidates for a good posttreatment vocal quality result with this approach. Multiple procedures may be necessary to control the disease and to prevent progression to an invasive cancer. Close follow-up examinations and smoking cessation are mandatory adjuncts of therapy. For early stage cancers of the glottis and the supraglottis, radiation therapy is equally as effective as surgery in controlling disease. Critical factors in determining the appropriate treatment modality are comorbid conditions (chronic obstructive pulmonary disease, cardiovascular, and renal disease) and tumor extension. Voice preservation and maintenance of quality of life are key issues and significantly impact therapeutic decisions. The use of radiation therapy for early stage disease of the glottis and supraglottis provides excellent disease control with reasonable, if not excellent, preservation of vocal quality. Partial laryngectomy for small glottic cancers provides excellent tumor control, but vocal quality can vary. For supraglottic cancers without arytenoid or vocal cord extension, standard supraglottic laryngectomy results in excellent disease control with good voice function. For advanced tumors with extension beyond the endolarynx or with cartilage destruction, total laryngectomy followed by postoperative radiation is considered the standard of care.67 In this setting, reconstruction by means of a pectoralis major flap (Fig. 18-35) or free flap reconstruction is required for lesions with pharyngeal extension. Subglottic cancers, constituting only 1% of laryngeal tumors, are typically treated with total laryngectomy. Of note, 40% of patients with these tumors present with regional adenopathy and special attention must be directed to the treatment of paratracheal lymph nodes.68 Laryngeal Preservation Techniques. Superficial cancers confined to the true vocal cord can be treated with a variety of surgical options. These include endoscopic vocal cord stripping, microflap dissection, partial cordectomy, and CO2 laser 592 UNIT II PART SPECIFIC CONSIDERATIONS open surgical approaches. The Radiation Therapy Oncology Group 91-11 trial demonstrated a higher laryngeal preservation rate among patients receiving concomitant chemotherapy and radiotherapy than in those patients receiving radiation alone or sequential chemotherapy followed by radiation therapy.69 A randomized laryngeal preservation trial of neoadjuvant induction chemotherapy followed by radiation therapy has yielded survival rates similar to those of laryngectomy, with the benefit of preservation of the larynx in 65% of patients.66 Surgical salvage is available in cases of treatment failure or recurrent disease. patients previously considered to have an unknown primary. In those individuals in whom a primary site cannot be ascertained, empiric treatment of the mucosal sources of the upper aerodigestive tract at risk (from nasopharynx to hypopharynx) and the cervical lymphatics with concomitant chemoradiation is advocated. For patients with advanced neck disease (N2a or greater) or with persistent lymphadenopathy after radiation, a postradiation neck dissection may be necessary. For patients in whom the primary lesion is identified, a more limited radiation treatment field may be used. Speech and Swallowing Rehabilitation. Involvement of a speech and swallowing therapist is critical in the preoperative counseling and postoperative rehabilitation of patients with laryngeal cancer. Speech rehabilitation options after total laryngectomy include esophageal speech, tracheoesophageal puncture, and use of an electrolarynx. Esophageal speech is produced by actively swallowing and releasing air from the esophagus which results in vibrations of the esophageal walls and pharynx. The sounds produced can be articulated into words. The ability to create esophageal speech depends on the motivation of patients and their ability to control the upper esophageal sphincter, allowing injection and expulsion of air in a controlled fashion. Unfortunately, less than 20% of postlaryngectomy patients develop fluent esophageal speech. A tracheoesophageal puncture is a fistula created between the trachea and esophagus that permits placement of a one-way valve that allows air from the trachea to enter the upper esophagus. The valve prevents retrograde passage of food or saliva into the trachea. Patients that undergo placement of a tracheoesophageal puncture have a success rate of >80% in achieving functional speech. For patients unable to develop esophageal speech, the electrolarynx creates vibratory sound waves when held against the neck or cheek. The vibrations create sound waves that the patient articulates into words. A disadvantage of the electrolarynx is the mechanical quality of the sound produced. This device is most useful in the postoperative period before training for esophageal speech. Postoperative swallowing rehabilitation is another important task performed by the speech and swallowing team. Patient instruction in various swallowing techniques and evaluation for the appropriate diet consistency allow a patient to initiate oral intake of nutrition while minimizing the risk of aspirating. Flexible fiberoptic laryngoscopy can be performed transnasally and provides valuable information to assist in the assessment of dysphagia. The oral intake of various consistencies of liquids and solids can be observed with endoscopic assessment of laryngeal penetration. A similar assessment may be performed with a modified barium swallow allowing the analysis of the various phases of swallowing. Nose and Paranasal Sinuses Unknown Primary Tumors. When patients present with cervical nodal metastases without clinical or radiologic evidence of an upper aerodigestive tract primary tumor, they are referred to as having an unknown primary. Given the difficulty in performing a detailed examination in the clinical setting of the base of tongue, the tonsillar fossa, and the nasopharynx, examination under anesthesia with directed tissue biopsy specimens has been advocated. Ipsilateral tonsillectomy, direct laryngoscopy with base of tongue and pyriform biopsy specimens, examination of the nasopharynx, and bimanual examination can allow for identification of a primary site in a portion of The nose and paranasal sinuses are the sites of a great deal of infectious and inflammatory pathology. The diagnosis of tumors within this region is frequently made after a patient has been unsuccessfully treated for recurrent sinusitis and undergoes diagnostic imaging. Symptoms associated with sinonasal tumors are subtle and insidious. They include chronic nasal obstruction, facial pain, headache, epistaxis, and facial numbness. As such, tumors of the paranasal sinuses frequently present at an advanced stage. Orbital invasion can result in proptosis, diplopia, epiphora, and vision loss. Paresthesia within the distribution of CN V2 is suggestive of pterygopalatine fossa or skull base invasion and is generally a poor prognostic factor. Maxillary sinus tumors can present with loose dentition indicating erosion of the alveolar and/or palatal bones. Tumors found to arise posterior to Ohngren’s line are associated with a worse prognosis than are more anteriorly based lesions (Fig. 18-36).70 A variety of benign tumors arise in the nasal cavity and paranasal sinuses and include inverted papillomas, hemangiomas, hemangiopericytomas, angiofibromas, minor salivary tumors, and benign fibrous histiocytomas. Fibro-osseous and osseous lesions, such as fibrous dysplasias, ossifying fibromas, osteomas, and myxomas, can also arise in this region. Additionally, herniation of intracranial contents into the nasal cavity can Medial canthus Maxillary sinus Angle of mandible Ohngren's line Figure 18-36. Example of the Ohngren’s line and the relationship to the maxilla. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ gaining increasing acceptance for low-grade resectable lesions such as inverted papilloma. If erosion of the cribriform has occurred, an anterior craniofacial resection is the standard operative approach. The head and neck surgeon and neurosurgeon work in concert to perform this procedure. The neurosurgeon performs a frontal craniotomy for exposure of the anterior cranial fossa floor, whereas the head and neck surgeon proceeds through a transfacial or endoscopic approach to resect the inferior bony attachments. Paranasal sinus malignancies that are deemed unresectable are those with bilateral optic nerve involvement, massive brain invasion, or carotid encasement. 73 Postoperative rehabilitation after orbital exenteration is accomplished by soft-tissue reconstruction and placement of a maxillofacial prosthesis. Combined treatment with surgery and postoperative radiotherapy for squamous cell carcinoma of the sinuses results in survival superior to either radiation or surgery alone. Chemotherapy has a limited application and may be used for specific indications. Rhabdomyosarcoma is primarily treated with chemotherapy followed by radiation therapy. Surgery is reserved for persistent disease after chemoradiation. Sinonasal undifferentiated carcinoma is highly aggressive and typically is not adequately controlled with standard therapy. Chemotherapy in this setting may help to reduce the tumor bulk and allow for orbital preservation. Nasopharynx The nasopharynx extends in a plane superior to the hard palate from the choana, to the posterior nasal cavity, to the posterior pharyngeal wall. It includes the fossa of Rosenmüller, the Eustachian tube orifices (torus tubarius), and the site of the adenoid pad. Tumors arising in the nasopharynx are usually of squamous cell origin and range from lymphoepithelioma to well-differentiated carcinoma. However, the differential diagnosis for nasopharyngeal tumors is broad and also includes lymphoma, chordoma, chondroma, nasopharyngeal cyst (Tornwaldt’s cyst), angiofibroma, minor salivary gland tumor, paraganglioma, rhabdomyosarcoma, extramedullary plasmacytoma, and sarcoma. Risk factors for nasopharyngeal carcinoma include area of habitation, ethnicity, and tobacco use. There is an increased incidence of nasopharyngeal cancer in southern China, Africa, Alaska, and in Greenland Eskimos. A strong correlation exists between nasopharyngeal cancer and the presence of EBV infection, such that EBV titers may be used as a means to follow a patient’s response to treatment. Symptoms associated with nasopharyngeal tumors include nasal obstruction, posterior (level V) neck mass, epistaxis, headache, serous otitis media with hearing loss, and otalgia. Cranial nerve involvement is indicative of skull base extension and advanced disease. Lymphatic spread occurs to the posterior cervical, upper jugular, and retropharyngeal nodes. Bilateral regional metastatic spread is common. Distant metastasis is present in 5% of patients at presentation. Examination of the nasopharynx is facilitated by the use of the flexible or rigid fiber-optic endoscope. Evaluation with imaging studies is important for staging and treatment planning. CT with contrast is used for determining bone destruction, while MRI is used to assess for intracranial and soft-tissue extension. Erosion or enlargement of neural foramina (on CT imaging) or enhancement of cranial nerves (on MRI) is indicative of perineural spread of disease and portends a worse prognosis. The status of the cavernous sinus and optic chiasm should also be assessed. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 593 CHAPTER 18 DISORDERS OF THE HEAD AND NECK occur with the erosion of the anterior skull base with the resultant presentation of a sinonasal mass on clinical examination. Malignant tumors of the sinuses are predominantly squamous cell carcinomas. Sinonasal undifferentiated carcinoma,71 adenocarcinoma, mucosal melanoma, lymphoma, olfactory neuroblastoma, rhabdomyosarcoma, and angiosarcoma are some of the other malignancies that have been described. Metastases from the kidney, breast, lung, and thyroid may also present as an intranasal mass. Regional metastasis is uncommon with tumors of the paranasal sinuses (14%–16%) and occurs in the parapharyngeal, retropharyngeal, and subdigastric nodes of the jugular chain. The diagnosis of an intranasal mass is made with the assistance of a headlight and nasal speculum or nasal endoscopy. The site of origin, involved bony structures, and the presence of vascularity should be assessed. For paranasal sinus tumors, MRI and CT scanning often are complementary studies in determining orbital and intracranial extension.72 Benign processes frequently present as slow-growing expansile tumors with limited erosion of surrounding bone, compared to the lytic destruction typically associated with malignancies. Skull base foramen should be closely examined for enlargement that may be suggestive of perineural invasion. Examination for cavernous sinus extension, cribriform plate erosion, and dural enhancement is necessary to assess for resectability and the type of ­surgical approach that is possible. A meningocele or encephalocele will present as a unilateral pulsatile mass. Biopsy of a unilateral nasal mass should be deferred until imaging studies are obtained. An untimely biopsy specimen can result in a CSF leak. If hypervascularity is suspected, biopsy should be performed under controlled conditions in the operating room. The standard treatment for malignant tumors of the paranasal sinuses is surgical resection with postoperative radiation therapy. Tumors arising along the medial wall of the maxillary sinus may be treated by means of a medial maxillectomy. The treatment of advanced tumors of the paranasal sinuses frequently involves a multispecialty approach. Members of this team include the head and neck surgeon, neurosurgeon, prosthodontist, ophthalmologist, and reconstructive surgeon. Each team member is necessary to facilitate the goal of safe and complete tumor removal. For vascular tumors, preoperative embolization performed within 24 hours of the planned surgical resection may reduce intraoperative hemorrhage. Prognosis is dependent on tumor location and extension to the surrounding anatomy. Infrastructure maxillectomy, which includes removal of the hard palate and the lower maxillary sinus, is necessary for inferiorly based tumors of the maxillary sinus. For tumors in the upper portion of the maxillary sinus, complete maxillectomy (including removal of the orbital floor) is performed. If there is invasion of the orbital fat, exenteration of the orbital contents is required. Removal of the bony floor of the orbit and preservation of the globe are possible where there is absence of invasion through the orbital periosteum. However, reconstruction of the orbital floor to recreate a stable support for the orbital contents is essential. Removal of anterior cheek skin is indicated when there is tumor extension into the overlying subcutaneous fat and dermis. For tumors involving the ethmoid sinuses, the integrity of the cribriform plate is assessed with preoperative imaging. Complete sphenoethmoidectomy or medial maxillectomy may suffice if the tumor is localized to the lateral nasal wall. Endoscopic resection with the assistance of image-guidance technology is 594 UNIT II PART SPECIFIC CONSIDERATIONS The standard treatment for nasopharyngeal carcinoma is chemoradiation. Combination therapy produces superior survival rates for nasopharyngeal carcinoma in comparison to radiation alone.74 Intracavitary radiation boost with implants to the tumor may be included as an adjunct to external beam radiotherapy to improve local control of advanced tumors. Surgical treatment for nasopharyngeal carcinoma is rarely feasible, but may be considered in selected cases as salvage therapy for patients with localized recurrences. For minor salivary gland and low-grade tumors of the nasopharynx, resection can be performed via a variety of approaches. Lateral rhinotomy or midface degloving approaches can provide good access for removal of tumors in the posterior nasal cavity extending into the nasopharynx. Endoscopic removal is also possible in selected cases. A variety of surgical approaches also exist for more posteriorly located tumors extending to the sphenoid and clivus. Transpalatal approaches used in combination with transmaxillary and transcervical routes can provide good surgical access in addition to providing adequate control of the carotid artery. The emergence of endoscopic techniques has provided a significant advancement in the surgical management of lesions in these two sites. Ear and Temporal Bone Tumors of the ear and temporal bone are uncommon and account for less than 1% of all head and neck malignancies. Primary sites include the external ear (pinna), EAC, middle ear, mastoid, or petrous portion of the temporal bone. The most common histology is squamous cell carcinoma. Minor salivary gland tumors, including adenoid cystic carcinoma and adenocarcinoma, may also present in this region. The pinna, because of its exposure to ultraviolet light, is a common site for basal cell and squamous cell carcinoma to arise. Direct extension of tumors from the parotid gland and periauricular skin may occur in this region. Metastases from distant sites occur primarily to the petrous bone and arise in the breast, kidney, lung, and prostate. In the pediatric population, tumors of the temporal bone are most commonly soft-tissue sarcomas. For advanced stage tumors with extensive temporal bone extension, the complex anatomy of the temporal bone makes removal of tumors with functional preservation challenging. The diagnosis of tumors of the ear and temporal bone is frequently delayed because the initial presentation of these patients is mistaken for benign infectious disease. When patients fail to improve with conservative care and symptoms evolve to potentially include facial nerve paralysis or worsening hearing loss, the need for imaging and biopsy become obvious. Granulation tissue in the EAC or middle ear should be biopsied in patients with atypical presentations or histories consistent with chronic otologic disease.75The complexity of the temporal bone anatomy makes the use of imaging studies of paramount importance in the staging and treatment of tumors in this region. Small skin cancers on the helix of the ear can be readily treated with simple excision and primary closure. Mohs’ microsurgery with frozen section margin control also can be used for cancer of the external ear. In lesions that are recurrent or invade the underlying perichondrium and cartilage, rapid spread through tissue planes can occur. Tumors may extend from the cartilaginous external canal to the bony canal and invade the parotid, temporomandibular joint, and skull base. For extensive, pinna-based lesions, procedures such as auriculectomy may be required. Postoperative radiation therapy may be required for advanced skin cancer with positive margins, perineural spread, or multiple involved lymph nodes. Tumors involving the EAC and middle ear may present with persistent otorrhea, otalgia, EAC or periauricular mass, hearing loss, and facial nerve weakness or paralysis. The patient resembles the presentation of an external otitis unresponsive to standard medical therapy. Sleeve resections are reserved for small superficial tumors involving the cartilaginous external canal. Tumors involving the petrous apex or intracranial structures may present with headache and palsies of CN V and VI. The optimal treatment for tumors of the middle ear and bony external canal is en bloc resection followed by radiation therapy. Management of the regional lymphatics is determined by the site and stage of the tumor at presentation. Temporal bone resections are classified as lateral or subtotal (Fig. 18-37). The lateral temporal bone resection removes the bony and cartilaginous canal, tympanic membrane, and ossicles. The subtotal temporal bone resection includes the removal of the ear canal, middle ear, inner ear, and facial nerve. It is indicated for malignant tumors extending into the middle ear. Postoperative radiation therapy in the treatment of malignancies of the temporal bone usually is indicated and improves local control over surgery alone. Five-year survival rates are approximately 50% for patients with tumors confined to the external canal and decrease with medial tumor extension. Prognosis is poor when tumor involves the petrous apex.76 The purpose of reconstruction after temporal bone resection is to provide vascularized tissue and bulk to the site of resection. Prevention of CSF leak by watertight dural closure and prevention of meningitis are important goals of repair. Additionally, the reconstruction enables protection of vascular structures and the surrounding bone to prepare the patient for postoperative radiation therapy. Commonly used reconstruction methods are regional pedicle myocutaneous flaps (e.g., Total temporal bone resection Subtotal temporal bone resection Lateral temporal bone resection Figure 18-37. Examples of resection specimens for lateral temporal bone resection, subtotal temporal bone resection, and total temporal bone resection. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ pectoralis major) and free flaps (e.g., rectus abdominis, radial forearm, or latissimus dorsi). The loss of the pinna produces significant external deformity; however, a prosthetic ear may produce acceptable rehabilitation. When the facial nerve is sacrificed, rehabilitation is necessary and includes the use of interposition nerve grafts, hypoglossal to facial nerve anastomosis, and static or dynamic sling techniques. In patients with poor eye closure, taping of the eyelids and the liberal use of eye lubrication can prevent exposure keratitis. Additionally, tarsorrhaphy, lid-shortening procedures, and the use of gold weight implants can provide upper eyelid closure and protect the cornea. 595 II I Neck The diagnostic evaluation of a neck mass requires a planned approach that does not compromise the effectiveness of future treatment options. A neck mass in a 50-year-old smoker/drinker with a synchronous oral ulcer is different from cystic neck mass in an 18-year-old that enlarges with an upper respiratory infection. As with all diagnoses, a complete history with full head and neck exam, including flexible laryngoscopy, are critical to complete evaluation. The differential diagnosis of a neck mass is dependent on its location and the patient’s age. In children, most neck masses are inflammatory or congenital. However, in the adult population, a neck mass >2 cm in diameter has a >80% probability of being malignant. Once the physician has developed a differential diagnosis, interventions to confirm or dispute diagnoses are initiated. Fine-needle aspiration (FNA), with or without the assistance of ultrasound or CT guidance, can provide valuable information for early treatment planning. The use of imaging (CT and/or MRI) is dictated by the patient’s clinical presentation. Imaging enables the physician to evaluate the anatomic relationships of the mass to the surrounding anatomy of the neck and sharpen the differential. A cystic lesion may represent benign pathology such as a branchial cleft cyst; however, it may also represent a regional metastasis of a tonsil/ base of tongue squamous cell carcinoma or a papillary thyroid carcinoma. In this circumstance, evaluation of these potential primary sites can alter the planned operative intervention. If a variety of diagnoses are still being entertained after FNA and imaging, an open biopsy may be necessary. For patients with the potential diagnosis of lymphoma, a biopsy sacrificing normal anatomical structures is not necessary. Ensuring appropriate processing of biopsied materials, sent in saline or in formalin, and sparing undue trauma to tissues can decrease the need for re-biopsy. Appropriate placement of the incision for an open biopsy should be considered if the need for neck dissection or composite resection is later required. Patterns of Lymph Node Metastasis. The regional lymphatic drainage of the neck is divided into seven levels. These levels allow for a standardized format for radiologists, surgeons, pathologists, and radiation oncologists to communicate concerning specific sites within the neck (Fig. 18-38). The levels are defined as the following: Level I—the submental and submandibular nodes Level Ia—the submental nodes; medial to the anterior belly of the digastric muscle bilaterally, symphysis of mandible superiorly, and hyoid inferiorly Level Ib—the submandibular nodes and gland; posterior to the anterior belly of digastric, anterior to the posterior belly of digastric, and inferior to the body of the mandible Level II—upper jugular chain nodes VI V IV Figure 18-38. Levels of the neck denoting lymph node bearing regions. Level IIa—jugulodigastric nodes; deep to sternocleidomastoid (SCM) muscle, anterior to the posterior border of the muscle, posterior to the posterior aspect of the posterior belly of digastric, superior to the level of the hyoid, inferior to spinal accessory nerve (CN XI) Level IIb—submuscular recess; superior to spinal accessory nerve to the level of the skull base Level III—middle jugular chain nodes; inferior to the hyoid, superior to the level of the cricoid, deep to SCM muscle from posterior border of the muscle to the strap muscles medially Level IV—lower jugular chain nodes; inferior to the level of the cricoid, superior to the clavicle, deep to SCM muscle from posterior border of the muscle to the strap muscles medially Level V—posterior triangle nodes Level Va—lateral to the posterior aspect of the SCM muscle, inferior and medial to splenius capitis and trapezius, superior to the spinal accessory nerve Level Vb—lateral to the posterior aspect of SCM muscle, medial to trapezius, inferior to the spinal accessory nerve, superior to the clavicle Level VI—anterior compartment nodes; inferior to the hyoid, superior to suprasternal notch, medial to the lateral extent of the strap muscles bilaterally Level VII—paratracheal nodes; inferior to the suprasternal notch in the upper mediastinum Patterns of spread from primary tumor sites in the head and neck to cervical lymphatics are well described.77 The location and incidence of metastasis vary according to the primary site. Primary tumors within the oral cavity and lip metastasize to the nodes in levels I, II, and III. Skip metastases may occur with oral tongue cancers such that involvement of nodes in level III or IV may occur without involvement of higher echelon nodes (levels I & II). Tumors arising in the oropharynx, hypopharynx, and larynx most commonly spread to the lymph nodes of the lateral neck in levels II, III, and IV. Isolated level V lymphadenopathy VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK III 596 UNIT II PART SPECIFIC CONSIDERATIONS is uncommon with oral cavity, pharyngeal, and laryngeal primaries. Malignancies of the nasopharynx and thyroid commonly spread to level V nodes in addition to the jugular chain nodes. Retropharyngeal lymph nodes are sites for metastasis from tumors of the nasopharynx, soft palate, and lateral and posterior walls of the oropharynx and hypopharynx. Tumors of the hypopharynx, cervical esophagus, and thyroid frequently involve the paratracheal nodal compartment, and may extend to the lymphatics in the upper mediastinum (level VII). The delphian node, a pretracheal lymph node, may become involved by advanced tumors of the glottis with subglottic spread. The philosophy for the treatment of the cervical lymphatics in head and neck cancer has evolved significantly since the mid-1970s. The presence of cervical metastasis decreases the 5-year survival rate in patients with upper aerodigestive malignancies by approximately 50%. As such, adequate treatment of the N0 and N+ neck in these patients has always been viewed as a priority in an effort to increase disease-free survival rates. Traditionally, the gold standard for control of cervical metastasis has been the radical neck dissection (RND) first described by Crile. The classic RND removes levels I to V of the cervical lymphatics in addition to the SCM, internal jugular vein, and the spinal accessory nerve (CN XI). Any modification of the RND that preserves nonlymphatic structures (i.e., CN XI, SCM muscle, or internal jugular vein) is defined as a modified radical neck dissection (MRND). A neck dissection that preserves lymphatic compartments normally removed as part of a classic RND is termed a selective neck dissection (SND). Bocca and colleagues demonstrated that the MRND, or “functional neck dissection,” was equally effective in controlling regional metastasis as the RND, in addition to noting that the functional results in patients were superior.78 With outcome data supporting the use of SND and MRND, these procedures have become the preferred alternative for the treatment of cervical metastases when indicated.79,80 SND options have become increasingly popular given the benefits of improved shoulder function and cosmetic impact on neck contour compared to MRND. The principle behind preservation of certain nodal groups is that specific primary sites preferentially drain their lymphatics in a predictable pattern. Types of SND include the supraomohyoid neck dissection, the lateral neck dissection, and the posterolateral neck dissection.81­The supraomohyoid dissection, typically used with oral ­cavity malignancies, removes lymph nodes in levels I to III­ (­Fig. 18-39). The lateral neck dissection, frequently used for laryngeal malignancies, removes those nodes in levels II through IV (Fig. 18-40). The posterolateral neck dissection, used with thyroid cancer, removes the lymphatics in levels II to V (Fig. 18-41). In the clinically negative neck (N0), if the risk for occult metastasis is >20%, elective treatment of the nodes at risk is generally advocated. This may be in the form of elective neck irradiation or elective neck dissection. An additional role of SND is as a staging tool to determine the need for postoperative radiation therapy. Regional control after selective dissection has been shown to be as effective for controlling regional disease as the MRND in the N0 patient. Awareness of the potential for “skip metastases,” in particular with lateral oral tongue lesions, may require extension of a standard SND to include additional levels for selected lesions.82 The treatment option selected for the primary site cancer is a significant factor in determining which therapeutic modality will be selected for the treatment of the regional lymphatics. Figure 18-39. Shaded region indicates the region included in a supraomohyoid neck dissection. For clinically N+ necks, frequently the surgical treatment of choice is the MRND or RND. SND options have been advocated by some authors for treatment of limited N1 disease, however, they do not have a role in the treatment of advanced N stage disease. When extracapsular spread, perineural invasion, Figure 18-40. Shaded region indicates the region included in a lateral neck dissection. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 597 Stylomandibular ligament Figure 18-41. Shaded region indicates the region included in a posterolateral neck dissection. vascular invasion, and the presence of multiple involved lymph nodes are noted, surgical management of the neck alone is not adequate.83 Adjuvant radiation therapy, and possibly chemoradiation, is indicated in these cases. A planned postradiation neck dissection for patients undergoing radiation as a primary therapy is another indication for the use of neck dissection. In patients with existing advanced N stage disease (N2a or greater) or in patients with a partial response in the neck to therapy, neck dissection is performed 6 to 8 weeks after completion of radiation. Regional metastases that encase the carotid artery or that demonstrate fixation of nodes to surrounding structures (e.g., prevertebral muscles) decrease 5-year survival rates significantly, to the range of 15% to 22%. The associated morbidity is high with procedures involving carotid resection (e.g., cerebrovascular accident and death) and must be weighed carefully when deciding if surgery is to be pursued. Surgically debulking metastatic disease does not improve survival and is not advocated. Recurrent neck metastasis after comprehensive neck dissection or radiation is associated with very poor survival. Parapharyngeal Space Masses. The parapharyngeal space is a potential space, shaped like an inverted pyramid spanning the skull base to the hyoid. The boundaries of the space are separated by the styloid process and its associated fascial attachments into the “prestyloid” and “poststyloid” compartments.84 The contents of the prestyloid space are the parotid, fat, and lymph nodes. The poststyloid compartment is composed of CN’s IX to XII, the carotid space contents, cervical sympathetic chain, fat, and lymph nodes. Tumors in this space can produce displacement of the lateral pharyngeal wall medially into the oropharynx (Fig. 18-42), dysphagia, cranial nerve dysfunction, Horner’s syndrome, or vascular compression. Figure 18-42. Parapharyngeal mass—prestyloid with prominent oropharyngeal presentation typical of a dumbbell tumor. Of the masses found in the parapharyngeal space, 40% to 50% of the tumors are of salivary gland origin. Tumors of neurogenic origin such as paragangliomas (glomus vagale, carotid body tumor), schwannomas, and neurofibromas are responsible for 20% to 25% of parapharyngeal masses. Lymph node metastases and primary lymphoma represent 15% of lesions. With this in mind, when reviewing preoperative imaging, one can assume that tumors arising anterior to the styloid process are most likely of salivary gland origin, whereas those of the poststyloid compartment are vascular or neurogenic. This is helpful in that angiography is not as necessary for prestyloid lesions as it may be for vascular poststyloid tumors. If a paraganglioma is suspected, a 24-hour urinary catecholamine collection should be obtained to allow for optimal premedication for patients with functional tumors. Embolization may be considered for vascular tumors before surgery in an attempt to decrease intraoperative blood loss. Surgical access to these tumors may require a transmandibular and/or lateral cervical approach. It is inadvisable to approach parapharyngeal space tumors transorally without VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 18 DISORDERS OF THE HEAD AND NECK Parotid gland 598 h­ aving the necessary exposure and control of the associated vasculature that is afforded by these approaches. Some tumors of the parapharyngeal space (e.g., dumbbell tumors of deep parotid origin) are amenable to removal by a combined transparotid and transcervical approach while allowing for dissection and displacement of the facial nerve to assist removal of tumor. Benign Neck Masses. A number of benign masses of the UNIT II PART SPECIFIC CONSIDERATIONS neck occur that require surgical management. Many of these masses are seen in the pediatric population. The differential diagnosis includes thyroglossal duct cyst, branchial cleft cyst, lymphangioma (cystic hygroma), hemangioma, and dermoid cyst. Thyroglossal duct cysts represent the vestigial remainder of the tract of the descending thyroid gland from the foramen cecum, at the tongue base, into the lower anterior neck during fetal development. They present as a midline or paramedian cystic mass adjacent to the hyoid bone. After an upper respiratory infection, the cyst may enlarge or become infected. Surgical management of a thyroglossal duct cyst requires removal of the cyst, the tract, and the central portion of the hyoid bone (Sistrunk procedure), as well as a portion of the tongue base up to the foramen cecum. Before excision of a thyroglossal duct cyst, an imaging study such as ultrasound is performed to identify if normal thyroid tissue exists in the lower neck, and lab assay is performed to assess if the patient is euthyroid. Congenital branchial cleft remnants are derived from the branchial cleft apparatus that persists after fetal development. There are several types, numbered according to their corresponding embryologic branchial cleft. First branchial cleft cysts and sinuses are associated intimately with the EAC and the parotid gland. Second and third branchial cleft cysts are found along the anterior border of the SCM muscle and can produce drainage via a sinus tract to the neck skin (Fig. 18-43). Secondary infections can occur, producing enlargement, cellulitis, and neck abscess that requires operative drainage. The removal of branchial cleft cysts and fistula requires removal of the fistula tract to the point of origin to decrease the risk of recurrence. The second branchial cleft remnant tract courses between the internal and external carotid arteries and proceeds into the tonsillar fossa. The third branchial cleft remnant courses posterior to the common carotid artery, ending in the pyriform sinus region. Cystic metastasis from squamous cell carcinoma of the tonsil or tongue base to a cervical lymph node can be confused for a branchial cleft cyst in an otherwise asymptomatic patient. Dermoid cysts tend to present as midline masses and represent trapped epithelium originating from the embryonic closure of the midline. Lymphatic malformations such as lymphangiomas and cystic hygromas can be difficult management problems. They typically present as mobile, fluid-filled masses. Because of their predisposition to track extensively into the surrounding soft tissues, complete removal of these lesions can be challenging. Recurrence and re-growth occur with incomplete removal. Cosmetic deformity and/or nerve injury can result when extensive surgical dissection is performed for large lesions. In newborns and infants, there is higher associated morbidity when cystic hygromas and lymphangiomas become massive, require tracheostomy, and involve the deep neck and mediastinum. Deep Neck Fascial Planes. The fascial planes of the neck provide boundaries that are clinically applicable because they determine the pathway of spread of an infection. The deep cervical fascia is composed of three layers. These are the investing (superficial deep), pretracheal, and the prevertebral fascias. The superficial layer of the deep cervical fascia forms a cone around the neck and spans from skull base and mandible to the clavicle and manubrium. This layer surrounds the SCM muscle and covers the anterior and posterior triangles of the neck. The pretracheal fascia is found within the anterior compartment, deep to the strap muscles and surrounds the thyroid gland, trachea, and esophagus. This fascia blends laterally to the carotid sheath. Figure 18-43. CT scan demonstrating a branchial cleft cyst with operative specimen. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Infections in this region may track along the trachea or esophagus into the mediastinum. The prevertebral fascia extends from the skull base to the thoracic vertebra and covers the prevertebral musculature and cervical spine. If an infection were to communicate anteriorly through the prevertebral fascia, it would enter the retropharyngeal space. Infectious extension into this space is complicated by the fact that this region, located 6 posterior to the buccopharyngeal fascia, extends from the skull base to the mediastinum. Tumors of the salivary gland are relatively uncommon and represent less than 2% of all head and neck neoplasms. The major salivary glands are the parotid, submandibular, and sublingual glands. Minor salivary glands are found throughout the submucosa of the upper aerodigestive tract with the highest density found within the palate. About 85% of salivary gland neoplasms arise within the parotid gland (Fig. 18-44). The majority of these neoplasms are benign, with the most common histology being pleomorphic adenoma (benign mixed tumor). In contrast, approximately 50% of tumors arising in the submandibular and sublingual glands are malignant. Tumors arising from minor salivary gland tissue carry an even higher risk for malignancy (75%). Salivary gland tumors are usually slow growing and well circumscribed. Patients with a mass and findings of rapid growth, pain, paresthesias, and facial nerve weakness are at increased risk of harboring a malignancy. The facial nerve, which separates the superficial and deep lobes of the parotid, may be directly involved by tumors in 10% to 15% of patients. Additional findings ominous for malignancy include skin invasion and fixation to the mastoid tip. Trismus suggests invasion of the masseter or pterygoid muscles.85 Submandibular and sublingual gland tumors present as a neck mass or floor of mouth swelling, respectively. Malignant tumors of the sublingual or submandibular gland may invade the lingual or hypoglossal nerves, causing paresthesias or paralysis.86 Bimanual examination is important for determining the size of the Temporal branches Facial n. Zygomatic branch Masseter m. Parotid duct Posterior belly of digastric m. Buccal branch Cervical branch Mandibular branch Anterior facial v. Figure 18-44. Example of a tumor in the parotid with the pattern of the facial nerve and associated anatomy. m. = muscle; n. = nerve; v. = vein. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 599 CHAPTER 18 DISORDERS OF THE HEAD AND NECK Salivary Gland Tumors tumor and possible fixation to the mandible or involvement of the tongue. Minor salivary gland tumors present as painless submucosal masses and are most frequently seen at the junction of the hard and soft palate. Minor salivary gland tumors arising in the prestyloid parapharyngeal space may produce medial displacement of the lateral oropharyngeal wall and tonsil. The incidence of metastatic spread to cervical lymphatics is variable and depends on the histology, primary site, and stage of the tumor. Parotid gland malignancies can metastasize to the intra- and periglandular nodes. The next echelon of lymphatics for the parotid is the upper jugular nodal chain. Although the risk of lymphatic metastasis is low for most salivary gland malignancies, lesions that are considered high grade or that demonstrate perineural invasion have a higher propensity for regional spread. Tumors arising in patients of advanced age also tend to have more aggressive behavior. Initial nodal drainage for the submandibular gland is the level Ia and Ib lymph nodes and submental nodes followed by the upper and midjugular nodes. Extraglandular extension of tumor and lymph node metastases are adverse prognostic factors for submandibular gland tumors. Diagnostic imaging is standard for the evaluation of salivary gland tumors. MRI is the most sensitive study to determine soft-tissue extension and involvement of adjacent structures. Unfortunately, imaging studies lack the specificity for differentiating benign and malignant neoplasms. Diagnosis of salivary gland tumors is frequently aided by the use of FNA. In the hands of an experienced cytologist familiar with salivary gland pathology, FNA can provide an accurate preoperative diagnosis in 70% to 80% of cases. This can help the operative surgeon with treatment planning and patient counseling, but should be viewed in the context that a more extensive procedure may be ultimately required. The final histopathologic diagnosis is confirmed by surgical excision. Benign and malignant tumors of the salivary glands are divided into epithelial, nonepithelial, and metastatic neoplasms. Benign epithelial tumors include pleomorphic adenoma (80%), monomorphic adenoma, Warthin’s tumor, oncocytoma, or sebaceous neoplasm. Nonepithelial benign lesions include hemangioma, neural sheath tumor, and lipoma. Treatment of benign neoplasms is surgical excision of the affected gland or, in the case of the parotid, excision of the superficial lobe with facial nerve dissection and preservation. The minimal surgical procedure for neoplasms of the parotid is superficial parotidectomy with preservation of the facial nerve. Enucleation of the tumor mass is not recommended because of the risk of incomplete excision and tumor spillage. Tumor spillage of a pleomorphic adenoma during removal can lead to problematic recurrences. Malignant epithelial tumors range in aggressiveness from low to high grade. Their behavior depends on tumor histology, degree of invasiveness, and the presence of regional metastasis. The most common malignant epithelial neoplasm of the salivary glands is mucoepidermoid carcinoma. The low-grade mucoepidermoid carcinoma is composed of largely mucin-secreting cells, whereas in high-grade tumors, the epidermoid cells predominate. High-grade mucoepidermoid carcinomas resemble nonkeratinizing squamous cell carcinoma in their histologic features and clinical behavior. Adenoid cystic carcinoma, which has a propensity for neural invasion, is the second most common malignancy in adults. Skip lesions along nerves are common 600 UNIT II PART SPECIFIC CONSIDERATIONS and can lead to treatment failures because of the difficulty in treating the full extent of invasion. Adenoid cystic carcinomas have a high incidence of distant metastasis, but display indolent growth. It is not uncommon for patients to experience lengthy survival despite the presence of disseminated disease. The most common malignancies in the pediatric population are mucoepidermoid carcinoma and acinic cell carcinoma. For minor salivary glands, the most common malignancies are adenoid cystic carcinoma, mucoepidermoid carcinoma, and low-grade polymorphous adenocarcinoma. Carcinoma ex pleomorphic adenoma is an aggressive malignancy that arises from a preexisting benign mixed tumor. The primary treatment of salivary malignancies is surgical excision. In this setting, basic surgical principles include the en bloc removal of the involved gland with preservation of all nerves unless directly invaded by tumor. For parotid tumors that arise in the lateral lobe, superficial parotidectomy with preservation of CN VII is indicated. If the tumor extends into the deep lobe of the parotid, a total parotidectomy with nerve preservation is performed. Although malignant tumors may about the facial nerve, if a plane of dissection can be developed without leaving gross tumor, it is preferable to preserve the nerve. If the nerve is encased by tumor (or is noted to be nonfunctional preoperatively) and preservation would result leaving gross residual disease, nerve sacrifice should be considered. The removal of submandibular malignancies includes en bloc resection of the gland and submental and submandibular lymph nodes. Radical resection is indicated with tumors that invade the mandible, tongue, or floor of mouth. Therapeutic removal of the regional lymphatics is indicated for clinical adenopathy or when the risk of occult regional metastasis exceeds 20%. High-grade mucoepidermoid carcinomas, for example, have a high risk of regional disease and require elective treatment of the regional lymphatics. When gross nerve invasion is found (lingual or hypoglossal), sacrifice of the nerve is indicated with retrograde frozen section biopsy specimens to determine the extent of involvement. If the nerve is invaded at the level of the skull base foramina, a surgical clip may be left in place to mark the area for inclusion in postoperative radiation fields. The presence of skip metastases in the nerve with adenoid cystic carcinoma makes recurrence common with this pathology. Postoperative radiation treatment plays an important role in the treatment of salivary malignancies. The presence of extraglandular disease, perineural invasion, direct invasion of regional structures, regional metastasis, and high-grade histology are all indications for radiation treatment. RECONSTRUCTION IN HEAD AND NECK SURGERY Defects of soft tissue and bony anatomy of the head and neck can occur after oncologic resection. Tumor surgery frequently necessitates removal of structures related to speech and swallowing. Loss of sensation and motor function can produce dysphagia through impairment of food bolus formation, manipulation, and propulsion. Removal of laryngeal, tongue base, and hypopharyngeal tumors can lead to impairment in airway protective reflexes and predispose to aspiration. Cosmetic deformities that result from surgery can also significantly the quality of life of a patient. Current surgical 7 impact management of head and neck tumors requires restoration of form and function through application of contemporary reconstruction techniques. Basic principles of reconstruction include attempting to replace resected tissue components (bone, skin, soft tissue) with tissue with similar qualities. However, restoring a patient’s functional capacity does not always require strict observation of this rule. The head and neck reconstructive surgeon must consider a patient’s preoperative comorbidities and anatomy when constructing a care plan. A stepladder analogy has been used to describe the escalation in complexity of reconstructive options in the repair of head and neck defects. It is important to remember that the most complex procedure is not always the most appropriate. Progression for closure by secondary intention, primary closure, skin grafts, local flaps, regional flaps, and free-tissue transfer flaps (free flaps) run the gamut of options available. The most appropriate reconstructive technique used is based on the medical condition of the patient, the location and size of the defect to be repaired, and the functional impairment associated with the defect. Small defects of the skin of the medial canthus, scalp, and nose may be allowed to heal by secondary intention with excellent cosmetic and functional results. When considering primary closure, the excision should be placed in the lines of relaxed skin tension and should attempt to not distort surrounding anatomy such as the hairline, eyelids, or lips. Skin Grafts Split and full-thickness skin grafts are used in the head and neck for a variety of defects. Following oral cavity resections, split-thickness grafts can provide adequate reconstruction of the mucosal surface if an adequate vascular tissue bed is available to support the blood supply needed for graft survival. These grafts start to incorporate into the recipient site in approximately 5 days and do not provide replacement of absent soft-tissue bulk; however, they are a simple low morbidity technique for covering mucosal defects that allow for monitoring for local recurrence. Full-thickness grafts are used on the face when local rotational flaps are not available. These grafts have less contracture over time than split-thickness grafts. Grafts can be harvested from the postauricular or supraclavicular areas to maximize the match of skin characteristics. Dermal grafts have been used to provide coverage for exposed vessels in the neck, reconstruct mucosal defects, and assist in providing soft-tissue bulk. Local Flaps Local flaps encompass a large number of mainly random-pattern flaps used to reconstruct defects in adjacent areas. It is beyond the scope of this chapter to enumerate all of these flaps, but they should be designed according to the relaxed skin tension lines of the face and neck skin. These lines are tension lines inherent in the facial regions and caused in part by the insertions of muscles of facial animation. Incisions paralleling the relaxed skin tension lines that respect the aesthetic subunits of the face heal with the least amount of tension and camouflage into a more appealing cosmetic result. Poorly designed incisions or flaps result in widened scars and distortion of important aesthetic units. Regional Flaps Regional flaps are those that are available as pedicled transfer of soft tissue from areas adjacent to the defect. These flaps have an axial blood supply that traverses the flap longitudinally from proximal to distal between the fascia and subcutaneous tissue. Single-stage reconstruction is possible, and harvest may occur simultaneously with the resection of primary disease resulting in a decrease in overall operative time. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Free-Tissue Transfer Free-tissue transfer with microvascular anastomosis affords the reconstructive surgeon unparalleled ability to replace tissue loss with tissues of similar characteristics. There are a number of donor sites available for various types of flaps, including ­osteomyocutaneous, myocutaneous, fasciocutaneous, fascial, and myo-osseous flaps. The flaps most popular in head and neck reconstructive armamentarium are those with ease of harvest from a standpoint of patient positioning and those that allow for a two-teamed approach for simultaneous flap harvesting and oncologic resection.87 The radial forearm fasciocutaneous flap (Fig. 18-45) is a hardy flap with constant vascular anatomy and a long vascular pedicle, allowing for ease of insetting and choice in anastomotic vascular recipient sites. It is pliable and can be reinnervated as a sensate flap, making it ideal for repair of oral cavity and oropharyngeal defects. It can be tubed to repair hypopharyngeal and upper esophageal defects.88,89 The anterolateral thigh flap, based on the descending branch of the lateral circumflex femoral artery, has the capacity for a large pliable skin paddle with muscle that is capable of being tubed and is used to reconstruct similar defects as that of the radial forearm flap while providing more tissue bulk. The fibular osteocutaneous or osteomyocutaneous flap allows for one-stage reconstruction of resected mandible. In the adult, up to 20 cm of bone can be harvested with a cuff of soleus and flexor hallucis longus muscle for additional soft-tissue bulk. The donor site defect is well tolerated as long as approximately 7 cm of bone are retained proximally and distally for knee and ankle stability.90 Iliac crest osteocutaneous flaps are also used for the reconstruction of mandible defects. The natural shape of this donor site bone is similar to the mandibular angle. The thick stock of bone provided by the iliac crest allows for better vertical reconstruction of the mandible while spanning a segmental defect. However, for lengthy mandibular defects (>10 cm), the fibular flap usually is chosen. Additionally, for shorter mandible defects, other free flaps, including osseous components such as scapular and radial forearm flaps, can be used. The scapular flap can provide approximately 12 cm of scapula bone and is based on Figure 18-45. Radial forearm free flap before harvest from the arm. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 601 CHAPTER 18 DISORDERS OF THE HEAD AND NECK The deltopectoral fasciocutaneous flap is a medially based flap from the anterior chest wall reliant on the perforators of the internal mammary artery. Its pliability permits folding, making it capable for use with reconstruction of pharyngoesophageal defects. A disadvantage is that use of the flap requires a second stage detaching the proximal chest component and completion of insetting approximately 3 to 4 weeks after the original ­procedure. Several myocutaneous flaps exist for head and neck reconstruction. The vascular pedicle of these flaps permits a wide arc of rotation, making them ideal for a variety of different reconstructive needs. The trapezius muscle provides a number of softtissue flaps that can be rotated to reconstruct a number of defects in the head and neck. The superior trapezius flap is based on paraspinous perforators and is ideal for lateral neck defects. The lateral island trapezius flap, based on the transverse cervical and dorsal scapular vessels, allows for harvest of a soft-tissue paddle below the inferior border of the scapula. This flap is ideal for reconstruction of scalp and lateral skull base defects. The pectoralis myocutaneous flap is based on the pectoral branch of the thoracoacromial artery (medial) and the lateral thoracic artery (lateral). The latter vessel may be sacrificed to increase the arc of rotation. This workhorse flap includes the pectoralis major muscle, either alone or with overlying anterior chest skin. The pectoralis myocutaneous flap has enjoyed tremendous popularity because of its ease of harvest, the ability to tailor its thickness to the defect, and limited donor site morbidity. It can be used for reconstruction of the oropharynx, oral cavity, and the hypopharynx and in some cases can be tubed to replace cervical esophageal defects. Bulk associated with this flap may make certain applications less practical, and this problem is exacerbated in obese patients. The arc of rotation limits the superior extent of this flap to the zygomatic arch externally and the superior pole of the tonsil internally. The latissimus dorsi flap provides a large source of soft tissue and has a wide arc of rotation. The flap is based on the thoracodorsal vasculature. This flap can be used as a regional rotational flap or as a free flap. Lateral decubitus positioning is typically required for harvesting this flap, making it less attractive for simultaneous cancer ablation and reconstruction. 602 UNIT II PART SPECIFIC CONSIDERATIONS the circumflex scapular artery. This flap can be combined with parascapular and scapular skin islands and portions of latissimus dorsi and serratus anterior muscle. The radial forearm osteocutaneous flap can provide a limited quantity of bone with the softtissue component of the flap but is associated with an increased risk of donor site fracture. Large soft-tissue defects can result from trauma, excision of skull base tumors, and tumors involving large segments of skin. Furthermore, after extensive skull base resections in the anterior and lateral skull base, the need for separation of the oropharyngeal and sinonasal tracts from the dura requires soft-tissue interposition between the dura and the contaminated upper aerodigestive tract. The rectus abdominis flap, based on the deep inferior epigastric vessels, provides a large amount of soft tissue and is ideal for closure of wounds of the lateral skull base and dura. For reconstruction of defects of the hypopharynx and cervical esophagus, both free flaps and regional pedicled flaps are available. The free transfer of a jejunal segment can be performed based on branches of the superior mesenteric artery. Other free flaps used in this area include fasciocutaneous flaps, such as tubed radial forearm flap. The gastric pull-up is a regional flap that is also in use for reconstruction of cervical esophageal defects. The stomach is mobilized and pedicled on the right gastric and gastroepiploic vessels into the defect via tunneling through the thoracic cavity. TRACHEOSTOMY Tracheostomy is indicated in the management of patients who require prolonged intubation, access for frequent pulmonary suctioning, and in those patients with neurologic deficits that impair protective airway reflexes. Its use in head and neck surgery is often for the temporary management of the airway in the perioperative period. After surgical resection of oral cavity and oropharyngeal cancers, edema of the upper aerodigestive tract occurs necessitating perioperative tracheostomy to prevent loss of the airway. The avoidance of prolonged orotracheal and nasotracheal intubation decreases the risk of laryngeal and subglottic injury and potential stenosis, facilitates oral and pulmonary suctioning, and decreases patient discomfort. When the tracheostomy is no longer needed, the tube is removed and closure of the opening usually occurs spontaneously over a 2-week period. Complications of tracheostomy include pneumothorax, RLN injury, tracheal stenosis, wound infection with large-vessel erosion, and failure to close after decannulation. The use of cricothyroidotomy as an alternative to tracheostomy for patients who require prolonged intubation is associated with a higher incidence of vocal cord dysfunction and subglottic stenosis. When cricothyroidotomy is used in the setting of establishing an emergency airway, conversion to a standard tracheostomy should be considered if decannulation is not anticipated within 5 to 7 days. Placement of a tracheostomy does not obligate a patient to loss of speech. When a large cuffed tracheostomy tube is in place, expecting a patient to be capable of normal speech is impractical. However, after a patient is downsized to an uncuffed tracheostomy tube, intermittent finger occlusion or Passy-Muir valve placement will allow a patient to communicate while still using the tracheostomy to bypass the upper airway. When a patient no longer has the original indication for the tracheostomy and can tolerate capping of the tracheal tube for >24 hours, decannulation is considered safe. LONG-TERM MANAGEMENT AND REHABILITATION Palliative Care For patients with unresectable disease or distant metastases, palliative care options exist. Palliative treatment is aimed at improving a patient’s symptoms and may include radiation, chemotherapy, or consultation with a pain specialist. The head and neck surgeon has the options of tracheostomy and gastrostomy tube placement for patients progressing with worsening airway compromise and dysphagia, respectively. Hospice is also an option for patients with a limited short-term outlook; hospice allows a patient to retain dignity at the time of greatest adversity. Follow-Up Care Patients diagnosed and treated for a head and neck tumor require follow-up care aimed at monitoring for recurrence and the side effects of therapy. For patients undergoing successful treatment for malignancies of the upper aerodigestive tract, the American Head and Neck Society advocates for follow-up assessment every 1 to 3 months for the first year after treatment, expanding to every 2 to 6 months for years 2 to 4, with an annual follow-up at 5 years posttreatment and thereafter.91 In addition to a formal head and neck examination, patients should be questioned about any emerging symptoms related to their primary tumor. New-onset pain, otalgia, and dysphagia are some of the problems that may indicate the need to evaluate further for recurrence. Worsening dysphagia may 8 also be a presenting symptom for a patient developing a pharyngeal stricture. Such a patient may require dilatation and/ or placement of a gastrostomy tube for nutrition. Additionally, a number of patients who undergo head and neck radiation will develop hypothyroidism years after treatment. Patients with shoulder dysfunction after surgery should be considered for physical therapy consultation to minimize the long-term effects of their surgical care. Patients with chronic pain-related issues can benefit from consultation with a pain specialist to construct a treatment regimen to provide adequate control of long-term discomfort. Long-term follow-up with a dentist experienced in caring for patients with a history of therapeutic radiation therapy is vital if prevention of osteoradionecrosis is to be achieved. REFERENCES Entries highlighted in bright blue are key references. 1. Kaushik V, Malik T, Saeed SR. Interventions for acute otitis externa. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004740. 2. Carfrae MJ, Kesser BW. Malignant otitis externa. Otolaryngol Clin North Am. 2008; 41(3):537-549. 3. Sutton D, Derkay CS, Darrow DH, et al: Resistant bacteria in the middle ear fluid at the time of tympanostomy tube surgery. Ann Otol Rhinol Laryngol 2000;109:24. 4. 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Ann Otol Rhinol Laryngol Suppl. 1989;98:2-32. 17. Statham MM, Myer CM III. Complications of adenotonsillectomy. Curr Opin Otolaryngol Head Neck Surg. 2010; 18(6):539-543. 18. Friedman M, Tanyeri H, La Rossa M, et al: Clinical predictors of obstructive sleep apnea. Laryngoscope 1999;109:1901-1907. 19. Vasu TS, Grewal R, Doghramji K. Obstructive sleep apnea syndrome and perioperative complications: a systematic review of the literature. J Clin Sleep Med. 2012;8(2):199-207. 20. Zeitels SM, Casiano RR, Gardner GM, et al: Management of common voice problems: committee report. Otolaryngol Head Neck Surg. 2002;126:333. 21. Rosen CA, Woodson GE, Thompson JW, et al: Preliminary results of the use of indole 3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 1998;118:810-815. 22. Gray S, Hammond E, Hanson DF: Benign pathologic responses of the larynx. Ann Otol Rhinol Laryngol. 1995;104:13-18. 23. Koufman JA: The otolaryngologic manifestations of gastroesophageal reflux disease (GERD); a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope. 1991; 53:1:1-78. 24. Kamargiannis N, Gouveris H, Katsinelos P, et al. Chronic pharyngitis is associated with severe acidic laryngopharyngeal reflux in patients with Reinke’s edema. Ann Otol Rhinol Laryngol. 2011;120(11):722-726. 25. Tsikoudas A, Paleri V, El-Badawey MR, et al. Recommendations on follow-up strategies for idiopathic vocal fold paralysis: evidence-based review. J Laryngol Otol. 2012;126(6):570-573. 26. Modi VK. Vocal fold injection medialization laryngoplasty. Adv Otorhinolaryngol. 2012;73:90-94. 27. Hochman M, Vural E, Suen J, et al: Contemporary management of vascular lesions of the head and neck. Curr Opin Otolaryngol Head Neck Surg. 1999;7:161. 28. Scherer K, Waner M. Nd:Yag lasers (1064nm) in the treatment of venous malformations of the face and neck:challenges and benefits. Lasers Med Sci. 2007;22(2):119-26. 29. Richter GT, Suen JY. Pediatric extracranial arteriovenous malformations. Curr Opin Otolaryngol Head Neck Surg. 2011;19(6):455-461. 30. Giguere CM, Bauman NM, Smith RJH: New treatment options for lymphangioma in infants and children. Ann Otol Rhinol Laryngol. 2002;111:1066-1075. 604 UNIT II PART SPECIFIC CONSIDERATIONS 54. Beckhardt RN, Weber RS, Zane R, et al: Minor salivary gland tumors of the palate: clinical and pathologic correlates of outcome. Laryngoscope. 1995;11:1155-1160. 55. Fakhy C, Westra WH, Cmelak A, et al. Improved survival of patients with human papillomavirus-postive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261-269. 56. Lee, HJ, Zelefsky MJ, Kraus DH, et al: Long-term regional control after radiation therapy and neck dissection for base of tongue carcinoma. Int J Rad Oncology Biol Phys. 1997;38: 995-1000. 57. Peters LJ, Weber RS, Morrison WH, et al: Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy. Head Neck. 1996;18:552-559. 58. Ang KK, Peters LJ, Weber RS, et al: Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys. 1990;19:1339-1345. 59. Dean NR, Rosenthal EL, Carroll WR, et al. Robot-assisted surgery for primary and recurrent oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136(4):380-384. 60. Weinstein GS, O’Malley BW, Snyder W, et al. Transoral robotic surgery: radical tonsillectomy. Arch Otolaryngol Head Neck Surg. 2007;133(12):1220-1226. 61. Weber RS, Ohlms L, Bowman J, et al: Functional results after total or near total glossectomy with laryngeal preservation. Arch Otolaryngol Head Neck Surg. 1991;117:512-515. 62. Frank J, Garb J, Kay S, et al: Postoperative radiotherapy improves survival in squamous cell carcinoma of the hypopharynx. Am J Surg. 1994;168:476-480. 63. Lefebve JL, Chevalier D, Luboinski B, et al: Larynx preservation in piriform sinus cancer: preliminary results of a European organization for research and treatment of cancer phase III trial. J Natl Cancer Inst. 1996;88:890-899. 64. Hartig G, Truelson J, Weinstein GS. Supraglottic cancer. Head Neck. 2000;22:426-434. 65. Laccourreye H, Laccourreye O, Weinstein GS, et al: Supracricoid laryngectomy with cricohyoidoepiglottopexy: a partial laryngeal procedure for selected glottic carcinoma. Ann Otol Rhinol Laryngol. 1990;99:421-426. 66. Wolf GT, Hong WK, Fischer SG, et al: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991;324:1685-1690. 67. Medina JE, Khafif A: Early oral feeding following total laryngectomy. Laryngoscope. 2001;111:368-372. 68. Weber RS, Marvel J, Smith P, et al: Paratracheal lymph node dissection for carcinoma of the larynx, hypopharynx, and cervical esophagus. Otolaryngol Head Neck Surg. 1993;108:11-17. 69. Weber RS, Berket BA, Forastiere A, et al: Outcome of salvage total laryngectomy following organ preservation therapy: the Radiation Therapy Oncology Group trial 91-11. Arch Otolaryngol Head Neck Surg. 2003;129:44-49. 70. Lund VJ, Chisholm EJ, Takes RP, et al. Evidence for treatment strategies in sinonasal adenocarcinoma. Head Neck. 2012; 34(8):1168-1178. 71. Reiersen DA, Pahilan ME, Devaiah AK. Meta-analysis of treatment outcomes for sinonasal undifferentiated carcinoma. Otolaryngol Head Neck Surg. 2012;147(1):7-14. 72. Eggesbø HB. Imaging of sinonasal tumours. Cancer Imaging. 2012;12:136-152. 73. Robbins KT, Ferlito A, Silver CE, et al. Contemporary management of sinonasal cancer. Head Neck. 2011;33(9):1352-1365. 74. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy vs. radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup 0099. J Clin Oncol. 1998;16:1310-1317. 75. Kuhel W, Hume CR, Selesnick SH: Cancer of the external auditory canal and temporal bone. Otolaryngol Clin North Am. 1996;29:827-852. 76. Morris LG, Mehra S, Shah JP, et al. Predictors of survival and recurrence after temporal bone resection for cancer. Head Neck. 2012; 34(9):1231-1239. 77. Wang Y, Ow TJ, Myers JN. Pathways for cervical metastasis in malignant neoplasms of the head and neck region. Clin Anat. 2012;25(1):54-71. 78. Bocca E, Pignataro O, Oldino C: Functional neck dissection: an evaluation and review of 843 cases. Laryngoscope. 1984;94:942-945. 79. Medina JE, Byers RM: Supraomohyoid neck dissection: rationale, indications and surgical technique. Head Neck. 1989;11:111-122. 80. Eicher SA, Weber RS: Surgical management of cervical lymph node metastases. Curr Opin Oncol. 1996;8:215-220. 81. Robbins KT, Atkinson JLD, Byers RM, et al: The use and misuse of neck dissection for head and neck cancer. J Am Coll Surg. 2001;193:91-102. 82. Byers RM, Weber RS, Andrews T, et al: Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997;19:14-19. 83. Strojan P, Ferlito A, Langendijk JA, et al. Indications for radiotherapy after neck dissection. Head Neck. 2012; 34(1):113-119. 84. Eisele DE, Netterville J, Hoffman H, et al: Parapharyngeal space masses. Head Neck. 1999;21:154-159. 85. Gidley PW, Thompson CR, Roberts DB, et al.The results of temporal bone surgery for advanced or recurrent tumors of the parotid gland. Laryngoscope. 2011;121(8):1702-1707. 86. Weber RS, Byers RM, Petit B, et al: Submandibular gland tumors: Adverse histologic factors and therapeutic implications. Arch Otolaryngol Head Neck Surg. 1990;116:1055-1060. 87. Blackwell KE, Buchbinder D, Biller HF: Reconstruction of massive defects in the head and neck: the role of simultaneous distant and regional flaps. Head Neck. 1997;19:620-628. 88. Agrawal A, Husein OF, Schuller DE. Esophageal reconstruction with larynx preservation using forearm-free flap. Laryngoscope. 2008;118(10):1750-1752. 89. Fujiwara T, Shih HS, Chen CC, et al. Interdigitation of the distal anastomosis between tubed fasciocutaneous flap and cervical esophagus for stricture prevention. Laryngoscope. 2011;121(2):289-293. 90. Urken ML, Buchbinder D, Costantino PD, et al: Oromandibular reconstruction using microvascular composite flaps: report of 210 cases. Arch Otolaryngol Head Neck Surg. 1998;124:46-56. 91. The American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons: Clinical Practice Guidelines for the Diagnosis and Management of Cancer of the Head and Neck. 1996. Also see http://www.headandneckcancer.org/ clinicalresources/docs/oralcavity.php. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 19 chapter Trachea 605 Anatomy / 605 Tracheal Injury / 605 Tracheal Fistulas / 608 Tracheal Neoplasms / 609 Lung 611 Anatomy / 611 Normal Lung Histology / 612 Preinvasive Lesions / 613 Invasive or Malignant Lesions / 614 Lung Cancer Epidemiology / 617 Screening for Lung Cancer in High-Risk Populations / 619 Solitary Pulmonary Nodule / 621 Metastatic Lesions to the Lung / 622 Primary Lung Cancer-Associated Signs and Symptoms / 623 Lung Cancer Management / 627 Lung Cancer Treatment / 637 Chest Wall, Lung, Mediastinum, and Pleura Katie S. Nason, Michael A. Maddaus, and James D. Luketich Options for Thoracic Surgical Approaches / 645 Postoperative Care / 647 Postoperative Complications / 649 Spontaneous Pneumothorax / 649 Pulmonary Infections / 650 Massive Hemoptysis / 661 End-Stage Lung Disease / 663 Chest Wall Pleura and Pleural Space 664 Chest Wall Mass / 664 Benign Chest Wall Neoplasms / 666 Primary Malignant Chest Wall Tumors / 666 Other Tumors of the Chest Wall / 669 Chest Wall Reconstruction / 669 Mediastinum 670 Anatomy and Pathologic Entities / 670 History and Physical Examination / 671 Imaging and Serum Markers / 671 TRACHEA Anatomy Diagnostic Nonsurgical Biopsies of the Mediastinum / 672 Surgical Biopsies and Resection of Mediastinal Masses / 673 Mediastinal Neoplasms / 674 Mediastinal Cysts / 679 Mediastinitis / 679 The trachea is composed of cartilaginous and membranous portions, beginning with the cricoid cartilage, the first complete cartilaginous ring of the airway. The cricoid cartilage consists of an anterior arch and a posterior broad-based plate. Articulating with the posterior cricoid plate are the arytenoid cartilages. The vocal cords originate from the arytenoid cartilages and then attach to the thyroid cartilage. The subglottic space, the narrowest part of the trachea with an internal diameter of approximately 2 cm, begins at the inferior surface of the vocal cords and extends to the first tracheal ring. The remainder of the distal trachea is 10.0 to 13.0 cm long, consists of 18 to 22 rings, and has an internal diameter of 2.3 cm (Fig. 19-1).1 Bronchoscopically, the tracheal rings are visible as C-shaped hyaline cartilaginous structures that provide rigidity to the anterior and lateral tracheal walls. The open ends of the C-rings are connected by the trachealis smooth muscle and encased in a dense band of connective tissue called perichondrium. The first tracheal ring is attached directly to the cricoid cartilage; there are approximately two rings for every 1 cm of tracheal length. The tracheal blood supply, which includes the inferior thyroid, subclavian, supreme intercostal, internal thoracic, 680 Anatomy / 680 Pleural Effusion / 680 Access and Drainage of Pleural Fluid Collections / 680 Malignant Pleural Effusion / 682 Empyema / 682 Chylothorax / 685 Tumors of the Pleura / 687 Acknowledgement 690 innominate, and superior and middle bronchial arteries, enters the airway near the junction of the membranous and cartilaginous portions (Fig. 19-2). Each arterial branch supplies a segment of 1.0 to 2.0 cm, thereby limiting circumferential mobilization to that same distance. The vessels are interconnected along the lateral surface of the trachea by an important longitudinal vascular anastomosis that feeds transverse segmental vessels to the soft tissues between the cartilages. Tracheal Injury Tracheal injury can result from a variety of causes, including inhalation of smoke or toxic fumes, aspiration of liquids or solid objects, endotracheal intubation, blunt and penetrating trauma, and iatrogenic injury during operative procedures. Early diagnosis is critical to avoid subsequent complications, including respiratory infection and tracheal stenosis. Management of smoke or toxic fume inhalation and liquid aspiration is commonly supportive; use of antibiotics, respiratory support, and airway clearance with flexible bronchoscopy is dictated by the patient’s condition. In rare circumstances, extracorporeal membrane oxygenation is required if there is associated injury to the more distal airways and lung parenchyma. Despite ubiquitous use of high-volume–low-pressure cuffs, overinflation of the endotracheal cuff is the most common VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 5 6 Historically, non-small cell cancer (NSCLC) subtypes were considered to be a uniform group based on limited understanding of the distinct clinical behaviors of the subtypes as well as the fact that there were few treatment options available. With increasing understanding of the molecular biology underlying these tumor subtypes, however, the approach to diagnosis and management and the terminology used in describing these tumors are evolving rapidly. In particular, the evaluation and management of adenocarcinoma of the lung has shifted dramatically and firm establishment of NSCLC cell type prior to chemotherapy for advanced stage lung cancer is essential. A multidisciplinary approach to evaluation of NSCLC, with standardized criteria and terminology for diagnosis in cytologic and small biopsy specimens, and routine molecular testing for known mutations, such as EGFR mutations and EML4-ALK fusion oncogenes is now recommended for the evaluation and management of lung nodules due to major advances in targeted therapy. Adequate tissue acquisition at the time of diagnostic workup is critical and facilitates patient care while minimizing the number of procedures to which the patient is subjected. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma have been eliminated from the classification of lung adenocarcinoma as a result of increased understanding of important clinical, radiologic, pathologic, and genetic differences between mucinous and nonmucinous adenocarcinomas, The new classification system delineated a stepwise pathologic progression, from AAH to invasive adenocarcinoma based on the predominant histologic growth patterns. Lung cancer continues to be a highly lethal and extremely common cancer, with 5-year survival of 16%. Lung cancer incidence is second only to the incidence of prostate cancer in men and breast cancer in women. Squamous cell carcinoma and adenocarcinoma of the lung are the most common subtypes and are rarely found in the absence of a smoking history. Nonsmokers who live with smokers have a 24% increased risk of lung cancer compared to nonsmokers who do not live with smokers. Navigational bronchoscopy is a valuable new tool that can be used to obtain tissue diagnosis for intraparenchymal lesions or small, peripherally located lesions that have historically been difficult to biopsy with transbronchial or transthoracic approaches. It is also a useful tool for tattooing the lung lesion for subsequent operative resection and for placement of fiducial markers for stereotactic body radiation. This technique should become part of the surgeon’s armamentarium for the diagnosis and treatment of lung cancer. Impaired exchange of carbon monoxide is associated with a significant increase in the risk of postoperative pulmonary complications, independent of the patient’s smoking history. In patients undergoing pulmonary resection, the risk of any pulmonary complication increases by 42% for every 10% 7 8 9 10 11 12 decline in the percent carbon monoxide diffusion capacity (%Dlco), and this measure may be a useful parameter in risk stratification of patients for surgery. . Maximum oxygen consumption (Vo2 max) values provide important additional information in those patients with severely impaired Dlco and forced expiratory volume in 1 second. Values of <10 mL/kg per minute generally prohibit any major pulmonary resection, because the mortality in patients with these levels is 26% compared with only 8.3% in patients whose is ≥10 mL/kg per minute; values of >15 mL/kg per minute generally indicate the patient’s ability to tolerate pneumonectomy. The assessment of patient risk before thoracic resection is based on clinical judgment and data. Tumor ablative strategies are viable alternatives to surgical resection for early stage lung cancer in inoperable patients. While premature, ablative techniques may ultimately be shown to have efficacy equivalent to lobectomy for the primary treatment of very small peripheral early-stage lung cancers and become primary therapy, even in operable patients. Multidisciplinary collaboration between thoracic surgery, interventional radiology/pulmonology, and radiation oncology is required to ensure that development of these ablative techniques occurs through properly designed and well-controlled prospective studies and will ensure that patients receive the best available therapy, regardless of whether it is surgical resection or ablative therapy. Increasing evidence suggests a significant role for gastroesophageal reflux disease in the pathogenesis of chronic lung diseases such as bronchiectasis and idiopathic pulmonary fibrosis, and it may also contribute to bronchiolitis obliterans syndrome in lung transplant patients. Treatment of pulmonary aspergilloma is individualized. Asymptomatic patients can be observed without any additional therapy. Similarly, mild hemoptysis, which is not life-threatening, can be managed with medical therapy, including antifungals and cough suppressant. Amphotericin B is the drug of choice, although voriconazole has recently been used for treatment of aspergillosis, with fewer side effects and equivalent efficacy. Massive hemoptysis had traditionally been an indication for urgent or emergent operative intervention. However, with the advancement of endovascular techniques, bronchial artery embolization in select centers with experience in these techniques has been effective.  In patients with malignant pleural effusion, poor expansion of the lung (because of entrapment by tumor or adhesions) generally predicts a poor result with pleurodesis and is the primary indication for placement of indwelling pleural catheters. These catheters have dramatically changed the management of end-stage cancer treatment because they substantially shorten the amount of time patients spend in the hospital during their final weeks of life. 606 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 607 Epiglottis Internal laryngeal n. Transverse, oblique arytenoid mm. Lateral cricoarytenoid m. Thyroepiglottic m. Posterior cricoarytenoid m. Thyroarytenoid m. Thyroid cartilage facet Recurrent laryngeal n. Cricothyroid m. (cut) cause of injury secondary to endotracheal intubation. High cuff pressures can cause ischemia of the contiguous airway wall in as short as 4 hours. Prolonged overinflation can lead to scarring and stenosis; full-thickness injury can result in fistulae between the innominate artery anteriorly and the esophagus posteriorly. Avoidance requires careful cuff management to keep pressures Inferior thyroid a. Branch from internal thoracic a. Superior bronchial a. 3 2 1 Lateral longitudinal anastomosis Middle bronchial a. Figure 19-2. Arterial blood supply to the larynx and upper trachea. a. = artery. Figure 19-1. Anatomy of the larynx and upper trachea. m. = muscle; n. = nerve. as low as possible; in circumstances of prolonged ventilatory support and high airway pressure, cuff pressure monitoring (to maintain pressures <20 mmHg) is advisable. Historically, clinically significant tracheal stenosis after tracheostomy occurred in 3% to 12% of cases, with severe stenosis in 1% to 2%.2 With the use of low-pressure cuffs, the estimated incidence has decreased to 4.9 cases per million patients per year.3 Intubation-related risk factors include: prolonged intubation; high tracheostomy through the first tracheal ring or cricothyroid membrane; transverse rather than vertical incision on the trachea; oversized tracheostomy tube; prior tracheostomy or intubation; and traumatic intubation. Stenosis is also more common in older patients, in females, after radiation, or after excessive corticosteroid therapy, and in the setting of concomitant diseases such as autoimmune disorders, severe reflux disease, or obstructive sleep apnea and the setting of severe respiratory failure. However, even a properly placed tracheostomy can lead to tracheal stenosis because of scarring and local injury. Mild ulceration and stenosis are frequently seen after tracheostomy removal. Use of the smallest tracheostomy tube possible, rapid downsizing, and a vertical tracheal incision minimize the risk for posttracheostomy stenosis. Stridor and dyspnea on exertion are the primary symptoms of tracheal stenosis. In the setting of postintubation injury, a significant portion of the cartilaginous structural support to the airway is destroyed by regional ischemic necrosis; during healing, a web-like fibrous growth develops and narrows the airway (Fig. 19-3). In contrast, stenosis caused by tracheostomy is most commonly due to an excess of granulation tissue formation around the tracheal stoma site. Time to onset of symptoms after extubation or tracheostomy decannulation usually ranges from 2 to 12 weeks, but symptoms can appear immediately or as long VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Aryepiglottic m. 608 UNIT II PART SPECIFIC CONSIDERATIONS Figure 19-3. Diagram of the principal postintubation lesions. A. A circumferential lesion at the cuff site after the use of an endotracheal tube. B. Potential lesions after the use of tracheostomy tubes. Anterolateral stenosis can be seen at the stomal level. Circumferential stenosis can be seen at the cuff level (lower than with an endotracheal tube). The segment in between is often inflamed and malacotic. C. Damage to the subglottic larynx. D. Tracheoesophageal fistula occurring at the level of the tracheostomy cuff; circumferential damage is usual at this level. E. Tracheoinnominate artery fistula. (Adapted with permission from Grillo H. Surgical treatment of postintubation tracheal injuries. J Thorac Cardiovasc Surg. 1979;78:860. Copyright Elsevier) as 1 to 2 years later. Frequently, patients are misdiagnosed as having asthma or bronchitis, and treatment for such illnesses can persist for some time before the correct diagnosis is discovered. Generally, symptom intensity is related to the degree of stenosis and to the patient’s underlying pulmonary disease. Acute Management. A comprehensive bronchoscopic evaluation is critical in the initial phase of evaluation. Stenosis length, location, distance between the vocal cords and proximal stenosis, and distance from the distal aspect to the major carina must be documented. In patients with severe stenosis and respiratory compromise, rigid bronchoscopy can be used to dilate the stenosis; this provides immediate relief of the airway obstruction and facilitates thorough evaluation of the stenosis. Rarely, if ever, is tracheostomy necessary. Most intubation injuries are located in the upper third of the trachea and can be accessed for resection through a collar incision. Resection typically involves 2 to 4 cm of trachea for benign stenosis. It is critical to fully resect all inflamed and scarred tissue. However, a primary anastomosis can still be performed without undue tension, even if up to one half of the trachea requires resection.2 Ideally, the patient is extubated in the operating room or shortly thereafter. For patients in whom tracheal resection is not possible, such as patients with significant comorbidities or with an excessively long stenosis, endotracheal stenting, typically silicone T-tubes, can provide palliation. Wire mesh stents should not be used, given their known propensity to erode through the wall of the airway. Balloon dilation, laser ablation, and tracheoplasty have also been described, although the efficacy is marginal. Tracheal replacement is evolving as an option for management of tracheal stenosis as bioengineering techniques for decellularizing donor trachea have been developed. This removes all antigens against which the recipient immune system might react and enables use of the donor trachea scaffolding without risk of rejection. Following decellularization, the donor tracheal scaffolding is seeded with recipient chondrocytes, to restore tracheal rigidity, and with recipient epithelial cells, to recreate the inner epithelial lining. Several case reports of successful allogeneic tracheal transplantation have been published, but the technique continues to be limited to a few highly specialized centers. This is due, in part, to the scarcity of donor trachea and the need for tissue bioengineering expertise. Current efforts are focused on creation of biosynthetic scaffolding that can be used instead of donor trachea. This would substantially increase the availability of the tracheal replacement material and enable widespread use of the technique. Tracheal Fistulas Tracheoinnominate Artery Fistula. Tracheoinnominate artery fistula has two main causes: low placement of a tracheostomy and hyperinflation of the tracheal cuff. Tracheostomy placement should be through the second to fourth tracheal rings without reference to the location of the sternal notch. When placed below the fourth tracheal ring, the inner curve of the tracheostomy cannula will be positioned to exert pressure on the posterior aspect of the innominate artery, leading to arterial erosion. Similarly, the tracheal cuff, when hyperinflated, will cause ischemic injury to the anterior airway and subsequent erosion into the artery. Most cuff-induced fistulas will develop within 2 weeks after placement of the tracheostomy. Clinically, tracheoinnominate artery fistulas present with bleeding. A premonitory hemorrhage often occurs and, although it is usually not massive, must not be ignored or simply attributed to general airway irritation or wound bleeding. With significant VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 609 1 Cuff hyperinflation Orotracheal tube ready in place if needed Forward pressure applied with bronchoscope 3 Bronchoscopic compression Figure 19-4. Steps in the emergency management of a tracheoinnominate artery fistula. bleeding, the tracheostomy cuff can be hyperinflated to temporarily occlude the arterial injury. If such an effort is unsuccessful, the tracheostomy incision should be immediately opened widely and a finger inserted to compress the artery against the manubrium (Fig. 19-4). The patient can then be orally intubated, and the airway suctioned free of blood. Emergent surgical resection of the involved segment of artery is performed, usually without reconstruction. Tracheoesophageal Fistula. Tracheoesophageal fistulas (TEFs) occur primarily in patients receiving prolonged mechanical ventilatory support concomitant with an indwelling nasogastric tube.4 Cuff compression of the membranous trachea against the nasogastric tube leads to airway and esophageal injury and fistula development. Clinically, airway suctioning reveals saliva, gastric contents, or tube feedings. Gastric insufflation, secondary to positive pressure ventilation, can occur. Bronchoscopy is diagnostic; with the bronchoscope inserted, the endotracheal tube is withdrawn and the fistula at the cuff site is exposed. Alternatively, esophagoscopy demonstrates the cuff of the endotracheal tube in the esophagus. Treatment, first and foremost, requires removing tubes from the esophagus and weaning the patient from the ventilator. The cuff of the endotracheal tube should be placed below the fistula, avoiding overinflation. To minimize aspiration, a gastrostomy tube should be placed for gastric decompression (to prevent reflux) and a jejunostomy tube for feeding. If aspiration persists, esophageal diversion with cervical esophagostomy can be performed. Once weaned from the ventilator, tracheal resection and primary anastomosis, repair of the esophageal defect, and interposition of a muscle flap between the trachea and esophagus can be performed (Fig. 19-5).5 Tracheal Neoplasms Although extremely rare, the most common primary tracheal neoplasms are squamous cell carcinomas (related to smoking) and adenoid cystic carcinomas. Clinically, tracheal tumors present with cough, dyspnea, hemoptysis, stridor, or symptoms of invasion of contiguous structures (such as the recurrent laryngeal nerve or the esophagus). The most common radiologic finding of tracheal malignancy is tracheal stenosis, but is found in only 50% of cases. With tumors other than squamous cell carcinomas, symptoms may persist for months because of slow tumor growth rates. Stage of presentation is advanced, with approximately 50% of patients presenting with stage IV disease. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Orotracheal tube replacing tracheostomy tube 2 Digital control 610 UNIT II PART Sternohyoid m. Esophagus SPECIFIC CONSIDERATIONS A C Cricoid Figure 19-5. Single-stage operation for closure of a tracheoesophageal fistula and tracheal resection. A. The fistula is divided and the trachea is transected below the level of damage. B. The fistula is closed on the tracheal side in a single layer and the esophageal side in a double layer. The damaged trachea segment is resected. C. View of completed tracheal anastomosis. m. = muscle. B D Five-year survival for all tracheal neoplasms is 40% but falls to 15% for those with stage IV disease.6 Squamous cell carcinomas often present with regional lymph node metastases and are frequently unresectable at presentation. Their biologic behavior is similar to that of squamous cell carcinoma of the lung. Adenoid cystic carcinomas, a type of salivary gland tumor, are generally slow-growing, spread submucosally, and tend to infiltrate along nerve sheaths and within the tracheal wall. Although indolent in nature, adenoid cystic carcinomas are malignant and can spread to regional lymph nodes, lung, and bone. Squamous cell carcinoma and adenoid cystic carcinomas represent approximately 65% of all tracheal neoplasms. The remaining 35% is comprised of small cell carcinomas, mucoepidermoid carcinomas, adenocarcinomas, lymphomas, and others.7 Therapy. Evaluation and treatment of patients with tracheal tumors should include neck and chest computed tomography (CT) and rigid bronchoscopy. Rigid bronchoscopy permits general assessment of the airway and tumor; it also allows debridement or laser ablation of the tumor to provide relief of dyspnea. If the tumor is judged to be completely resectable, primary resection and anastomosis is the treatment of choice for these tumors (Fig. 19-6). Up to 50% of the length of the trachea can be resected with primary anastomosis. In most tracheal resections, anterolateral tracheal mobilization and suturing of the chin to the sternum for 7 days are done routinely. Use of laryngeal and hilar release is determined at the time of surgery, based on the surgeon’s judgment of the degree of tension present. For longer resections, specialized maneuvers are necessary such as laryngeal release and right hilar release to minimize tension on the anastomosis. Postoperative mortality, which occurs in up to 10% of patients, is associated with the length of tracheal resection, use of laryngeal release, the type of resection, and the histologic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 611 High-index of suspicion (cough, dyspnea, hemoptysis, stridor and hoarseness) Flexible/rigid bronchoscopy Debridement and/or laser ablation Tumor unresectable Tumor resectable Performance status adequate for surgery Poor performance status 1) Probable grossly positive tracheal resection margin 2) Metastatic disease 3) Length of resection precludes safe reconstruction 4) Invasion of unresectable adjacent organs Principles of tracheal resection • • • • May resect up to 50% of tracheal length Anterolateral mobilization only Suture head in forward flexion for 7 days Laryngeal and hilar release as needed for relief of tension Radiotherapy 50 Gy (±chemotherapy) (primary treatment or postoperatively) type of the cancer. Factors associated with improved long-term survival include complete resection and use of radiation as adjuvant therapy in the setting of incomplete resection.8 Due to their radiosensitivity, radiotherapy is frequently given postoperatively after resection of both adenoid cystic carcinomas and squamous cell carcinomas.9 A dose of 50 Gy or greater is usual. Nodal positivity does not seem to be associated with worse survival. Survival at 5 and 10 years is much better for adenoid cystic (73% and 57%, respectively) than for tracheal cancers (47% and 36%, respectively; P < .05). For patients with unresectable tumors, radiation may be given as the primary therapy to improve local control, but is rarely curative. For recurrent airway compromise, stenting or laser therapies should be considered part of the treatment algorithm. LUNG Anatomy Segmental Anatomy. The segmental bronchial and vascular anatomy of the lungs allows subsegmental and segmental resections, if the clinical situation requires it or if lung tissue can be preserved10 (Fig. 19-7). Note the continuity of the pulmonary parenchyma between adjacent segments of each lobe. Lymphatic Drainage. Lymph nodes that drain the lungs are divided into two groups according to the tumor-node-metastasis (TNM) staging system for lung cancer: the pulmonary lymph nodes (N1) and the mediastinal nodes (N2) (Fig. 19-8). The N1 lymph nodes constitute the following: (a) intrapulmonary or segmental nodes that lie at points of division Figure 19-6. Algorithm for evaluation and treatment of tracheal neoplasm. PET = positron emission tomography. of segmental bronchi or in the bifurcations of the pulmonary artery; (b) lobar nodes that lie along the upper, middle, and lower lobe bronchi; (c) interlobar nodes located in the angles formed by the main bronchi bifurcating into the lobar bronchi; and (d) hilar nodes along the main bronchi. The interlobar lymph nodes lie in the depths of the interlobar fissure on each side and constitute a lymphatic sump for each lung, referred to as the lymphatic sump of Borrie; all of the pulmonary lobes of the corresponding lung drain into this group of nodes (Fig. 19-9). On the right, the nodes of the lymphatic sump lie around the bronchus intermedius (bounded above by the right upper lobe bronchus and below by the middle lobe and superior segmental bronchi). On the left, the lymphatic sump is confined to the interlobar fissure, with the lymph nodes in the angle between the lingular and lower lobe bronchi and in apposition to the pulmonary artery branches. The N2 lymph nodes consist of four main groups. (a) The anterior mediastinal nodes are located in association with the upper surface of the pericardium, the phrenic nerves, the ligamentum arteriosum, and the left innominate vein. (b) The posterior mediastinal group includes paraesophageal lymph nodes within the inferior pulmonary ligament and, more superiorly, between the esophagus and trachea near the arch of the azygos vein. (c) The tracheobronchial lymph nodes are made up of three subgroups that are located near the bifurcation of the trachea. These include the subcarinal nodes, which lie in the obtuse angle between the trachea and each main stem bronchus, and the nodes that lay anterior to the lower end of the trachea. (d) Paratracheal lymph nodes are located in proximity to the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Complete staging: computed tomography/PET scan/mediastinoscopy 612 trachea in the superior mediastinum. Those on the right side form a chain with the tracheobronchial nodes inferiorly and with some of the deep cervical nodes above (scalene lymph nodes). Lymphatic drainage to the mediastinal lymph nodes from the right lung is ipsilateral, except for occasional bilateral drainage to the superior mediastinum. In contrast, in the left lung, particularly the left lower lobe, lymphatic drainage occurs with equal frequency to ipsilateral and contralateral superior mediastinal nodes. Right lung and bronchi 1 2 2 3 6 10 1 1 6 6 5 5 74 8 9 3 3 4 2 9 10 7 5 8 10 7 8 Normal Lung Histology 9 UNIT II PART The lung can be conveniently viewed as two linked components: the tracheobronchial tree (or conducting airways component) and the alveolar spaces (or gas exchange component). The tracheobronchial tree consists of approximately 23 airway divisions to the level of the alveoli. It includes the main bronchi, lobar bronchi, segmental bronchi (to designated bronchopulmonary segments), and terminal bronchioles (i.e., the smallest airways still lined by bronchial epithelium and without alveoli). The tracheobronchial tree is normally lined by pseudostratified ciliated columnar cells and mucous (or goblet) cells, which both derive from basal cells (Fig. 19-10). Ciliated cells predominate. Goblet cells, which release mucus, can significantly increase in number in acute bronchial injury, such as exposure to cigarette smoke. The normal bronchial epithelium also contains bronchial submucosal glands, which are mixed salivary-type glands containing mucous cells, serous cells, and neuroendocrine cells called Kulchitsky cells, which are also found within the surface epithelium. The bronchial submucosal glands can give rise to salivary gland–type tumors, including mucoepidermoid carcinomas and adenoid cystic carcinomas. Two cell types, called type I and type II pneumocytes, make up the alveolar epithelium. Type I pneumocytes comprise 40% of the total number of alveolar epithelial cells, but cover 95% of the surface area of the alveolar wall. These cells are not Segments 6. Superior 7. Medial Basal * 8. Anterior Basal 9. Lateral Basal 10. Posterior Basal SPECIFIC CONSIDERATIONS 1. Apical 2. Posterior 3. Anterior 4. Lateral 5. Medial * Medial basal (7) not present in left lung Left lung and bronchi 1 1+2 3 3 3 4 4 8 9 6 6 6 5 1+2 2 10 4 10 5 8 9 10 5 8 10 8 9 Figure 19-7. Segmental anatomy of the lungs and bronchi. 3p 1 2R 2L Brachiocephalic artery 3a Ao 4R Azygos vein 4L Ao 10R 5 PA 7 11R 12,13,14R 6 8R 9R 10L 8L 9L PA 11L 12,13,14L Figure 19-8. The location of regional lymph node stations for lung cancer. (Reproduced with permission from Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest. 1997;111:1718.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ capable of regeneration because they have no mitotic potential. Type II pneumocytes cover only 3% of the alveolar surface, but comprise 60% of the alveolar epithelial cells. In addition, clusters of neuroendocrine cells are seen in the alveolar spaces. 613 Preinvasive Lesions 1. Figure 19-9. The lymphatic sump of Borrie includes the groups of lymph nodes that receive lymphatic drainage from all pulmonary lobes of the corresponding lung. Squamous dysplasia and carcinoma in situ. Cigarette smoke can induce a transformation of the tracheobronchial pseudostratified epithelium to metaplastic squamous mucosa, with subsequent evolution to dysplasia as cellular abnormalities accumulate. Dysplastic changes include A B Figure 19-10. Normal lung histology. A. Pseudostratified ciliated columnar cells and mucous cells normally line the tracheobronchial tree. B. A Kulchitsky cell is depicted (arrow). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura The term “precancerous” does not mean that an inevitable progression to invasive carcinoma will occur, but such lesions, particularly those with high-grade dysplasia,11,12 do constitute a clear marker for potential development of invasive cancer. Three precancerous lesions of the respiratory tract are currently recognized. 614 2. UNIT II PART 3. SPECIFIC CONSIDERATIONS altered cellular polarity and increased cell size, number of cell layers, nuclear-to-cytoplasmic ratio, and number of mitoses. Gradations are considered mild, moderate, or severe. Carcinoma in situ represents carcinoma still confined by the basement membrane. Atypical adenomatous hyperplasia (AAH). AAH is a lesion smaller than 5.0 mm, comprising epithelial cells lining the alveoli that are similar to type II pneumocytes. Histologically, AAH is similar to adenocarcinoma in situ; it represents the beginning stage of a stepwise evolution to adenocarcinoma in situ and then to adenocarcinoma. With the availability of thin-section CT, it is possible to detect preinvasive adenocarcinoma lesions as early as AAH. These lesions can be multiple, are typically small (5 mm or less), and have a ground-glass appearance. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. This rare lesion represents a diffuse proliferation of neuroendocrine cells, but without invasion of the basement membrane. It can exist as a diffuse increase in the number of single neuroendocrine cells, or as small lesions less than 5.0 mm in diameter. Lesions over 5.0 mm in size or that breach the basement membrane are carcinoid tumors. Invasive or Malignant Lesions The pathologic diagnosis of lung cancer is currently based on light microscopic criteria and is broadly divided into two main groups: non–small cell lung carcinoma and neuroendocrine tumors.13 Immunohistochemical staining and electron microscopy are used as adjuncts in diagnosis, particularly in the assessment of potential neuroendocrine tumors. Non–Small Cell Lung Carcinoma. The term non–small cell lung carcinoma (NSCLC) includes many tumor cell types, including large cell, squamous cell, and adenocarcinoma. Historically, these subtypes were considered to be a uniform group based on limited understanding of the distinct clinical behaviors of the subtypes as well as the fact that there were few treatment options available. With increasing understanding of the 1 molecular biology underlying these tumor subtypes, however, the approach to diagnosis and management and the terminology used in describing these tumors are evolving rapidly. Adenocarcinoma. The incidence of adenocarcinoma has increased over the last several decades, and it is now the most common lung cancer, accounting for 30% of lung cancers in male smokers and 40% of lung cancers in female smokers. Adenocarcinoma is the histologic subtype for 80% and 60% of lung cancers in nonsmoking females and males, respectively. It occurs more frequently in females than in males. It is the most frequent histologic subtype in women, patients who are under 45 years of age, and Asian populations.14 Histologic Subtyping of Adenocarcinoma. Increasing understanding of lung adenocarcinoma, such as important clinical, radiologic, pathologic, and genetic differences between 2 mucinous and nonmucinous adenocarcinomas, prompted multiple changes in the classification system in 2011.15 Based on consensus, the international working group proposed a multidisciplinary approach, with standardized criteria and terminology for diagnosis in cytologic and small biopsy specimens, and routine molecular testing for known mutations, such as EGFR and KRAS mutations (Table 19-1). The new classification system delineated a stepwise pathlogic progression, from AAH to invasive adenocarcinoma based on the predominant histo3 logic growth patterns; the terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma were eliminated in favor of more biologically driven classification (Table 19-2). Table 19-1 Difference between invasive mucinous adenocarcinoma and nonmucinous adenocarcinoma in situ/minimally invasive adenocarcinoma/lepidic predominant adenocarcinoma Invasive Mucinous Adenocarcinoma (Formerly Mucinous BAC) Nonmucinous AIS/MIA/LPA (Formerly Nonmucinous BAC) Female 49/84 (58%)52,120–123 101/140 (72%)52,120–123 Smoker 39/87 (45%) 75/164 (46%)52,120–122,124 Radiographic appearance Majority consolidation; air bronchogram125 52,120–122,124 Majority ground-glass attenuation23,56,58,103,129–134 Frequent multifocal and multilobar presentation56,125–128 Cell type Mucin-filled, columnar, and/or goblet50–52,125,135 Type II pneumocyte and/or Clara cell50–52,125,135 CK7 Mostly positive (~88%)a54,55,136–139 Positive (~98%)a54,55,136–139 CK20 Positive (~54%)a54,55,136–139 Negative (~5%)a54,55,136–139 TTF-1 Mostly negative (~17%)1 a54,55,120,137–139 Positive (~67%)a54,55,120,137–139 Phenotype Genotype KRAS mutation Frequent (~76%)a55,94,121,127,140–144 Some (~13%)a55,121,127,140–144 EGFR mutation Almost none (~3) Frequent (~45%)a55,121,127,140–142 a55,121,127,140–142 Source: Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244. a Numbers represent the percentage of cases that are reported to be positive. BAC, bronchioloalveolar carcinoma; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; LP A, lepidic predominant adenocarcinoma; EGFR, epidermal growth factor receptor; TTF, thyroid transcription factor. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 19-2 New classification system for lung adenocarcinoma Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ (≤3 cm formerly BAC)   Nonmucinous   Mucinous   Mixed mucinous/nonmucinous Invasive adenocarcinoma  Lepidic predominant (formerly nonmucinous BAC pattern, with >5 mm invasion) Acinar predominant Papillary predominant Micropapillary predominant Solid predominant with mucin production Variants of invasive adenocarcinoma  Invasive mucinous adenocarcinoma (formerly mucinous BAC) Colloid Fetal (low and high grade) Enteric Source: Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society: International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244. BAC = bronchioloalveolar carcinoma; IASLC = International Association for the Study of Lung Cancer; ATS = American Thoracic Society; ERS = European Respiratory Society. 1. 2. Adenocarcinoma in situ (AIS). AISs are small (≤3 cm) solitary adenocarcinomas that have pure lepidic growth; lepidic growth is characterized by tumor growth within the alveolar spaces. These lesions are not invasive into the stroma, vascular system, or pleura and do not have papillary or micropapillary patterns or intra-alveolar tumor cells. They are very rarely mucinous, consisting of type II pneumocytes or Clara cells. These patients are expected to have 100% disease-specific survival with complete surgical resection. On CT scan, AIS can appear as a pure groundglass neoplasm, but occasionally will present as part of a solid or part-solid nodule. Mucinous AIS is more likely to appear solid or to have the appearance of consolidation. As with AAH, the lesions can be single or multiple; the ground-glass changes in AIS, however, tend to have a higher attenuation compared to AAH. Minimally invasive adenocarcinoma (MIA). In the same size solitary lesion, if less than 5 mm of invasion are noted within a predominantly lepidic growth pattern, the lesion is termed minimally invasive adenocarcinoma (MIA) to indicate a patient group with near 100% survival when the lesion is completely resected. This differentiates patients with AIS, but recognizes the fact that the presence of invasion becomes prognostically significant when the size of the invasive component reaches 5 mm or greater in size.16 If multiple areas of microscopic invasion are found within VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 615 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Minimally invasive adenocarcinoma (≤3 cm lepidic predominant tumor with ≤5 mm invasion) Nonmucinous Mucinous Mixed mucinous/nonmucinous the lepidic growth, the size of the largest invasive area, measured in the largest dimension, is used; this area must be ≤5 mm to be considered MIA. As with AIS, MIA is very rarely mucinous. The invasive component histologically is acinar, papillary, micropapillary, and/or solid and shows tumor cells infiltrating into the surrounding myofibroblastic stroma. On CT scan, the appearance of MIA is often a part-solid nodule (≤5 mm) with a predominant groundglass component, but can be highly variable. 3. Lepidic predominant adenocarcinoma (LPA). If lymphovascular invasion, pleural invasion, tumor necrosis, or more than 5 mm of invasion are noted in a lesion that has lepidic growth as its predominant component, MIA is excluded and the lesion is called lepidic predominant adenocarcinoma (LPA), and the size of the invasive component is recorded for the T stage. 4. Invasive adenocarcinoma. The new classification system now recommends classifying invasive adenocarcinoma by the most predominant subtype after histologic evaluation of the resection specimen. To determine the predominant subtype, histologic sections are evaluated and the patterns are determined, in 5% increments, throughout the specimen. This semiquantitative method encourages the viewer to identify and quantify all patterns present, rather than focusing on a single pattern. In the pathology report, the tumor is classified by the predominant pattern, with percentages of the subtypes also reported (Fig. 19-11).Subtypes include: a. Lepidic predominant b. Acinar predominant c. Papillary predominant d. Micropapillary predominant e. Solid predominant    Adenocarcinoma is often peripherally located and frequently discovered incidentally on routine chest radiographs, unlike squamous cell cancers. When symptoms occur, they are due to pleural or chest wall invasion (pleuritic or chest wall pain) or pleural seeding with malignant pleural effusion. Invasive adenocarcinoma is usually solid by CT scan, but can also be part-solid and even a groundglass nodule. Occasionally, a lobar ground-glass opacification may be present, which is often associated with significant respiratory compromise and can be mistaken for lobar pneumonia. Bubble-like or cystic lucencies on CT scan in small (≤2 cm) adenocarcinomas or extensive associated ground-glass components correlate with slow growth and well-differentiated tumors and a more favorable prognosis. Intratumoral air bronchograms are usually indicative of well-differentiated tumor, whereas spiculations that are coarse and thick (≥2 mm) portend vascular invasion and nodal metastasis and are associated with decreased survival following complete surgical resection. Pleural retraction is also a poor prognostic indicator. 5. Additional histologic variants include colloid adenocarcinoma (formerly mucinous cystadenocarcinoma), fetal adenocarcinoma, and enteric adenocarcinoma. Clear cell and signet ring cell types are no longer considered to be distinct subtypes as they are found in association with most of the five dominant histologic patterns (lepidic, acinar, papillary, micropapillary, and solid). However, they are still notable, as they can signal clinically relevant molecular changes, such as the presence of the EML4-ALK fusion gene in solid tumors with signet ring features. 616 UNIT II PART SPECIFIC CONSIDERATIONS Figure 19-11. Major histologic patterns of invasive adenocarcinoma. A. Lepidic predominant pattern with mostly lepidic growth (right) and a smaller area of invasive acinar adenocarcinoma (left). B. Lepidic pattern consists of a proliferation type II pneumocytes and Clara cells along the surface alveolar walls. C. Area of invasive acinar adenocarcinoma (same tumor as in A and B). D. Acinar adenocarcinoma consists of round to oval-shaped malignant glands invading a fibrous stroma. E. Papillary adenocarcinoma consists of malignant cuboidal to columnar tumor cells growing on the surface of fibrovascular cores. F. Micropapillary adenocarcinoma consists of small papillary clusters of glandular cells growing within this airspace, most of which do not show fibrovascular cores. G. Solid adenocarcinoma with mucin consisting of sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli. No acinar, papillary, or lepidic patterns are seen, but multiple cells have intracytoplasmic basophilic globules that suggest intracytoplasmic mucin. H. Solid adenocarcinoma with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this diastase-periodic acid Schiff stain. (Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/ European Respiratory Society: International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244.) Squamous Cell Carcinoma. Representing 30% to 40% of lung cancers, squamous cell carcinoma is the most frequent cancer in men and highly correlated with cigarette smoking. They arise primarily in the main, lobar, or first segmental bronchi, which are collectively referred to as the central airways. Symptoms of airway irritation or obstruction are common, and include cough, hemoptysis, wheezing (due to high-grade airway obstruction), dyspnea (due to bronchial obstruction with or without postobstructive atelectasis), and pneumonia (caused by airway obstruction with secretion retention and atelectasis). Occasionally a more peripherally based squamous cell carcinoma will develop in a tuberculosis scar or in the wall of a bronchiectatic cavity. Histologically, cells develop a pattern of clusters with intracellular bridges and keratin pearls. Central necrosis is frequent and may lead to the radiographic findings VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ of a cavity (possibly with an air-fluid level). Such cavities may become infected, with resultant abscess formation. Large Cell Carcinoma. Large cell carcinoma accounts for 10% to 20% of lung cancers and may be located centrally or peripherally. These tumors have cell diameters of 30 to 50 μm, which are often admixed with various other malignant cell types. Large cell carcinoma can be confused with a large cell variant of neuroendocrine carcinoma, but can be differentiated by special immunohistochemical stains. Neuroendocrine Neoplasms. Neuroendocrine lung tumors are classified into neuroendocrine hyperplasia and three separate grades of neuroendocrine carcinoma (NEC). Immunohistochemical staining for neuroendocrine markers (including chromogranins, synaptophysin, CD57, and neuron-specific enolase) is essential to accurately diagnose most tumors.17 Grade I NEC (classic or typical carcinoid) is a low-grade NEC; 80% arise in the epithelium of the central airways. It occurs primarily in younger patients. Because of the central location, it classically presents with hemoptysis, with or without airway obstruction and pneumonia. Histologically, tumor cells are arranged in cords and clusters with a rich vascular stroma. This vascularity can lead to life-threatening hemorrhage with even simple bronchoscopic biopsy maneuvers. Regional lymph node metastases are seen in 15% of patients, but rarely spread systemically or cause death. Grade II NECs (atypical carcinoid) have a much higher malignant potential and, unlike grade I NEC, are etiologically linked to cigarette smoking and are more likely to be peripherally located. Histologic findings may include areas of necrosis, nuclear pleomorphism, and higher mitotic rates. Lymph node metastases are found in 30% to 50% of patients. At diagnosis, 25% of patients already have remote metastases. Grade III NEC large cell–type tumors occur primarily in heavy smokers and in the mid to peripheral lung fields. They are often large with central necrosis and a high mitotic rate. Their neuroendocrine nature is revealed by positive immunohistochemical staining for at least one neuroendocrine marker. Grade IV NEC (small cell lung carcinoma [SCLC]) is the most malignant NEC and accounts for 25% of all lung cancers; these NECs often have early, widespread metastases. These cancers also arise primarily in the central airways. As with squamous cell cancers, symptoms include cough, hemoptysis, wheezing (due to high-grade airway obstruction), dyspnea (due to bronchial obstruction with or without postobstructive atelectasis), and pneumonia (caused by airway obstruction with secretion retention and atelectasis). Evaluation includes expert pathology review and comprehensive evaluation for metastatic disease. Three groups of grade IV NEC are recognized: pure small cell carcinoma (sometimes referred to as oat cell carcinoma), Lung Cancer Epidemiology Lung cancer is the leading cancer killer and second most frequently diagnosed cancer in the United States, accounting for nearly 28% of all cancer deaths—more than cancers of the breast, prostate, ovary, and colon and rectum combined (Fig. 19-12). In 2008, it was estimated that 1 in 13 men and 1 in 16 women would develop lung cancer in their lifetime. The overall 5-year survival for all patients with lung cancer is 16%, making lung cancer the most lethal of the leading four cancers (Fig. 19-13A, B) It is encouraging, however, that the average annual death rate declined by 2.8% per year for men and 1.1% per year for women from 2005 to 2009.18 Unfortunately, most patients are still diagnosed at an advanced stage of disease, so therapy is rarely curative. Prognostic markers for lung cancer survival include female sex (5-year survival of 18.3% for women vs. 13.8% for men), younger age (5-year survival of 22.8% for those <45 years vs. 13.7% for those >65 years), and white race (5-year survival of 16.1% for whites vs. 12.2% for blacks). When access to advanced medical care is unrestricted, as for the military population, the racial difference in survival disappears, suggesting that, at least in part, differences in survival may be explained by less access to advanced medical care and later diagnosis.19 Risk Factors for Lung Cancer. Cigarette smoking was implicated as a causal factor in approximately 75% of all lung cancers worldwide in 2007. According to the U.S. Surgeon General’s report in 2004, 90% of lung cancers in men and nearly 80% in women can be attributed to cigarette smoking or secondhand cigarette smoke exposure. Two lung cancer types—squamous cell and small cell carcinoma—are extraordinarily rare in the absence of cigarette smoking. The risk of developing lung cancer escalates with the number of cigarettes smoked, the number of years of smoking, and the use of unfiltered cigarettes. Conversely, the risk of lung cancer declines with smoking cessation, but never drops to that of never smokers, regardless of the length of abstinence (Table 19-3).20 Radon exposure accounts for the vast majority of the remaining cancers. Approximately 25% of all lung cancers worldwide and 53% of cancers in women are not related to smoking, and most of them (62%) are adenocarcinomas. Table 19-4 summarizes the existing data regarding the etiology of lung cancer in nonsmokers.21 Nearly 3500 deaths from lung cancer each year are attributable to secondhand (environmental) smoke exposure, which confers an excess risk for lung cancer of 24% when a nonsmoker lives with a smoker.22 Risk is conferred by exposure to any burning tobacco, including cigars. The amount of secondhand exposure from one large cigar is equivalent to the exposure from 21 cigarettes. As with active smoking, risk of developing lung VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 617 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Salivary Gland–Type Neoplasms. Salivary-type submucosal bronchial glands throughout the tracheobronchial tree can give rise to tumors that are histologically identical to those seen in the salivary glands. The two most common are adenoid cystic carcinoma and mucoepidermoid carcinoma. Both tumors occur centrally due to their site of origin. Adenoid cystic carcinoma is a slow-growing tumor that is locally and systemically invasive, growing submucosally and infiltrating along perineural sheaths. Mucoepidermoid carcinoma consists of squamous and mucous cells and is graded as low or high grade, depending on the mitotic rate and degree of necrosis. small cell carcinoma with a large cell component, and combined (mixed) tumors. Grade IV NECs consist of smaller cells (diameter 10 to 20 μm) with little cytoplasm and very dark nuclei; they can be difficult to distinguish from lymphoproliferative lesions and atypical carcinoid tumors. Histologically, a high mitotic rate with easily visualized multiple mitoses and areas of extensive necrosis are characteristic. Importantly, very small bronchoscopic biopsies can distinguish NSCLC from SCLC, but crush artifact may make NSCLC appear similar to SCLC. If uncertainty exists, special immunohistochemical stains or rebiopsy (or both) will be necessary. These tumors are the leading producer of paraneoplastic syndromes. 618 Leading New Cancer Cases and Deaths – 2012 Estimates UNIT II PART Estimated New Cases* Male Female Prostate Breast 241,740 (29%) 226,870 (29%) Lung & bronchus Lung & bronchus 116,470 (14%) 109,690 (14%) Colon & rectum Colon & rectum 73,420 (9%) 70,040 (9%) Urinary bladder Uterine corpus 55,600 (7%) 47,130 (6%) Melanoma of the skin Thyroid 44,250 (5%) 43,210 (5%) Kidney & renal pelvis Melanoma of the skin 40,250 (5%) 32,000 (4%) Non-Hodgkin lymphoma Non-Hodgkin lymphoma 38,160 (4%) 31,970 (4%) Oral cavity & pharynx Kidney & renal pelvis 28,540 (3%) 24,520 (3%) Leukemia Ovary 26,830 (3%) 22,280 (3%) Pancreas Pancreas 22,090 (3%) 21,830 (3%) All sites All sites 848,170 (100%) 790,740 (100%) * Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. Figure 19-12. Leading new cancer cases and deaths: 2012 estimates. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. (Modified with permission from John Wiley and Sons: Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2012;62:10. © 2012 American Cancer Society, Inc.) Age-adjusted Cancer Death Rates,* Males by Site, US, 1930–2008 100 Lung & bronchus 80 Rate per 100,000 male population SPECIFIC CONSIDERATIONS Estimated Deaths Female Male Lung & bronchus Lung & bronchus 87,750 (29%) 72,590 (26%) Prostate Breast 28,170 (9%) 39,510 (14%) Colon & rectum Colon & rectum 26,470 (9%) 25,220 (9%) Pancreas Pancreas 18,850 (6%) 18,540 (7%) Liver & intrahepatic bile duct Ovary 13,980(5%) 15,500 (6%) Leukemia Leukemia 13,500 (4%) 10,040 (4%) Esophagus Non-Hodgkin lymphoma 12,040 (4%) 8,620 (3%) Urinary bladder Uterine corpus 10,510 (3%) 8,010 (3%) Non-Hodgkin lymphoma Liver & intrahepatic bile duct 10,320 (3%) 6,570 (2%) Kidney & renal pelvis Brain & other nervous system 8,650 (3%) 5,980 (2%) All sites All sites 301,820 (100%) 275,370 (100%) 60 Stomach Colon & rectum 40 Prostate 20 Pancreas Leukemia Liver 0 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 *Per 100,000, age adjusted to the 2000 US standard population. Note: Due to changes in ICD coding, numerator information has changed over time. Rates for cancer of the liver, lung and bronchus, and colon and rectum are affected by these coding changes. Figure 19-13. Age-adjusted cancer death rates. A. Males by site, United States, 1930 to 2008. B. Females by site, United States, 1930 to 2008. *Per 100,000, age adjusted to the 2000 U.S. standard population. (Modified with permission from John Wiley and Sons: Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2012;62:10. © 2012 American Cancer Society, Inc.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 619 Age-adjusted Cancer Death Rates,* Females by Site, US, 1930 –2008 100 60 Lung & bronchus Uterus† 40 Breast Colon & rectum Stomach 20 Ovary 0 1930 1935 1940 1945 Pancreas 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 *Per 100,000, age adjusted to the 2000 US standard population. †Uterus cancer death rates are for uterine cervix and uterine corpus combined. Note: Due to changes in ICD coding, numerator information has changed over time. Rates for cancer of the lung and bronchus, colon and rectum, and ovary are affected by these coding changes. Figure 19-13. (Continued) 4 cancer increases with longer duration and higher level of exposure to environmental tobacco. Over 7000 chemicals have been identified in tobacco smoke, and more than 70 of the compounds are known to be carcinogens. The main chemical carcinogens are polycyclic aromatic hydrocarbons, which are actively or passively inhaled in the tobacco smoke and absorbed; these compounds are activated by specific enzymes and become mutagenic, bind to macromolecules such as deoxyribonucleic acid (DNA), and induce genetic mutations. In treating any patient with a previous smoking Table 19-3 Relative risk of lung cancer in smokers Smoking Category Relative Risk Never smoked 1.0 Currently smoke 15.8–16.3 Formerly smoked Years of abstinence 1–9 5.9–19.5 10–19 2.0–6.1 >20 1.9–3.7 Source: Adapted from Samet, p 673. 20 history, it is important to remember that there has been field cancerization of the entire aerodigestive tract. The patient’s risk is increased for cancers of the oral cavity, pharynx, larynx, tracheobronchial tree and lung, and esophagus. In examining such patients, a detailed history and physical examination of these organ systems must be performed. Other causes of lung cancer include exposure to a number of industrial compounds, including asbestos, arsenic, and chromium compounds. In fact, the combination of asbestos and cigarette smoke exposure has a multiplicative effect on risk. Pre-existing lung disease confers an increased risk of lung cancer—up to 13%—for individuals who have never smoked. Patients with chronic obstructive pulmonary disease are at higher risk for lung cancer than would be predicted based on smoking risk alone. Patients with secondary scar formation related to a history of tuberculosis also have a higher risk of primary lung carcinoma. This increase is thought to be related to poor clearance of inhaled carcinogens and/or to the effects of chronic inflammation. Screening for Lung Cancer in High-Risk Populations In 2002, the National Lung Screening Trial (NLST) was launched to determine whether screening with CT in high-risk populations would reduce mortality from lung cancer. The study randomized 53,353 eligible patients age 55 to 74 years to either three annual low-dose helical CT scans (LDCT; aka spiral CT) or posteroanterior view chest radiograph. Patients were eligible VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Rate per 100,000 female population 80 620 Table 19-4 Summary of selected studies of risk factors for lung cancer in individuals who never smoked Risk Factor Risk Estimate (95% CI) Comments Reference Environmental tobacco smoke 1.19 (90% CI: 1.04–1.35) Meta-analysis of 11 U.S. studies of spousal exposure (females only) Meta-analysis of 44 case-control studies worldwide of spousal exposure Meta-analysis of 25 studies worldwide of workplace exposure Meta-analysis of 22 studies worldwide of workplace exposure 225 1.21 (1.13–1.30) 1.22 (1.13–1.33) UNIT II PART 1.24 (1.18–1.29) 226 226 227 SPECIFIC CONSIDERATIONS Residential radon 228 8.4% (3.0%–15.8%) per 100 Bq m3 increase Meta-analysis of 13 European studies in measured radon Meta-analysis of 7 North American studies 229 11% (0%–28%) per 100 Bq m3 Cooking oil vapors 2.12 (1.81–2.47) Meta-analysis of 7 studies from China and Taiwan (females who never smoked) 230 Indoor coal and wood burning 2.66 (1.39–5.07) Meta-analysis of 7 studies from China and Taiwan (both sexes) Large case-control study (2861 cases and 3118 controls) from Eastern and Central Europe (both sexes) Large case-control study (1205 cases and 1541 controls) from Canada (significant for women only) 230 Meta-analysis of 28 case-control, 17 cohort, and 7 twin studies Meta-analysis of 14 case-control studies of Caucasian never smokers Meta-analysis of 21 case-control studies of Caucasian and Asian never smokers (significant for Caucasians only) Meta-analysis of 13 case-control studies Large case-control study from Europe (2188 cases and 2198 controls) 233 Large case-control study from the United States (1091 cases and 1240 controls) 238 1.22 (1.04–1.44) 2.5 (1.5–3.6) Genetic factors: family history, CYP1A1 Ile462Val polymorphism, XRCC1 variants 1.51 (1.11–2.06) 2.99 (1.51–5.91) 2.04 (1.17–3.54) No association No association overall; reduced risk 0.65 (0.46–0.83) with Arg194Trp polymorphism and 0.56 (0.36–0.86) with Arg280His for heavy smokers Increased risk for never smokers 1.3 (1.0–1.8) and decreased risk for heavy smokers 0.5 (0.3–1.0) with Arg299Gln Viral factors: HPV 16 and 18 10.12 (3.88–26.4) for never smoking women >60 y 231 232 234 235 236 237 Case-control study (141 cases, 60 controls) 239 from Taiwan of never smoking women Bq = becquerels; CI = confidence interval; CYP1A1 = cytochrome P450 enzyme 1A1; HPV = human papilloma virus. Source: Reprinted by permission from Macmillan Publishers Ltd. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers–a different disease. Nat Rev Cancer. 2007;7:778 Copyright © 2007. for the trial if they had a greater than 30 pack-year history of cigarette smoking; had smoked within the past 15 years if a former smoker; had no prior history of lung cancer; had no history of other life-threatening cancers in the prior 5 years; did not have symptoms suggestive of an undiagnosed lung cancer (such as hemoptysis or weight loss); and had not had a chest CT scan in the prior 18 months. Accrual to the study was excellent, and the primary endpoint of a 20% relative reduction in mortality was achieved in 2010. An absolute risk reduction of lung cancer death of four per 1000 individuals screened by LDCT was realized. Interestingly, all-cause mortality was also reduced by nearly 7% in the LDCT group, further emphasizing the impact of lung cancer on the mortality of smokers and former smokers.23 An estimated 320 individuals need to be screened to save one life from lung cancer. Additional considerations require further evaluation before widespread LDCT screening will become reality. First, there was a 7% false-positive rate in this trial. False-positive scans lead to patient anxiety, invasive testing, and potentially morbid procedures to further evaluate the finding. The impact of these issues on patient quality of life and cost-effectiveness has yet to be elucidated. It is also critical that regulatory guidelines for patient eligibility, frequency of screening, interpretation of the scans, processes for further evaluation and management of positive findings, and dose of radiation are VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ well established and well accepted to ensure the generalizability of the results for patients who will be screened in the general medical community rather than in the specialized centers that performed the trial. Solitary Pulmonary Nodule A B C D Figure 19-14. Spiral computed tomography scan showing normal transverse chest anatomy at four levels. A. At the level of the tracheal bifurcation, the aorticopulmonary window can be seen. B. The origin of the left pulmonary artery can be seen at a level 1 cm inferior to A. C. The origin and course of the right pulmonary artery can be seen at this next most cephalad level. The left upper lobe bronchus can be seen at its origin from the left main bronchus. D. Cardiac chambers and pulmonary veins are seen in the lower thorax. AA = ascending aorta; APW = aorticopulmonary window; DA = descending aorta; LA = left ventricle; LMB = left main bronchus; LPA = left pulmonary artery; MPA = main pulmonary artery; RA = right atrium; RPA = right pulmonary artery; RV = right ventricle; SVC = superior vena cava; T = trachea. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 621 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura A solitary pulmonary nodule is typically described as a single, well-circumscribed, spherical lesion that is 3 cm or less in diameter and completely surrounded by normal aerated lung parenchyma.24 Lung atelectasis, hilar enlargement, and pleural effusion are absent. The majority are detected incidentally on chest radiographs (CXRs) or CT scans obtained for some other purpose. About 150,000 solitary nodules are found incidentally each year. The clinical significance of such a lesion depends on whether or not it represents a malignancy. The differential diagnosis of a solitary pulmonary nodule should include a broad variety of congenital, neoplastic, inflammatory, vascular, and traumatic disorders. The probability of cancer in a solitary pulmonary nodule increases if the patient has a history of smoking (50% or higher for smokers compared to 20%–40% in never smokers). It is also more likely to be malignant if it is symptomatic or the patient is older, male, or has had occupational exposures. Solitary pulmonary nodules were defined by findings on CXR, but with the increased sensitivity of low-dose screening CT, up to 50% of solitary lesions are found to be associated with multiple (one to six) other, usually subcentimeter, nodules. In the Early Lung Cancer Action project, almost 7% of healthy volunteers were found to have between one and three nodules and 25% had up to six nodules. CT scanning is necessary to characterize nodule number, location, size, margin morphology, calcification pattern, and growth rate.25 Spiral (helical) CT allows continuous scanning as the patient is moved through a scanning gantry, allowing the entire thorax to be imaged during a single breath hold (Fig. 19-14). Compared to conventional CT, this provides a superior image quality, because motion artifacts are eliminated, and improves detection of pulmonary nodules and central airway abnormalities.26 The shorter acquisition time of spiral CT also allows for consistent contrast filling of the great vessels, resulting in markedly improved visualization of pathologic states and anatomic variation contiguous to vascular structures. In addition, three-dimensional spiral CT images can 622 UNIT II PART SPECIFIC CONSIDERATIONS be reconstructed for enhanced visualization of spatial anatomic relationships.27 Thin sections (1–2 mm collimation) at 1-cm intervals should be used to evaluate pulmonary parenchyma and peripheral bronchi. If the goal is to find any pulmonary metastases, thin sections at intervals of 5 to 7 mm collimation are recommended. For assessing the trachea and central bronchi, collimation of 3 to 5 mm is recommended. Providing accurate clinical history and data is of paramount importance to obtaining appropriate imaging. CT findings characteristic of benign lesions include small size, calcification within the nodule, and stability over time. Four patterns of benign calcification are common: diffuse, solid, central, and laminated or “popcorn.” Granulomatous infections such as tuberculosis can demonstrate the first three patterns, whereas the popcorn pattern is most common in hamartomas. In areas of endemic granulomatous disease, differentiating benign versus malignant can be challenging. Infectious granulomas arising from a variety of organisms account for 70% to 80% of this type of benign solitary nodules; hamartomas are the next most common single cause, accounting for about 10%. CT findings characteristic of malignancy include growth over time; increasing density on CT scan (40%–50% of partial solid lesions are malignant compared to only 15% of subcentimeter solid or nonsolid nodules); size >3 cm; irregular, lobulated, or spiculated edges; and the finding of the corona radiata sign (consisting of fine linear strands extending 4–5 mm outward and appearing spiculated on radiographs) (Fig. 19-15). Calcification that is stippled, amorphous, or eccentric is usually associated with cancer. Growth over time is an important characteristic for differentiating benign and malignant lesions. Lung cancers have volume-doubling times from 20 to 400 days; lesions with shorter doubling times are likely due to infection, and longer doubling times suggest benign tumors, but can represent slower-growing lung cancer. Positron emission tomography (PET) scanning can differentiate benign from malignant nodules28; most lung tumors have increased signatures of glucose uptake, as compared with healthy tissues and, thus, glucose metabolism can be measured using radio-labeled 18F-fluorodeoxyglucose (FDG). Metaanalysis estimates 97% sensitivity and 78% specificity for predicting malignancy in a nodule. False-negative results can occur (especially in patients who have AIS, MIA, or LPA, carcinoids, and tumors <1 cm in diameter), as well as false-positive results (because of confusion with other infectious or inflammatory processes). Metastatic Lesions to the Lung The cause of a new pulmonary nodule(s) in a patient with a previous malignancy can be difficult to discern.29 Features suggestive of metastatic disease are multiplicity; smooth, round borders on CT scan; and temporal proximity to the original primary lesion. One must always entertain the possibility that a single new lesion is a primary lung cancer. The probability of a new primary cancer vs. metastasis in patients presenting with solitary lesions depends on the type of initial neoplasm. The highest likelihood of a new primary lung cancer is in patients with a history of uterine (74%), bladder (89%), lung (92%), and head and neck (94%) carcinomas. Surgical resection of pulmonary metastases has a role in properly selected patients.30 The best data regarding outcomes of resection of pulmonary metastases come from the International Registry of Lung Metastases (IRLM). The registry A B C Figure 19-15. Computed tomography scan images of solitary pulmonary nodules. A. The corona radiata sign demonstrated by a solitary nodule. Multiple fine striations extend perpendicularly from the surface of the nodule like the spokes of a wheel. B. A biopsy-proven adenocarcinoma demonstrating spiculation. C. A lesion with a scalloped border, an indeterminate finding suggesting an intermediate probability for malignancy. was established in 1991 by 18 thoracic surgery departments in Europe, the United States, and Canada, and included data on 5206 patients. About 88% of patients underwent complete resection. Survival analysis at 5, 10, and 15 years (grouping all primary tumor types) was performed (Table 19-5). Multivariate analysis showed a better prognosis for patients with germ cell tumors, osteosarcomas, a disease-free interval over 36 months, and a single metastasis.31 Depicted in Fig. 19-16, survival after metastasectomy in a variety of cancers is optimal when metastatic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Complete Resection (%) Incomplete Resection (%) 5 years 36 13 Nonpulmonary Thoracic Symptoms. Nonpulmonary tho- 10 years 26 7 15 years 22 — racic symptoms result from invasion of the primary tumor directly into a contiguous structure (e.g., chest wall, diaphragm, pericardium, phrenic nerve, recurrent laryngeal nerve, superior vena cava, and esophagus), or from mechanical compression of a structure (e.g., esophagus or superior vena cava) by enlarged tumor-bearing lymph nodes. Peripherally located tumors (often adenocarcinomas) extending through the visceral pleura lead to irritation or growth into the parietal pleura and potentially to continued growth into the chest wall structures. Three types of symptoms, depending on the extent of chest wall involvement, are possible: (a) pleuritic pain, from noninvasive contact of the parietal pleura with inflammatory irritation or direct parietal pleural invasion; (b) localized chest wall pain, from deeper invasion and involvement of the rib and/or intercostal muscles; and (c) radicular pain, from involvement of the intercostal nerve(s). Radicular pain may be mistaken for renal colic in the case of tumors invading the inferoposterior chest wall. Other specific nonpulmonary thoracic symptoms include: Actuarial survival data from the International Registry of Lung Metastases disease is resectable, solitary, and identified 36 or more months after initial treatment. When any or all of these optimal characteristics are absent, survival progressively declines. The general principles of patient selection for metastasectomy are listed in Table 19-6. The technical aim of pulmonary metastasectomy is complete resection of all macroscopic tumors. In addition, any involved adjacent structures should be resected en bloc (i.e., chest wall, diaphragm, and pericardium). Multiple lesions and/or hilar lesions may require lobectomy. Pneumonectomy is rarely justified or employed. Pulmonary metastasectomy can be approached through a thoracotomy or via video-assisted thoracic surgery (VATS) techniques. McCormack and colleagues reported their experience at Memorial Sloan-Kettering in a prospective study of 18 patients who presented with no more than two pulmonary metastatic lesions and underwent VATS resection.32 A thoracotomy was performed during the same operation; if palpation identified any additional lesions, they were resected. The study concluded that the probability that a metastatic lesion will be missed by VATS excision is 56%. Patients in the Memorial study were evaluated before the advent of spiral CT scanning, however, and it remains controversial whether metastasis resection should be performed via VATS. Proponents of VATS argue that the resolution of spiral CT scanning is so superior that prior studies using standard CT scanners are no longer relevant. Indeed, a recent study suggested that only 18% of malignant nodules would be missed using a VATS approach in the current era while another study from the United Kingdom found equivalent outcomes with regard to missed lesions and pulmonary progression comparing open and VATS approaches. To date, no prospective study using spiral CT scan has been performed to resolve this clinical dilemma. Primary Lung Cancer-Associated Signs and Symptoms Lung cancer displays one of the most diverse presentation patterns of all human maladies (Table 19-7). The wide range of symptoms and signs is related to (a) histologic features, which often help determine the anatomic site of origin in the lung; (b) the specific tumor location in the lung and its relationship to surrounding structures; (c) biologic features and the production of a variety of paraneoplastic syndromes; and (d) the presence or absence of metastatic disease. Symptoms related to the local intrathoracic effect of the primary tumor can be conveniently divided into two groups: pulmonary and nonpulmonary thoracic. Pulmonary Symptoms. Pulmonary symptoms result from the direct effect of the tumor on the bronchus or lung tissue. Symptoms (in order of frequency) include cough (secondary to irritation 1. 2. 3. 4. Pancoast’s syndrome. Tumors originating in the superior sulcus (posterior apex) elicit: apical chest wall and/or shoulder pain (from involvement of the first rib and chest wall); Horner’s syndrome (unilateral enophthalmos, ptosis, miosis, and facial anhidrosis from invasion of the stellate sympathetic ganglion); and radicular arm pain (from invasion of T1, and occasionally C8, brachial plexus nerve roots). Phrenic nerve palsy. The phrenic nerve traverses the hemithorax along the mediastinum, parallel and posterior to the superior vena cava and anterior to the pulmonary hilum. Tumors at the medial lung surface or anterior hilum can directly invade the nerve; symptoms include shoulder pain (referred), hiccups, and dyspnea with exertion because of diaphragm paralysis. Radiographically, unilateral diaphragm elevation on CXR is present; the diagnosis is confirmed by fluoroscopic examination of the diaphragm with breathing and sniffing (the “sniff” test). Recurrent laryngeal nerve palsy. Recurrent laryngeal nerve (RLN) involvement most commonly occurs on the left side, given the hilar location of the left RLN as it passes under the aortic arch. Paralysis results from: (a) invasion of the vagus nerve above the aortic arch by a medially based left upper lobe tumor; or (b) direct invasion of the RLN by hilar tumor and/or hilar or aortopulmonary lymph node metastases. Symptoms include voice change, often referred to as hoarseness, but more typically a loss of tone associated with a breathy quality, and coughing, particularly when drinking liquids. Superior vena cava (SVC) syndrome. As a result of bulky enlargement of involved mediastinal lymph nodes compressing or a medially based right upper lobe tumor invading the SVC, SVC syndrome symptoms include variable degrees of swelling of the head, neck, and arms; headache; VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 623 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Survival or compression of a bronchus), dyspnea (usually due to central airway obstruction or compression, with or without atelectasis), wheezing (with narrowing of a central airway of >50%), hemoptysis (typically, blood streaking of mucus that is rarely massive; indicates a central airway location), pneumonia (usually due to airway obstruction by the tumor), and lung abscess (due to necrosis and cavitation, with subsequent infection). Table 19-5 624 Osteosarcoma All Sites 100 100 80 1 80 2 3 60 60 4 UNIT II PART 40 40 20 20 0 0 0 24 48 72 96 0 120 SPECIFIC CONSIDERATIONS A Soft Tissue Sarcomas 72 96 120 80 60 60 40 40 20 20 0 24 48 72 Colon Cancer 100 80 96 0 120 C 0 24 48 72 96 120 96 120 D Breast Cancer Melanoma 100 100 80 80 60 60 40 40 20 20 0 0 0 E 48 B 100 0 24 24 48 72 96 120 0 24 48 72 F Figure 19-16. The actuarial survival after metastasectomy is depicted for patients with various tumor types further categorized into four groups according to resectability, solitary or multiple, the interval between primary resection and metastesectomy, and a combination of factors known in our work and in others, as follows: (1) resectable, solitary, and disease-free interval (DFI) greater than or equal to 36 months; (2) resectable, solitary, or DFI 36+ months; (3) resectable, multiple metastases, and DFI <36 months; and (4) unresectable. (Reprinted with permission from Pastorino, U. (2010). The Development of an International Registry. J Thorac Oncol. 5(6): S196-S197) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 19-6 General principles governing appropriate selection of patients for pulmonary metastasectomy 5. 6. 7. and conjunctival edema. It is seen most commonly with NEC grade IV (small cell) lung cancer. Pericardial tamponade. Pericardial effusions (benign or malignant), associated with increasing levels of dyspnea and/or arrhythmias, and pericardial tamponade occur with direct pericardial invasion. Diagnosis requires a high index of suspicion in the setting of a medially based tumor with symptoms of dyspnea and is confirmed by CT scan or echocardiography. Back pain. Results from direct invasion of a vertebral body and is often localized and severe. If the neural foramina are involved, radicular pain may also be present. Other local symptoms. Dysphagia is usually secondary to external esophageal compression by enlarged lymph Table 19-7 Clinical presentation of lung cancer Category Symptom Cause Pulmonary symptoms Cough Bronchus irritation or compression Dyspnea Airway obstruction or compression Wheezing >50% airway obstruction Hemoptysis Tumor erosion or irritation Pneumonia Airway obstruction Nonpulmonary Pleuritic pain thoracic symptoms Parietal pleural irritation or invasion Local chest wall pain Rib and/or muscle involvement Radicular chest pain Intercostal nerve involvement Pancoast’s syndrome Stellate ganglion, chest wall, brachial plexus involvement Hoarseness Recurrent laryngeal nerve involvement Swelling of head Bulky involved and arms mediastinal lymph nodes Medially based right upper lobe tumor 625 Associated Paraneoplastic Syndromes All lung cancer histologies are capable of producing a variety of paraneoplastic syndromes, most often from systemic release of tumor-derived biologically active materials (Table 19-8). Paraneoplastic Table 19-8 Paraneoplastic syndromes in patients with lung cancer Endocrine Hypercalcemia (ectopic parathyroid hormone) Cushing’s syndrome Syndrome of inappropriate secretion of antidiuretic hormone Carcinoid syndrome Gynecomastia Hypercalcitoninemia Elevated growth hormone level Elevated levels of prolactin, follicle-stimulating hormone, luteinizing hormone Hypoglycemia Hyperthyroidism Neurologic Encephalopathy Subacute cerebellar degeneration Progressive multifocal leukoencephalopathy Peripheral neuropathy Polymyositis Autonomic neuropathy Eaton-Lambert syndrome Optic neuritis Skeletal Clubbing Pulmonary hypertrophic osteoarthropathy Hematologic Anemia Leukemoid reactions Thrombocytosis Thrombocytopenia Eosinophilia Pure red cell aplasia Leukoerythroblastosis Disseminated intravascular coagulation Cutaneous Hyperkeratosis Dermatomyositis Acanthosis nigricans Hyperpigmentation Erythema gyratum repens Hypertrichosis lanuginosa acquista Other Nephrotic syndrome Hypouricemia Secretion of vasoactive intestinal peptide with diarrhea Hyperamylasemia Anorexia or cachexia VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura 1. Primary tumor must already be controlled. 2. Patient must be able to tolerate general anesthesia, potential single-lung ventilation, and the planned pulmonary resection. 3. Metastases must be completely resectable based on computed tomographic imaging. 4. There is no evidence of extrapulmonary tumor burden. 5. Alternative superior therapy must not be available. nodes involved with metastatic disease, usually with lower lobe tumors. Finally, dyspnea, pleural effusion, or referred shoulder pain can result from invasion of the diaphragm by a tumor at the base of a lower lobe. 626 syndromes may produce symptoms even before any local symptoms are produced by the primary tumor, thereby aiding in early diagnosis. Their presence does not influence resectability or treatment options. Symptoms often abate with successful treatment; paraneoplastic symptom recurrence may herald tumor recurrence. The majority of such syndromes are associated with grade IV NEC (small cell carcinoma), including many endocrinopathies. 1. UNIT II PART SPECIFIC CONSIDERATIONS 2. Hypertrophic pulmonary osteoarthropathy (HPO). Often severely debilitating, symptoms of HPO may antedate the diagnosis of cancer by months. Clinically, ankle, feet, forearm, and hand tenderness and swelling are characteristic, resulting from periostitis of the fibula, tibia, radius, metacarpals, and metatarsals. Clubbing of the digits may occur in up to 30% of patients with grade IV NEC (Fig. 19-17). Plain radiographs show periosteal inflammation and elevation, while bone scans demonstrate intense but symmetric uptake in the long bones. Aspirin or nonsteroidal anti-inflammatory agents provide temporary relief; treatment requires successful surgical or medical tumor eradication. Hypercalcemia. Up to 10% of patients with lung cancer will have hypercalcemia, most often due to metastatic disease. Ectopic parathyroid hormone secretion by the tumor, most often squamous cell carcinoma, is causative in up to 15%, however, and should be suspected if metastatic bone 3. 4. disease is not present. Symptoms of hypercalcemia include lethargy, depressed level of consciousness, nausea, vomiting, and dehydration. Most patients have resectable tumors, and, following complete resection, the calcium level will normalize. Unfortunately, tumor recurrence is extremely common and may manifest as recurrent hypercalcemia. Hyponatremia. Characterized by confusion, lethargy, and possible seizures, hyponatremia can result from the inappropriate secretion of antidiuretic hormone from the tumor into the systemic circulation (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) in 10% to 45% of patients with grade IV NEC (small cell). It is diagnosed by the presence of hyponatremia, low serum osmolality, and high urinary sodium and osmolality. Another cause of hyponatremia can be the ectopic secretion of atrial natriuretic peptide (ANP). Cushing’s syndrome. Autonomous tumor production of an adrenocorticotropic hormone (ACTH)-like molecule leads to rapid serum elevation of ACTH and subsequent severe hypokalemia, metabolic alkalosis, and hyperglycemia. Symptoms are primarily related to the metabolic changes while the physical signs of Cushing’s syndrome (e.g., truncal obesity, buffalo hump, striae) are unusual due to the rapidity of ACTH elevation. Diagnosis is made by demonstrating hypokalemia (<3.0 mmol/L); nonsuppressible elevated plasma cortisol levels that lack the normal diurnal variation; elevated blood ACTH levels; or elevated A B C Figure 19-17. Hypertrophic pulmonary osteoarthropathy associated with small cell carcinoma. A. Painful clubbing of the fingers. B. Painful clubbing of the toes (close-up). C. The arrows point to new bone formation on the femur. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 5. Symptoms Associated with Metastatic Lung Cancer. Lung cancer metastasizes most commonly to the CNS, vertebral bodies, bone, liver, adrenal glands, lungs, skin, and soft tissues. CNS metastases are present at diagnosis in 10% of patients; another 10% to 15% will develop CNS metastases following diagnosis. Focal symptoms, including headache, nausea, vomiting, seizures, hemiplegia, and dysarthria, are common. Lung cancer is the most common cause of spinal cord compression, either by primary tumor invasion of an intervertebral foramen or direct extension of vertebral metastases. Bony metastases are identified in 25% of all patients with lung cancer. They are primarily lytic and produce pain locally; thus any new and localized skeletal symptoms must be evaluated radiographically. Liver metastases are most often an incidental finding on CT scan. Adrenal metastases are also typically asymptomatic and are usually discovered by routine CT scan. They may lead to adrenal hypofunction. Skin and soft tissue metastases occur in 8% of patients dying of lung cancer and generally present as painless subcutaneous or intramuscular masses. Occasionally, the tumor erodes through the overlying skin, with necrosis and creation of a chronic wound; excision may then be necessary for both mental and physical palliation. Nonspecific Cancer-Related Symptoms. Lung cancer often produces a variety of nonspecific symptoms such as anorexia, weight loss, fatigue, and malaise. The cause of these symptoms is often unclear, but should raise concern about possible metastatic disease. 627 Lung Cancer Management Role of Histologic Diagnosis and Molecular Testing. Establishing a clear histologic diagnosis early in the evaluation and management of lung cancer is critical to effective treatment. Molecular signatures are also key determinants of treatment algorithms for adenocarcinoma and will likely become important for squamous cell carcinoma as well. Currently, differentiation between adenocarcinoma and squamous cell carcinoma in cytologic specimens or small biopsy specimens is imperative in patients with advanced stage disease, as treatment with pemetrexed or bevacizumab-based chemotherapy is associated with improved progression-free survival in patients with adenocarcinoma but not squamous cell cancer. Furthermore, life-threatening hemorrhage has occurred in patients with squamous cell carcinoma who were treated with bevacizumab. Finally, EGFR mutation predicts response to EGFR tumor kinase inhibitors and is now recommended as first-line therapy in advanced adenocarcinoma. Because adequate tissue is required for histologic assessment and molecular testing, each institution should have a clear, multidisciplinary approach to patient evaluation, tissue acquisition, tissue handling/processing, and tissue analysis (Fig. 19-18). In many cases, tumor morphology differentiates adenocarcinoma from the other histologic subtypes. If no clear morphology can be identified, then additional testing for one immunohistochemistry marker for adenocarcinoma and one for squamous cell carcinoma will usually enable differentiation. Immunohistochemistry for neuroendocrine markers is reserved for lesions exhibiting neuroendocrine morphology. Additional molecular testing should be performed on all adenocarcinoma specimens for known predictive and prognostic tumor markers (e.g. EGFR, KRAS, and EML4-ALK fusion gene). Ideally, use of tissue sections and cell block material is limited to the minimum necessary at each decision point. This emphasizes the importance of a multidisciplinary approach; surgeons and radiologists must work in direct cooperation with the cytopathologist to ensure that tissue samples are adequate for morphologic diagnosis as well as providing sufficient cellular material to enable molecular testing. With adoption of endobronchial and endoscopic ultrasound, electromagnetic navigational bronchoscopy, VATS, and even transthoracic image-guided fine-needle and core-needle biopsy, surgeons are increasingly involved in the acquisition of diagnostic tissue for primary, metastatic, and recurrent intrathoracic disease, and a thorough understanding of key issues is necessary to ensure optimal treatment and patient outcomes. Patient Evaluation. Evaluation prior to treatment encompasses three areas: diagnosis and assessment of the primary tumor, assessment for metastatic disease, and determination of functional status (the patient’s ability to tolerate the prescribed treatment regimen). A discrete approach to each area allows the surgeon to systematically evaluate the patient, perform accurate clinical staging, and enable assessment of the patient’s functional suitability for therapy, including pulmonary resection (Table 19-9). Assessment of the Primary Tumor. Assessment of the primary tumor begins with the history and directed questions regarding the presence or absence of pulmonary, nonpulmonary, thoracic, and paraneoplastic symptoms. Because patients often present to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura 6. urinary 17-hydroxycorticosteroids, all of which are not suppressible by administration of exogenous dexamethasone. Immunoreactive ACTH is present in nearly all extracts of SCLC, and a high percentage of patients with SCLC have elevated ACTH levels by radioimmunoassay, yet fewer than 5% have symptoms of Cushing’s syndrome. Peripheral and central neuropathies. Unlike other paraneoplastic syndromes, which are usually due to ectopic secretion of an active substance, these syndromes are felt to be immune mediated. Cancer cells are thought to secrete antigens normally expressed only by the nervous system, generating antibodies leading either to interference with neurologic function or to immune neurologic destruction. Up to 16% of lung cancer patients have neuromuscular disability, and, of these, half have grade IV NEC (small cell) and 25% have squamous cell carcinomas. In patients with neurologic or muscular symptoms, central nervous system (CNS) metastases must be ruled out with CT or magnetic resonance imaging (MRI) of the head. Other metastatic disease leading to disability must also be excluded. Lambert-Eaton syndrome. This myasthenia-like syndrome is caused by tumor secretion of immunoglobulin G (IgG) antibodies targeting voltage-gated calcium channels, which causes a neuromuscular conduction defect by decreasing the amount of acetylcholine released from presynaptic sites at the motor end plate. Symptoms, including gait abnormalities from proximal muscle weakness and impaired coordination, may actually precede radiographic evidence of the tumor. Therapy is directed at the primary tumor with resection, radiation, and/or chemotherapy. Many patients have dramatic improvement after successful therapy. For patients with refractory symptoms, treatment consists of guanidine hydrochloride, immunosuppressive agents such as prednisone and azathioprine, and occasionally plasma exchange. Unlike with myasthenia gravis patients, neostigmine is usually ineffective. 628 STEP 1 POSITIVE BIOPSY (FOB, TBBx, Core, SLBx) POSITIVE CYTOLOGY (effusion, aspirate, washings, brushings) NE morphology, large cells, NE IHC+ NSCLC, ?LCNEC NE morphology, small cells, no nucleoli, NE IHC+, TTF-1 +/–, CK+ SCLC Keratinization, pearls and/or intercellular bridges UNIT II PART SPECIFIC CONSIDERATIONS Histology: Lepidic, papillary, and/or acinar architecture(s) Cytology: 3-D arrangements, delicate foamy/vacuolated (translucent) cytoplasm, Fine nuclear chromatin and often prominent nucleoli Nuclei are often eccentrically situated Classic Morphology: SQCC No clear ADC or SQCC morphology: NSCLC-NOS NSCLC, favor SQCC Classic morphology: ADC ADC marker and/or Mucin +ve; SQCC marker –ve (or weak in same cells) SQCC marker +ve ADC marker -ve/or Mucin -ve STEP 2 Apply ancillary panel of One SQCC and one ADC marker +/OR Mucin IHC –ve and Mucin -ve ADC marker or Mucin +ve; as well as SQCC marker +ve in different cells NSCLC, favor ADC NSCLC NOS NSCLC, NOS, possible adenosquamous ca Molecular analysis: e.g. EGFR mutation† STEP 3 If tumor tissue inadequate for molecular testing, discuss need for further sampling - back to Step 1 Figure 19-18. Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology. Step 1: When positive biopsies (fiberoptic bronchoscopy [FOB], transbronchial [TBBx], core, or surgical lung biopsy [SLBx]) or cytology (effusion, aspirate, washings, and brushings) show clear adenocarcinoma (ADC) or squamous cell carcinoma (SQCC) morphology, the diagnosis can be firmly established. If there is neuroendocrine (NE) morphology, the tumor may be classified as small cell carcinoma (SCLC) or non–small cell lung carcinoma (NSCLC), probably large cell neuroendocrine carcinoma (LCNEC) according to standard criteria (+ = positive, – = negative, and ± = positive or negative). If there is no clear ADC or SQCC morphology, the tumor is regarded as NSCLC–not otherwise specified (NOS). Step 2: NSCLC-NOS can be further classified based on (a) immunohistochemical stains, (b) mucin (DPAS or mucicarmine) stains, or (c) molecular data. If the stains all favor ADC-positive ADC marker(s) (i.e., TTF-1 and/or mucin positive) with negative SQCC markers, then the tumor is classified as NSCLC, favor ADC. If SQCC markers (i.e., p63 and/or CK5/6) are positive with negative ADC markers, the tumor is classified as NSCLC, favor SQCC. If the ADC and SQCC markers are both strongly positive in different populations of tumor cells, the tumor is classified as NSCLC-NOS, with a comment it may represent adenosquamous carcinoma. If all markers are negative, the tumor is classified as NSCLC-NOS. †EGFR mutation testing should be performed in (1) classic ADC, (2) NSCLC, favor ADC, (3) NSCLC-NOS, and (4) NSCLC-NOS, possible adenosquamous carcinoma. In NSCLC-NOS, if EGFR mutation is positive, the tumor is more likely to be ADC than SQCC. Step 3: If clinical management requires a more specific diagnosis than NSCLC-NOS, additional biopsies may be indicated. CD = cluster designation; CK = cytokeratin; DPAS = diastase-periodic acid Schiff; DPAS +ve = periodic-acid Schiff with diastase; EGFR = epidermal growth factor receptor; IHC = immunohistochemistry; NB = of note; TTF-1 = thyroid transcription factor-1; –ve = negative; +ve = positive. (Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 629 Table 19-9 Evaluation of patients with lung cancer History Primary Tumor Metastatic Disease Functional Assessment Pulmonary Weight loss Ability to walk up two flights of stairs Nonpulmonary thoracic Malaise Ability to walk on a flat surface indefinitely Paraneoplastic New bone pain Skin lesions Physical examination Voice Supraclavicular node palpation Accessory muscle usage Skin examination Air flow by auscultation Neurologic examination Force of cough Radiographic examination Chest CT Chest CT, PET Chest CT: tumor anatomy, atelectasis Tissue analysis Bronchoscopy Bone scan, head MRI, abdominal CT Quantitative perfusion scan Transthoracic needle aspiration and biopsy Bronchoscopic lymph node FNA Endoscopic ultrasound Mediastinoscopy Biopsy of suspected metastasis Other Thoracoscopy Pulmonary function tests (FEV1, Dlco, O2 consumption) — CT = computed tomography; Dlco = carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second; FNA = fine-needle aspiration; MRI = magnetic resonance imaging; O2 = oxygen; PET = positron emission tomography. the surgeon with a CXR or CT scan demonstrating the lesion, the location of the tumor can help direct the clinician in performing the history and physical examination. If the patient does not already have a chest CT scan, this should be performed expeditiously as the next stage in evaluating a new patient. A routine chest CT scan should include intravenous contrast material to enable assessment of the primary tumor, delineation of mediastinal lymph nodes relative to normal mediastinal structures, and the tumor’s relationship to surrounding and contiguous structures. Recommendations for treatment and options for obtaining tissue diagnosis require a thorough understanding and assessment of CT findings. Concern for contiguous invasion of adjacent structures often is raised in response to a combination of symptom history, location of the primary tumor, and CT imaging. It is common to see the primary tumor abutting the chest wall without clear radiographic evidence of rib destruction. In this circumstance, a history of pain in the area is an accurate guide to the likelihood of parietal pleural, rib, or intercostal nerve involvement. Similar observations apply to tumors abutting the recurrent laryngeal nerve, phrenic nerve, diaphragm, vertebral bodies, and chest apex. Thoracotomy should not be denied because of presumptive evidence of invasion of the chest wall, vertebral body, or mediastinal structures; proof of invasion may require thoracoscopy or even thoracotomy. MRI of pulmonary lesions and mediastinal nodes, overall, offers no real improvement over CT scanning. It is an excellent modality, however, for defining a tumor’s relationship to a major vessel, given its excellent imaging of vascular structures. This is especially true if the use of iodine contrast material is contraindicated. Thus, use of MRI in lung cancer patients is reserved for those with contrast allergies or with suspected mediastinal, vascular, or vertebral body invasion. Options for Tissue Acquistion. The surgeon must have an evidence-based algorithm for approaching the diagnosis and treatment of a pulmonary nodule and masses (Fig. 19-19).24 Depending on nodule size, proximity to the bronchial tree, and the prevalence of cancer in the population being sampled, bronchoscopy has 20% to 80% sensitivity for detecting neoplastic processes within a pulmonary lesion. Diagnostic tissue from bronchoscopy can be obtained by one of four methods: 1. 2. 3. 4. Brushings and washings for cytology Direct forceps biopsy of a visualized lesion Endobronchial ultrasound-guided fine-needle aspiration (FNA) of an externally compressing lesion without visualized endobronchial tumor Transbronchial biopsy with fluoroscopy to guide forceps to the lesion or electromagnetic navigational bronchoscopy Electromagnetic navigation bronchoscopy is a recent addition to the surgeon’s armamentarium for transbronchial biopsy of peripheral lung lesions. Using electromagnetic markers that create a three-dimensional image and align the recorded CT images to the patient’s true anatomy, a catheter is advanced transbronchially and brushings, FNA, cup biopsy, and washings can be performed. Diagnostic yield using electromagnetic navigation bronchoscopy as an adjunct to standard bronchoscopy is reported as high as 80%. The VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Neurologic signs or symptoms 630 New SPN (8mm to 30mm) identified on CXR or CT scan Benign calcification present or 2-year stability demonstrated? UNIT II PART SPECIFIC CONSIDERATIONS Establish diagnosis by biopsy when possible. Consider XRT or monitor for symptoms and palliate as necessary. Yes No further intervention required except for patients with pure ground glass opacities, in whom longer annual follow-up should be considered No No Surgical risk acceptable? Yes Assess clinical probability of cancer Low probability of cancer (<5%) Serial high-resolution CT at 3, 6, 12 and 24 months Intermediate probability of cancer (>5%–60%) Negative tests Additional testing • PET imaging, if available • Contrast-enhanced CT, depending on institutional expertise • Transthoracic fine-needle aspiration biopsy, if nodule is peripherally located • Bronchoscopy, if airbronchogram present or if operator has expertise with newer guided techniques High probability of cancer (>60%) Positive tests Video-assisted thoracoscopic surgery: examination of a frozen section, followed by resection if nodule is malignant Figure 19-19. Recommended management algorithm for patients with solitary pulmonary nodules (SPNs) measuring 8 mm to 30 mm in diameter. CT = computed tomography; CXR = chest radiograph; PET = positron emission tomography; XRT = radiotherapy. (Reproduced with permission from the American College of Chest Physicians from Gould MK, et al. Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP Evidence-based Clinical Practice Guidelines. (2nd edition) Chest. 2007;132:108S.) approach can also be used for placement of fiducial markers for subsequent stereotactic body radiation therapy and for tattooing the perilesional region to guide subsequent videoassisted thoracoscopic resection. Pneumothorax rates with this approach are approximately 1% in larger series and up to 3.5% in reports of early experience. For peripheral lesions (roughly the outer half of the lung), transbronchial biopsy is performed first, followed by 5 brushings and washings. This improves diagnostic yield by disrupting the lesion with the biopsy forceps and mobilizing additional cells. For central lesions, direct forceps biopsy by bronchoscopic visualization is often possible. For central lesions with external airway compression but no visible endobronchial lesions, endobronchial ultrasound (EBUS) is highly accurate and safe for transbronchial biopsies of both the primary tumor (when it abuts the central airways) as well as the mediastinal lymph nodes.33 Image-guided transthoracic FNA (ultrasound or CT FNA) biopsy can accurately diagnose appropriately selected peripheral pulmonary lesions in up to 95% of patients. Three biopsy results are possible after image-guided biopsy procedures: malignant, a specific benign process, or indeterminate. Because falsenegative rates range from 3% to 29%, further diagnostic efforts are warranted in the absence of a specific benign diagnosis (such as granulomatous inflammation or hamartoma) because malignancy is not ruled out.34 The primary complication is pneumothorax in as many as 30% of cases. Intrapulmonary bleeding occurs, but rarely causes clinically significant hemoptysis or respiratory compromise. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Assessment for Metastatic Disease. Distant metastases are found in approximately 40% of patients with newly diagnosed lung cancer. The presence of lymph node or systemic metastases may imply inoperability. As with the primary tumor, assessment for the presence of metastatic disease should begin with the history and physical examination, focusing on the presence or absence of new bone pain, neurologic symptoms, and new skin lesions. In addition, constitutional symptoms (e.g., anorexia, malaise, and unintentional weight loss of >5% of body weight) suggest either a large tumor burden or the presence of metastases. Physical examination should focus on the patient’s overall appearance, noting any evidence of weight loss such as redundant skin or muscle wasting, and a complete examination of the head and neck, including evaluation of cervical and supraclavicular lymph nodes and the oropharynx. This is particularly true for patients with a significant tobacco history. The skin should be thoroughly examined. Routine laboratory studies include serum levels of hepatic enzymes (e.g., serum glutamic oxaloacetic transaminase and alkaline phosphatase), as well as those of serum calcium (to detect bone metastases or the ectopic parathyroid syndrome). Elevation of either hepatic enzymes or serum calcium levels typically occurs with extensive metastases. Mediastinal Lymph Nodes. Chest CT scanning permits assessment of possible metastatic spread to the mediastinal lymph nodes. It continues to be the most effective noninvasive method available to assess the mediastinal and hilar nodes for enlargement. However, a positive CT result (i.e., nodal diameter >1.0 cm) predicts actual metastatic involvement in only about 70% of lung cancer patients. Thus even with enlarged mediastinal lymph nodes on a CT scan, up to 30% of such nodes are enlarged from noncancerous reactive causes such as inflammation due to atelectasis or pneumonia secondary to the tumor. Therefore, no patient should be denied an attempt at curative resection just because of a positive CT result for mediastinal lymph node enlargement. Any CT finding of metastatic nodal involvement must be confirmed histologically. The negative predictive value of normal-appearing lymph nodes by CT (lymph nodes <1.0 cm) is better than the positive predictive value of a suspiciousappearing lymph node, particularly with small squamous cell tumors. With normal-size lymph nodes and a T1 tumor, the false-negative rate is less than 10%, leading many surgeons to omit mediastinoscopy. However, the false-negative rate increases to nearly 30% with centrally located and T3 tumors. It has also been demonstrated that T1 adenocarcinomas or large cell carcinomas have a higher rate of early micrometastasis. Therefore, all such patients should undergo mediastinoscopy. Mediastinal lymph node staging by PET scanning appears to have greater accuracy than CT scanning. PET staging of mediastinal lymph nodes has been evaluated in two meta-analyses. The overall sensitivity for mediastinal lymph node metastasis was 79% (95% confidence interval 76%–82%), with a specificity of 91% (95% CI 89%–93%) and an accuracy of 92% (95% CI 90%–94%).35 In comparing PET with CT scans in patients who also underwent lymph node biopsies, PET had a sensitivity of 88% and a specificity of 91%, whereas CT scanning had a sensitivity of 63% and a specificity of 76%. Combining CT and PET scanning may lead to even greater accuracy.36 In one study of CT, PET, and mediastinoscopy in 68 patients with potentially operable NSCLC, CT correctly identified the nodal stage in 40 patients (59%). It understaged the tumor in 12 patients and overstaged it in 16 patients. PET correctly identified the nodal stage in 59 patients (87%). It understaged the tumor in five patients and overstaged it in four. For detecting N2 and N3 disease, the combination of PET and CT scanning yielded a sensitivity, specificity, and accuracy of 93%, 95%, and 94%, respectively. CT scan alone yielded 75%, 63%, and 68%, respectively. Studies examining combined PET-CT consistently show improved accuracy compared to PET or CT alone; accuracy for PET-CT nodal positivity confirmed by mediastinoscopy is approximately 75%, with a negative predictive value of approximately 90%. Right upper lobe lesions were more likely to have occult N2 disease than other lobes of the lung.37-40 PET-positive mediastinal lymph nodes require histologic verification of node positivity, either by EBUS-guided FNA/core-needle biopsy or mediastinoscopy, to minimize the risk of undertreatment. Assuming node positivity without histologic confirmation relegates the patient to, at a minimum, induction chemotherapy. If there is a suggestion of N3 disease, the patient would be incorrectly staged as having IIIB disease and would not be considered a candidate for potentially curative surgical resection. It is important for surgeons who are managing patients with lung cancer to have a clear algorithm for invasive mediastinal staging. In general, invasive staging is underused, placing many patients at risk for over- or understaging and, thus, inappropriate treatment. An absolute indication for obtaining a tissue diagnosis is mediastinal lymph node enlargement greater than 1.0 cm by CT scan. There are several options for invasive mediastinal staging: 1. Less invasive than mediastinoscopy, EBUS enables imageguided transtracheal and transbronchial FNA cytologic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 631 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Some groups advocate use of video-assisted thoracoscopic biopsy as the first option for diagnosis, citing superior diagnostic accuracy and low surgical risk. With VATS, the nodule can be excised with a wedge or segmental resection, if less than 3 cm, or a core-needle biopsy can be performed under direct vision for larger lesions. VATS can also provide valuable staging information, including sampling/dissection of mediastinal lymph nodes and assessing whether the primary tumor has invaded a contiguous structure (such as the chest wall or mediastinum). Lesions most suitable for VATS are those that are located in the outer one third of the lung. The surgeon should avoid direct manipulation of the nodule or violation of the visceral pleura overlying the nodule. In addition, the excised nodule must be extracted from the chest within a bag to prevent seeding of the chest wall. If the patient’s pulmonary reserve is adequate, the surgeon can proceed to lobectomy (either VATS or open) after frozen section diagnosis. A thoracotomy is occasionally necessary to diagnose and stage a primary tumor. Although this occurs rarely, two circumstances may require such an approach: (a) a deep-seated lesion that yielded an indeterminate needle biopsy result or that could not be biopsied for technical reasons; or (b) inability to determine invasion of a mediastinal structure by any method short of palpation. In the circumstance of a deep-seated lesion without a diagnosis, tissue can be obtained via thoracotomy using FNA, core-needle biopsy, or excisional biopsy. Intraoperative frozen-section analysis is required; if the open biopsy frozensection result is indeterminate, a lobectomy may be necessary in extremely rare situations. If a pneumonectomy is required to remove the lesion, a tissue diagnosis of cancer must be made before proceeding. 632 UNIT II PART 2. SPECIFIC CONSIDERATIONS 3. samples from hilar masses and lymph nodes from level 4R and 4L, level 7, level 10, and level 11. A core-needle biopsy device recently became available for the EBUS and will improve the diagnostic yield when sampling mediastinal lymphadenopathy. Rapid onsite pathologic evaluation with expert cytopathologist evaluation greatly increases the diagnostic accuracy of the procedure; importantly, the intraoperative evaluation will confirm whether the target lesion is being sampled and greatly facilitates acquisition of satisfactory samples for determining the morphologic diagnosis as well as sufficient material for cell block for immunohistochemistry and molecular testing. Like mediastinoscopy, EBUS does not allow assessment of level 3, 5, or 6 nodal stations. Endoscopic ultrasound (EUS) can accurately visualize mediastinal paratracheal lymph nodes (stations 4R, 7, and 4L) and other lymph node stations (stations 8 and 9) and is able to visualize primary lung lesions contiguous with or near the esophagus (see Fig. 19-8). Using FNA or core-needle biopsy, samples of lymph nodes or primary lesions can be obtained. Diagnostic yield is improved with intraoperative cytologic evaluation, which can be performed with the cytopathologist in the operating room. Limitations of EUS include the inability to visualize the anterior (pretracheal) mediastinum; thus, EUS does not replace mediastinoscopy for complete mediastinal nodal staging. However, it may not be necessary to perform mediastinoscopy if findings on EUS are positive for N2 nodal disease, particularly if more than one station is found to harbor metastases. Cervical mediastinoscopy provides tissue sampling of all paratracheal and subcarinal lymph nodes and permits visual determination of the presence of extracapsular extension of nodal metastasis (Fig. 19-20). With complex hilar or right paratracheal primary tumors, it allows direct biopsies and assessment of invasion into the mediastinum. When the size of mediastinal lymph nodes is normal, mediastinoscopy is generally recommended for centrally located tumors, for T2 and T3 primary tumors, and occasionally for T1 adenocarcinomas or large cell carcinomas (due to their higher rate of metastatic spread). Some surgeons perform mediastinoscopy in all lung cancer patients because of the poor survival associated with surgical resection of N2 disease. It is important to note that EBUS or EUS can be used for initial diagnosis in enlarged lymph nodes, but the predictive value of a negative EBUS in a patient with radiographically suspicious mediastinal disease is not sufficient to accurately guide treatment. At the authors’ institutions, it is standard to begin mediastinal lymph node staging with EBUS-guided FNA of clinically suspicious mediastinal lymphadenopathy. If the FNA is negative by intraoperative rapid onsite cytologic evaluation, cervical video mediastinoscopy is performed in the same operative setting to ensure accurate staging of the mediastinal nodes. However, if the FNA is positive, mediastinoscopy is not performed and the patient is referred to medical oncology for induction chemotherapy; avoiding a pretreatment mediastinoscopy in this manner facilitates the safe performance of a postinduction mediastinoscopy for restaging of the mediastinum in patients who respond favorably to induction therapy. 4. Left video-assisted thoracoscopic lymph node sampling may be needed for patients with left upper lobe tumors who have localized regional spread to station 5 and 6 lymph nodes, without mediastinal paratracheal involvement (see Fig. 19-8). If there is a low index of suspicion for nodal metastasis, the patient can be schedule for VATS biopsy and lobectomy under the same anesthesia; the procedure begins by sampling the level 5 and 6 nodes for frozen section, and if the nodes are negative, the anatomic lung resection is performed. If the index of suspicion is high, the VATS biopsy is performed as a separate procedure. Cervical mediastinoscopy should precede VATS biopsy, even if patients have normal paratracheal lymph nodes. Additional diagnostic evaluation of the lymph nodes in station 5 and 6 may be unnecessary if the mediastinal lymph nodes are proven to be benign with biopsy during cervical mediastinoscopy and the preoperative CT scan suggests complete respectability of the tumor. There are, however, several indications for prethoracotomy biopsy of station 5 and 6 lymph nodes, which are listed in Table 19-10. It is particularly important to prove that mediastinal lymph nodes are pathologically involved and not just radiographically suspicious for nodal metastasis prior to deciding that the patient is not a candidate for resection. Pleural Effusion. The presence of pleural effusion on radiographic imaging should not be assumed to be malignant. Table 19-10 Indications for prethoracotomy biopsy of station 5 and 6 lymph nodes Figure 19-20. Cervical mediastinoscopy. Paratracheal and subcarinal lymph node tissues (within the pretracheal space) can be sampled using a mediastinoscope introduced through a suprasternal skin incision. 1. Enrollment criteria for induction therapy protocol require pathologic confirmation of N2 disease. 2. Computed tomographic scan shows evidence of bulky nodal metastases or extracapsular spread that could prevent complete resection. 3. Tissue diagnosis of a hilar mass or of lymph nodes causing recurrent laryngeal nerve paralysis is needed. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Pleural effusion may be secondary to atelectasis or consolidation, seen with central tumors, reactive, or secondary to cardiac dysfunction. Pleural effusion associated with a peripherally based tumor, particularly one that abuts the visceral or parietal pleural surface, does have a higher probability of being malignant, which would alter the pathologic stage of the disease to stage IV by the American Joint Committee on Cancer (AJCC) 7th edition TNM staging criteria. If this is the only site concerning for metastatic disease, pathologic confirmation is mandatory. Cytology reveals malignant cells in 50% of malignant effusions. Thoracoscopy, performed as part of a separate staging procedure, often with mediastinoscopy or immediately before a planned thoracotomy, may be needed to rule out pleural metastases in select patients. Tumor, Node, and Metastasis: Lung Cancer Staging. The staging of any tumor is an attempt to estimate the extent of disease and determine the patient’s prognosis; in a given patient, tumors are typically classified into a clinical stage and a pathologic stage. Clinical staging information includes the history and physical examination, radiographic test results, and diagnostic biopsy information. Therapeutic plans are generated based on clinical stage. After surgical resection of the tumor and lymph nodes, a postoperative pathologic stage (pTNM) is determined, providing further prognostic information. The staging of solid epithelial tumors is based on the TNM staging system. The primary tumor “T” status provides information about tumor size and relationship to surrounding structures; the “N” status provides information about regional lymph nodes; and the “M” status provides information about the presence or absence of metastatic disease. The designation of lymph nodes as N1, N2, or N3 requires familiarity with the lymph node mapping system41 (see Fig. 19-8). Based on clearly delineated anatomic boundaries, accurate and reproducible localization of thoracic lymph nodes is possible, which facilitates detailed nodal staging for individual patients and standardization of nodal assessment between surgeons. Pathologic staging criteria are based on the predicted survival relative to each combination of tumor, node, and metasta- A B C Figure 19-21. Imaging of non–small cell lung cancer by integrated positron emission tomography (PET)-computed tomography (CT) scan. A. CT of the chest showing a tumor in the left upper lobe. B. PET scan of the chest at the identical cross-sectional level. C. Coregistered PET-CT scan clearly showing tumor invasion (confirmed intraoperatively). (Reprinted with permission from Lardinois D, Weder W, Hany TF, et al. Staging of non-small–cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003;348:2504. Copyright © 2003 Massachusetts Medical Society.) sis status. In 2010, the AJCC 7th edition incorporated multiple changes into the staging system for NSCLC based on analysis of survival predictors from more than 100,000 patients worldwide. Table 19-11 shows the clinical and pathologic criteria for each VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Distant Metastases. Currently, chest CT and PET are routine in the evaluation of patients with lung cancer. Integrated PET-CT scanners have become standard and have substantially improved accuracy of detection and localization of lymph node and distant metastases, as compared with independently performed PET and CT scans (Fig. 19-21). This technology overcomes the imprecise information on the exact location of focal abnormalities seen on PET and has become the standard imaging modality for lung cancer. Compared to routine chest or abdominal CT and bone scans, PET scanning detects 10% to 15% more distant metastases, but should be confirmed with MRI and/or biopsies if the patient otherwise has early-stage disease. Brain MRI should be performed when the suspicion or risk of brain metastases is increased, such as in patients with clinical stage III disease. In the absence of neurologic symptoms or signs, the probability of a negative head CT scan is 95%. Liver abnormalities that are not clearly simple cysts or hemangiomas and adrenal enlargement, nodules, or masses are further evaluated by MRI scanning and, occasionally, by needle biopsy. Adrenal adenomas have a high lipid content (secondary to steroid production), but metastases and most primary adrenal malignancies contain little if any lipid; thus MRI is usually able to distinguish the two. 633 634 Table 19-11 American Joint Committee on Cancer Seventh Edition Staging of Non–Small Cell Lung Cancer CLINICAL Extent of disease before any treatment Stage Category Definitions UNIT II PART ❑ y clinical–staging completed after neoadjuvant therapy but before subsequent surgery TUMOR SIZE: ———— SPECIFIC CONSIDERATIONS ❑ TX ❑ TO ❑ Tis ❑ T1 ❑ T1a ❑ T1b ❑ T2 ❑ T2a ❑ T2b ❑ T3 ❑ T4 pathologic Extent of disease through completion of definitive surgery LATERALITY: ❑ left ❑ right ❑ bilateral Primary Tumor (T) Primary tumor cannot be assessed No evidence of primary tumor Tis Carcinoma in situ Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)* Tumor ≤2 cm in greatest dimension Tumor > 2 cm but ≤3 cm in greatest dimension Tumor > 3 cm but ≤7 cm or tumor with any of the following features (T2 tumors with these features are classified T2a if ≤5 cm) Involves main bronchus, ≥2 cm distal to the carina Invades visceral pleura (PL1 or PL2) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung Tumor > 3 cm but ≤5 cm in greatest dimension Tumor > 5 cm but ≤7 cm in greatest dimension Tumor > 7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus (< 2 cm distal to the carina* but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a. Regional Lymph Nodes (N) Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension Metastasis in ipsilateral mediastinal and/or subcarinal llymph node(s) Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) Distant Metastasis (M) No distant metastasis (no pathologic MO; use clinical M to complete stage group) Distant metastasis Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion** Distant metastasis ** Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pencardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgement dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as MO. ❑ y pathologic–staging completed after neoadjuvant therapy AND subsequent surgery ❑ TX ❑ TO ❑ Tis ❑ T1 ❑ T1a ❑ T1b ❑ T2 ❑ T2a ❑ T2b ❑ T3 ❑ T4 * ❑ NX ❑ NO ❑ N1 ❑ N2 ❑ N3 ❑ MO ❑ M1 ❑ M1a ❑ M1b VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ ❑ NX ❑ NO ❑ N1 ❑ N2 ❑ N3 ❑ M1 ❑ M1a ❑ M1b 635 Table 19-11 American Joint Committee on Cancer Seventh Edition Staging of Non–Small Cell Lung Cancer (continued) Anatomic stage . prognostic groups CLINICAL PATHOLOGIC T N M ❑ Occult ❑0 ❑ IA TX Tis T1a T1b T2a T2b T1a T1b T2a T2b T3 T1a T1b T2a T2b T3 T3 T4 T4 T1a T1b T2a T2b T3 T4 T4 Any T Any T N0 N0 N0 N0 N0 N0 N1 N1 N1 N1 N0 N2 N2 N2 N2 N1 N2 N0 N1 N3 N3 N3 N3 N3 N2 N3 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b ❑ IB ❑ IIA ❑ IIB ❑ IIIA ❑ IIIB ❑ IV ❑ Stage unknown GROUP T N M ❑ Occult ❑0 ❑ IA TX Tis T1a T1b T2a T2b T1a T1b T2a T2b T3 T1a T1b T2a T2b T3 T3 T4 T4 T1a T1b T2a T2b T3 T4 T4 Any T Any T N0 N0 N0 N0 N0 N0 N1 N1 N1 N1 N0 N2 N2 N2 N2 N1 N2 N0 N1 N3 N3 N3 N3 N3 N2 N3 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b ❑ IB ❑ IIA ❑ IIB ❑ IIIA ❑ IIIB ❑ IV ❑ Stage unknown PROGNOSTIC FACTORS (SITE-SPECIFIC FACTORS) REQUIRED FOR STAGING: None CLINICALLY SIGNIFICANT: Pleural/Elastic Layer Invasion (based on H&E and elastic stains) _________ Separate Tumor Nodules ____________________________ General Notes: For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis. Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source of the material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com. of the TNM descriptors currently used in staging NSCLC and the overall stage classifications. In addition to the TNM stage, it is recommended that histologic grade, presence or absence of pleural/elastic layer invasion, separate tumor nodules, lymphovascular invasion, and residual tumor after treatment also be recorded into cancer registries to facilitate evaluation of these potential predictors in future analysis of staging criteria. Staging for small cell lung cancer (SCLC) is typically based on the extent of disease. SCLC presenting with bulky locoregional disease confined to the ipsilateral hemithorax, with no evidence for distant metastatic disease, is termed “limited” SCLC. Limited disease must be treatable within a tolerable field of radiation. Using AJCC descriptors, this includes any T stage, any N stage, without metastatic disease (M0). The only exception is when multiple lung nodules are widely spread throughout the ipsilateral lung in the same hemithorax; in these patients, the size of the involved area would preclude a “safe” radiation field. In contrast, in “disseminated” disease, tumor is beyond the ipsilateral hemithorax or widely spread within the ipsilateral lung and to distant sites. Metastases to the pleura and pericardium, with resultant effusions, are considered disseminated disease. Metastases to brain, bone, bone marrow, and the pleural and pericardial spaces are common. Assessment of Functional Status. Patients with potentially resectable tumors require careful assessment of their functional status and ability to tolerate either lobectomy or pneumonectomy. The surgeon should first estimate the likelihood VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura GROUP UNIT II PART SPECIFIC CONSIDERATIONS of pneumonectomy, lobectomy, or possibly sleeve resection, based on the CT images. A sequential process of evaluation then unfolds. A patient’s history is the most important tool for gauging risk. Specific questions regarding performance status should be routinely asked. If the patient can walk on a flat surface indefinitely, without oxygen and without having to stop and rest secondary to dyspnea, he will be very likely to tolerate lobectomy. If the patient can walk up two flights of stairs (up two standard levels), without having to stop and rest secondary to dyspnea, she will likely tolerate pneumonectomy. Finally, nearly all patients, except those with carbon dioxide (CO2) retention on arterial blood gas analysis, will be able to tolerate periods of single-lung ventilation and wedge resection. Current smoking status and sputum production are also pertinent. Current smokers and patients with a greater than 60 pack-year history of smoking have a significantly increased risk of postoperative pulmonary complications; heavy smokers are 2.5 times more likely to develop pulmonary complications and three times more likely to develop pneumonia compared to patients with a ≤60 pack-year history (odds ratio [OR] 2.54; 95% CI 1.28–5.04; P = .0008). Impaired exchange of CO2 is also predictive of increased risk, independent of the smoking history. For every 10% decline in percent carbon monoxide diffusion capacity (%Dlco), the risk of any pulmonary compliincreased by 42% (OR 1.42; 95% CI 1.16–1.75; 6 cation P = .008).42 Risk reduction requires smoking cessation at least 8 weeks preoperatively, a requirement that is often not feasible in a cancer patient. Nevertheless, abstinence for at least 2 weeks before surgery should be encouraged. Smoking cessation on the day of surgery leads to increased sputum production and potential secretion retention postoperatively, and some authors have reported increased rates of pulmonary complications in this group.43 Patients with chronic daily sputum production will have more problems postoperatively with retention and atelectasis; they are also at higher risk for pneumonia. Sputum culture, antibiotic administration, and bronchodilators may be warranted preoperatively. Pulmonary function studies are routinely performed when any resection greater than a wedge resection will be performed. Of all the measurements available, the two most valuable are forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusion capacity (Dlco). General guidelines for the use of FEV1 in assessing the patient’s ability to tolerate pulmonary resection are as follows: greater than 2.0 L can tolerate pneumonectomy, and greater than 1.5 L can tolerate lobectomy. It must be emphasized that these are guidelines only. It is also important to note that the raw value is often imprecise because normal values are reported as “percent predicted” based on corrections made for age, height, and gender. For example, a raw FEV1 value of 1.3 L in a 62-year-old, 75-inch male has a percent predicted value of 30% (because the normal expected value is 4.31 L); in a 62-year-old, 62-inch female, the predicted value is 59% (normal expected value 2.21 L). The male patient is at high risk for lobectomy, while the female could potentially tolerate pneumonectomy. To calculate the predicted postoperative value for FEV1 or Dlco, the percent predicted value of FEV1 or Dlco is multiplied by the fraction of remaining lung after the proposed surgery. For example, with a planned right upper lobectomy, a total of three segments will be removed. Therefore, three of a total 20 segments will leave the patient with (20 – 3/20) × 100 = 85% 50 40 Percent mortality 636 30 20 10 0 20 30 40 50 60 70 ppoDLCO% 80 90 100 Figure 19-22. Operative mortality after major pulmonary resection for non–small cell lung cancer (334 patients) as a function of percent predicted postoperative carbon monoxide diffusion capacity (ppoDlco%). Solid line indicates logistic regression model; dashed lines indicate 95% confidence limits. (Adapted with permission from Wang J, Olak K, Ferguson M. Diffusing capacity predicts operative mortality but not long-term survival after resection for lung cancer. J Thorac Cardiovasc Surg. 1999;117:582. Copyright Elsevier.) of their original lung capacity. In the two patients mentioned earlier, the man will have a predicted postoperative FEV1 of 30% × 0.85 = 25%, whereas the woman will have a predicted postoperative FEV1 of 50%. Percent predicted value of less than 50% for either FEV1 or Dlco correlates with risk for postoperative complications, particularly pulmonary complications; the risk of complications increases in a stepwise fashion for each 10% decline. Figure 19-22 shows the relationship between predicted postoperative Dlco and estimated operative mortality. Quantitative perfusion scanning is used in select circumstances to help estimate the functional contribution of a lobe or whole lung. Such perfusion scanning is most useful when the impact of a tumor on pulmonary physiology is difficult to discern. With complete collapse of a lobe or whole lung, the impact is apparent, and perfusion scanning is usually unnecessary. Figure 19-23 shows a tumor with significant right main stem airway obstruction with associated atelectasis and volume loss of the right lung. At presentation, the patient was dyspneic with ambulation, and the FEV1 was 1.38 L. Six months prior, this patient could walk up two flights of stairs without dyspnea. The surgeon can anticipate that the patient will tolerate pneumonectomy because the lung is already not functioning due to main stem airway obstruction, and may, in fact, be contributing to a shunt. However, with centrally located tumors associated with partial obstruction of a lobar or main bronchus or of the pulmonary artery, perfusion scanning may be valuable in predicting the postoperative result of resection. For example, if the quantitative perfusion to the right lung is measured to be 21% (normal is 55%) and the patient’s percent predicted FEV1 is 60%, the predicted postoperative FEV1 after a right pneumonectomy would be 60% × 0.79 = 47%, indicating the ability to tolerate pneumonectomy. If the perfusion value is 55%, the predicted VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 637 postoperative value would be 27%, and pneumonectomy would pose a significantly higher risk. It is not uncommon to encounter patients with significant reductions in their percent predicted FEV1 and Dlco whose history shows a functional status that is inconsistent with the pulmonary function tests. In these circumstances, . exercise testing that yields maximal oxygen consumption (Vo2 max) has emerged as a valuable decision-making technique to help patients with abnormal FEV1 and Dlco (Table 19-12). Values of less than 10 mL/kg/min are associated with a 26% mortality after major pulmonary resection compared to only 8.3% 7 with V.o2 max ≥10 mL/kg/min. Values greater than 15 mL/ kg/min generally indicate the patient’s ability to tolerate pneumonectomy. The risk assessment of a patient is an amalgam of clinical judgment and data. The risk assessment described earlier must be integrated with the experienced clinician’s sense of the 8 patient and with the patient’s attitude toward the disease and toward life. Figure 19-24 provides a useful algorithm for determining suitability for lung resection.44 Lung Cancer Treatment is the current standard, ideally accomplished by video-assisted lobectomy or pneumonectomy, depending on the tumor location. Despite the term “early-stage,” the overall 5-year survival rate for stage I is 65% and only 41% for stage II. Median survival Table 19-12 . Relation between maximum oxygen consumption (Vo2 max) as determined by preoperative exercise testing and perioperative mortality Study . V o2 max 10–15 mL/kg per minute Smith et al196 1/6 (33%) Bechard and Wetstein 0/15 (0%) Olsen et al 1/14 (7.1%) 197 198 Walsh et al199 1/5 (20%) Bolliger et al 2/17 (11.7%) Markos et al 1/11 (9.1%) Wang et al202 0/12 (0%) Win et al 2/16 (12.5%) 200 201 Grade IV NEC (Small Cell) Lung Carcinoma. In rare circumstances where SCLC presents as an isolated lung lesion, lobectomy followed by chemotherapy is warranted after surgical mediastinal staging has confirmed the absence of N2 disease. Often, ultrasound-guided FNA provides a definitive positive diagnosis and more invasive approaches are not needed. However, less than 5% are stage I, and there is no benefit from surgical resection for more advanced-stage disease; treatment is chemotherapy with or without radiation therapy depending on the extent of disease and the patient performance status. Deaths/Total 203   Total . V o2 max <10 mL/kg per minute 8/96 (8.3%) Bechard and Wetstein197 2/7 (29%) Olsen et al198 3/11 (27%) Holden et al 2/4 (50%) 204 Markos et al 201 0/5 (0%) Early-Stage Non–Small Cell Lung Cancer. Early-stage disease   Total includes T1 and T2 tumors (with or without N1 nodal involvement) and T3 tumors (without N1 nodal involvement). This group represents a small but increasing proportion of the total number of patients diagnosed with lung cancer each year (approximately 20% of 101,844 patients from 1989 to 2003).45 Surgical resection Source: Reproduced with permission from the American College of Chest Physicians from Colice GL, et al: Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP Evidence-based Clinical Practice Guidelines. (2nd edition) Chest. 2007;132:161S. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 7/27 (26%) CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Figure 19-23. Chest computed tomography scan of an obstructing right main stem lung tumor. Arrow indicates location of right main bronchus. The right lung volume is much less than the left lung volume. 638 Perform spirometry FEV1 >1.5 L lobectomy FEV1 >2 L pneumonectomy FEV1 >80% predicted FEV1 <1.5 L lobectomy FEV1 <2 L pneumonectomy FEV1 <80% predicted UNIT II PART SPECIFIC CONSIDERATIONS Unexplained dyspnea or diffuse parenchymal disease on CXR/CT? No Yes Measure DLCO DLCO >80% predicted Estimate %ppo FEV1 and %ppo DLCO DLCO <80% predicted %ppo FEV1 and %ppo DLCO >40 %ppo FEV1 or %ppo DLCO <40 %ppo FEV1 <30 or %ppo FEV1 x %ppo DLCO <1650 Perform CPET VO VO22max max > >15 15 mL/kg/min ml/kg/min Average risk VO2max 10 to 15 mL/kg/min Increased risk VO2max <10 mL/kg/min Increased risk Figure 19-24. Algorithm for preoperative evaluation of pulmonary function and reserve prior to resectional lung surgery. CPET = cardiopulmonary exercise test; CT = computed tomographic scan; CXR = chest radiograph; Dlco =. carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second; %ppo = percent predicted postoperative lung function; Vo2 max = maximum oxygen consumption. (Reproduced with permission from the American College of Chest Physicians from Colice GL, et al: Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP Evidence-based Clinical Practice Guidelines. (2nd edition) Chest. 2007;132:161S.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Management of Early-Stage Lung Cancer in the High-Risk Patient. Lobectomy may not be an option for some patients with early-stage disease, due to poor cardiopulmonary function or other comorbid illnesses. The ultimate decision that a patient is not operable, both with regard to the ability of the patient to tolerate surgery and the likelihood of successful resection, should be accepted only after evaluation by an expert surgeon. Surgeons with limited expertise, when faced with a complicated patient, should refer the patient to a high-volume center for further evaluation if they are unable to offer the patient surgical resection in their own center. Rationale for Limited Resection in Early-Stage Lung Cancer. Limited resection, defined as segmentectomy or wedge resection, is a viable option for achieving local control in high-risk patients. Historically, limited resection with wedge or segmentectomy has been considered a compromise operation due to unacceptably high rates of local recurrence and concerns for worse survival.47,48 Subsequent meta-analysis of the literature shows that the difference in death rate is likely negligible49 (Table 19-13). The high rates of local recurrence demonstrated by Ginsberg and others, however, remain a significant concern and continue to restrict the use of limited resection for earlystage lung cancer to the high-risk patient. With the recent publication of a 20% reduction in lung cancer mortality with screening CT scans in high-risk populations, the topic of limited resection is again the subject of intensive review. Studies investigating anatomic segmentectomy (or extended wedge resection) with hilar and mediastinal lymph node dissection suggest that close attention to the ratio of surgical margin to tumor diameter and a careful assessment of the lymph nodes substantially reduce local recurrence.50-52 Recurrence rates were 6.2%, comparable to rates associated with lobectomy, when the margin-to-tumor diameter ratio exceeded 1, compared to 25% if the margin-to-tumor diameter ratio was less than 1.50 In most centers, this requires use of a thoracotomy, although increasing experience with VATS in high-volume centers shows that limited resection is safe and feasible, with perioperative adverse outcomes that are comparable to lobectomy.52-55 Rationale for Tumor Ablation in the Management of Primary Lung Cancer. Limited resection, by definition, requires that the patient has sufficient cardiopulmonary reserve to undergo a general anesthesia and loss of at least one pulmonary segment. For the high-risk or nonoperable patient, as determined by experience pulmonary surgeons, tumor ablation techniques have been developed for treatment of early-stage lung cancers. Current limitations of this approach include the absence of nodal staging, lack of tissue for molecular profiling, chemoresistance, or sensitivity testing, concerns about definitions of locoregional recurrence, and a lack of uniformity across centers. Surgeons typically define locoregional recurrence as tumor growth within the operative field, including resectable lymph nodes, whereas local recurrence after ablation is most commonly defined as tumor growth within the field of treatment. Despite the fact that in-transit or lymph node metastases are present in up to 27% of clinically stage I NSCLCs at resection, any tumor growth outside the field of ablative treatment is not be considered treatment failure.56 Despite these limitations, tumor ablative strategies are increasingly proposed as viable alternatives to surgical resection, even in potentially operable patients.57-62 While premature, ablative techniques may ultimately be shown to have efficacy equivalent to lobectomy for the primary treatment of very small peripheral early-stage lung cancers. Multidisciplinary collaboration between thoracic surgery, interventional radiology/ pulmonology, and radiation oncology is required to ensure that development of these ablative techniques occurs through 9 properly designed and well-controlled prospective studies and will ensure that patients receive the best available therapy, regardless of whether it is surgical resection or ablative therapy. The two most commonly applied ablation techniques are radiofrequency ablation and stereotactic body radiotherapy. Radiofrequency ablation. Radiofrequency ablation is performed using either monopolar or bipolar delivery of electrical current to electrodes placed within the tumor tissue. In lung tumors, the electrodes are typically inserted into the tumor mass under CT guidance. An electrical current is delivered; the current is converted by means of friction into heat, which quickly leads to immediate and irreparable tissue destruction in the tissue surrounding the electrode. The efficacy of radiofrequency ablation for controlling the primary tumor and improving survival in poor operative candidates (either due to significant comorbid diseases precluding general anesthesia or poor pulmonary function excluding lung resection) is safe and feasible for peripheral lung nodules. In tumors <3.5 cm, the rate of radiographic resolution of tumor is up to 80% and cancer-specific survival at 2 years was approximately 90%, indicating excellent local control of the primary site.57-59,63 It has become the preferred modality for small peripheral tumors over standard external-beam radiation in centers where the technique is available.   Radiofrequency ablation is an excellent modality for the patient at risk for adverse outcomes with pulmonary resection or for patients who refuse surgery, and surgeons should have an algorithm for determining which patients are optimal for this modality.64-69 (see Fig. 19-24). Target lesions larger than 5 cm, tumor abutting the hilum, associated malignant pleural or pericardial effusion, greater than three lesions in one lung, and the presence of pulmonary hypertension are all contraindications to radiofrequency ablation.64 Proximity to a large vessel is a contraindication not only due to the risk of massive bleeding, but also 1. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 639 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura for untreated patients with stage IA NSCLC is 14 months, and 5-year survival rate is 22%.46 After surgical resection of postoperative pathologic stage IA disease, 5-year survival is better than with no treatment, but still only 67%.41 Survival declines with higher stages. Advanced age at diagnosis, male sex, low socioeconomic status, nonsurgical treatment, and poor histologic grade are associated with increased mortality risk on multivariate analysis.45 Depending on tumor size and location, lobectomy, sleeve lobectomy, and occasionally pneumonectomy, with mediastinal lymph node dissection or sampling, are appropriate for patients with clinical early-stage disease. Sleeve resection is performed for tumors located at airway bifurcations when an adequate bronchial margin cannot be obtained by standard lobectomy. Pneumonectomy is rarely performed; primary indications for pneumonectomy in early-stage disease include large central tumors involving the distal main stem bronchus and inability to completely resect involved N1 lymph nodes. The latter circumstance occurs with bulky adenopathy or with extracapsular nodal spread. 640 Table 19-13 Summary of studies comparing limited resection and lobectomy Study Design Stage No. of Limited Resections No. of Reasons for Limited Lobectomies Resection Survival Difference Hoffman and Ransdell (1980)70 RS IA 33 (W) 40a Poor cardiopulmonary function and smaller lesions NS Read et al (1990)71 RS IA 113 (107 S + 6 W) 131 ND NS (CSS) UNIT II PART Date et al (1994)72 MPS IA 16 (6 S + 10 W) 16 Poor pulmonary function Lobectomy better Warren and Faber (1994)48 RS IA + IB 66 (S) 103 Poor cardiopulmonary function and smaller lesions Lobectomy better SPECIFIC CONSIDERATIONS Harpole et al (1995)73 RS IA + IB 75 (W) 193 Poor cardiopulmonary function and smaller lesions NS (CSS) LCSG (1996)47, 74 RCT IA 122 (82 S + 40 W) 125 Randomization NS Kodama et al (1997)75 RS IA 46b (W) 77 Intentional resection for NS small lesions Landreneau et al (1997)76 RS IA 102 (W) 117 Poor cardiopulmonary function NS Pastorino et al (1997)77 RS IA + IB 53 (S + W) 367 ND NS Kwiatkowski et al (1998)78 RS IA + IB 58 (S + W) 186 ND Lobectomy better Okada et al (2001)79 RS IA ≤2 cm 70 (S) 139 Intentional resection for NS small lesions ≤2 cm Koike et al (2003)80 RS IA ≤2 cm 74 (60 S + 14 W) 159 Intentional resection for NS small lesions ≤2 cm IA 21 (S) 100 Poor cardiopulmonary function NS IA + IB 54 (S) 147 Poor pulmonary function NS Study Campione et al (2004)81 RS Keenan et al (2004)82 RS c Tumors peripherally located. Only intentional resection. c Including 13 pneumonectomies. CSS = cancer-specific survival; LCSG = Lung Cancer Study Group; MPS = matched-pair study; ND = not described; NS = not significant; RCT = randomized controlled trial; RS = retrospective study; S = segmentectomy; W = wedge resection. Source: Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Nakamura H, Kawasaki N, Taguchi M, et al. Survival following lobectomy vs limited resection for stage I lung cancer: a meta-analysis. Br J Cancer. 2005;92:1033. Copyright © 2005. a b 2. because large blood vessels act as a heat sink and lethal cellular temperatures are less likely to be achieved. For these patients, stereotactic body radiotherapy may provide local tumor control with less risk of major complications. Combination therapy with either external-beam radiation or stereotactic body radiotherapy is also under investigation. Stereotactic body radiotherapy. Stereotactic body radiotherapy applies highly focused, high-intensity, threedimensional conformal radiation to the target lesion over a few sessions. Tumor motion quantification and image guidance technologies have significantly improved the delivery of radiation with high levels of precision to the target lesion. This accuracy is important because the lung is extremely sensitive to radiation injury and the majority of patients with early-stage lung cancer who are currently considered candidates for ablative therapy have marginal lung function; excessive injury to normal surrounding lung tissue is not desirable. Importantly, these techniques allow the safe delivery of up to 66 Gy of radiation to the target tumors without exceeding the maximum-tolerated dose.62,83 A phase II North American multicenter study recently demonstrated the safety and efficacy of this approach in 59 nonoperable patients.62 Patients with biopsy-proven, nodenegative peripheral NSCLCs less than 5 cm in diameter (T1 or T2) were treated with stereotactic body radiotherapy after they were deemed inoperable, based on coexisting medical conditions, by a thoracic surgeon and/or pulmonologist. Primary tumor control was excellent; at 3 years, 97.6% were deemed to have primary tumor control by the authors and 90.6% had local control. However, it is important VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Rationale for Chemotherapy in the Management of EarlyStage NSCLC. The role of chemotherapy in early-stage (stage I and II) NSCLC is evolving, with several prospective phase II studies having shown a potential benefit.84,85 Initial concerns that induction chemotherapy may result in increased perioperative morbidity or mortality appear to be unwarranted, as the incidence of perioperative morbidity and mortality is not different between the two groups, except in patients undergoing right-sided pneumonectomy after induction chemotherapy.86 As shown in Table 19-14, an absolute survival benefit of 4% to 7% can be realized using induction for all stages of lung cancer, and in situations where use of adjuvant chemotherapy is anticipated, induction chemotherapy is an acceptable alternative. Table 19-14 Five-year stage-specific survival after induction chemotherapy followed by surgery Stage 5-Year Survival (%) Absolute Benefit (%) New 5-Year Survival (%) IA 75 4 79 IB 55 6 61 IIA 50 7 57 IIB 40 7 47 IIIA 15–35 6–7 21–42 IIIB 5–10 3–5 8–15 Source: Reproduced with permission from Burdett SS, Stewart LA, Rydzewska L. Chemotherapy and surgery versus surgery alone in nonsmall cell lung cancer. Cochrane Database Syst Rev. 2007:CD006157. John Wiley & Sons, Ltd. Copyright Cochrane Collaboration. National Comprehensive Cancer Network guidelines currently recommend observation for T1a (≤2 cm) and T1b (>2–≤3 cm), node-negative, completely resected NSCLCs (T1abN0M0). For patients with larger tumors (T2a tumor >3 cm but ≤5 cm; T2b tumor >5 cm but ≤7 cm) that are node-negative, it is recommended that chemotherapy be considered in high-risk patients, ideally in the setting of a clinical trial. High-risk tumor characteristics include poorly differentiated tumors, moderately to poorly differentiated lung neuroendocrine tumors, vascular invasion, resection limited to wedge resection only, tumors >4 cm in size, visceral pleural involvement, and when lymph node sampling at the time of resection was incomplete (Nx). Evaluation and Management of Locally Advanced NSCLC. Five-year relative survival in patients with locoregional disease is 25%, but there is significant heterogeneity within the group. Stage III disease includes patients with small tumors that have metastasized to the mediastinal lymph nodes as well as large tumors invading unresectable structures or the major carina with no nodal metastasis at all. Patients with clinically evident N2 disease (i.e., bulky adenopathy present on CT scan or mediastinoscopy, with lymph nodes often replaced by tumor) have a 5-year survival rate of 5% to 10% with surgery alone. In contrast, patients with microscopic N2 disease discovered incidentally in one lymph node station after surgical resection have a 5-year survival rate that may be as high as 30%. As a result, many surgeons and oncologists differentiate between microscopic and bulky N2 lymphadenopathy and the number of involved N2 nodal stations in determining whether to proceed with resection following induction therapy. It is generally accepted that surgical resection is appropriate for patients with a single-station metastasis with a single lymph node smaller than 3 cm, although randomized trials specifically investigating resection following induction therapy for patients with singlestation microscopic disease have not yet been performed. Histologic confirmation of N2 nodal metastases is imperative; false-positive findings on PET scan are unacceptably high, and reliance on this modality will lead to significant undertreatment of patients with earlier stage cancers. This is particularly true in regions with high incidence of granulomatous diseases. When N2 nodes are found, incidentally, to harbor metastasis at the time of planned anatomic lung resection, the decision to proceed with resection varies depending on surgeon preference; it is acceptable to either proceed with anatomic resection and mediastinal lymph node sampling/dissection or to stop the procedure, refer the patient for induction therapy, and re-evaluate for resection after induction therapy is completed. When histologically confirmed metastases are found during preoperative staging evaluation, patients should be referred for induction chemotherapy; patients in whom the mediastinal nodes are sterilized by induction therapy have a better prognosis, and surgical resection is generally warranted as part of a multimodal approach. As with preinduction evaluation, histologic confirmation of persistent N2 disease after induction therapy is imperative; patients should not be denied surgical resection following induction chemotherapy based on radiographic evidence for N2 disease because the survival for resected NSCLC is significantly better than with definitive chemotherapy. Surgery in T4 and Stage IV Disease. Surgery is occasionally appropriate for highly selected patients with tumors invading the SVC, carinal or vertebral body involvement, or satellite nodules in the same lobe (T3, N0-1, M0) or in T4, N0-1 tumors VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 641 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura to note that primary tumor failure was defined specifically as at least a 20% increase in the longest diameter of the gross tumor volume by CT scan and evidence of tumor viability either by biopsy confirming carcinoma or by demonstration of FDG avidity on PET scan. For viability to be confirmed with PET scan, the uptake was required to be of similar intensity to the pretreatment staging PET scan. Failure beyond a 1.5- to 2-cm margin around the primary tumor volume was considered local failure. Failure in regional node basins was seen in two patients. When compared to locoregional control rates of approximately 6.5% with limited resection, the 3-year locoregional recurrence was higher at 12.8%.   Patient selection for stereotactic body radiotherapy, as with limited resection and radiofrequency ablation, is important. Because the radiation field is so precise, patients with severe emphysema and chronic obstructive pulmonary disease can be safely treated without significant concern for worsening lung function. However, patients with central tumors near the mediastinum and hilum have increased incidence of significant hypoxia, hemoptysis, atelectasis, pneumonitis, and reduced pulmonary function.83 In the multicenter trial detailed earlier, treated tumors were required to be greater than 2 cm from the proximal bronchial tree in all directions (which they defined as the distal 2 cm of the trachea, carina, and named major lobar bronchi up to their first bifurcation).62 642 UNIT II PART SPECIFIC CONSIDERATIONS with limited invasion into the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina through direct extension. Surgery generally does not have a role in the care of patients with any tumor with N3 disease or T4 tumors with N2 disease. Survival rates remain extremely low for these patients. Simlarly, the treatment of patients with stage IV disease is chemotherapy. However, on occasion, patients with a single site of metastasis are encountered, particularly with adenocarcinomas presenting with a solitary brain metastasis. In this highly select group, 5-year survival rates of 10% to 15% can be achieved with surgical excision of the brain metastasis and the primary tumor, assuming it is early stage. Surgery for Management of Pancoast’s Tumor. Carcinoma arising in the extreme apex of the chest with associated arm and shoulder pain, atrophy of the muscles of the hand, and Horner’s syndrome presents a unique challenge to the surgeon. Any tumor of the superior sulcus, including tumors without evidence for involvement of the neurovascular bundle, is now commonly known as Pancoast’s tumors, after Henry Pancoast who described the syndrome in 1932. The designation is reserved for tumors involving the parietal pleura or deeper structures overlying the first rib. Chest wall involvement at or below the second rib is not a Pancoast’s tumor.74 Treatment is multidisciplinary; due to the location of the tumor and involvement of the neurovascular bundle that supplies the ipsilateral extremity, preserving postoperative function of the extremity is critical. For this reason, resection should only be performed in patients who are proven negative for mediastinal lymph node involvement. Survival with N2 positive nodes is poor, and the morbidity and mortality associated with surgical resection are high. If bulky lymphadenopathy is present, EBUS- or EUS-guided FNA/coreneedle biopsy may prove nodal involvement. However, a negative FNA is not sufficient for proving the absence of mediastinal involvement and should be followed by mediastinoscopy to ensure accurate and complete evaluation of the mediastinum. Because Pancoast’s tumors have high rates of local recurrence and incomplete resection, induction chemoradiotherapy followed by surgery is recommended. This treatment regimen was well tolerated in a study performed by the Southwest Oncology Group, with 95% of patients completing induction treatment. Complete resection was achieved in 76%. Five-year survival was 44% overall and 54% when complete resection was achieved. Disease progression with this regimen was predominantly at distant sites, with the brain being the most common.75 The current treatment algorithm for Pancoast’s tumors is presented in Fig. 19-25. Surgical excision is performed via thoracotomy with en bloc resection of the chest wall and vascular structures and anatomic lobectomy. A portion of the lower trunk of the brachial plexus and the stellate ganglion are also typically resected. With chest wall involvement, en bloc chest wall resection, along with lobectomy, is performed, with or without chest wall reconstruction. Initial evaluation, biopsy and staging CT chest/upper abdomen MRI/MRA of vessels/brachial plexus Mediastinoscopy Brain CT or MRI and PET scan Confirm T3–4, N0-1 M0 NSCLC No evidence for metastatic or N2 nodal disease Assess performance status: performance score, cardiopulmonary reserve, renal function and neurologic function Metastatic disease or N2 nodal disease Definitive chemoradiotherapy Poor performance status Good to excellent performance status Concurrent induction chemotherapy (Cisplatin/Etoposide) And radiotherapy: 45 Gy over 5 weeks Reassessment performance score, physiologic reserve, tumor response Radiographic evaluation: CT scans of the chest, upper abdomen, and brain. PET scan for metastases Tumor stable/regression; good to excellent performance status Tumor progression or poor performance status Additional chemotherapy as tolerated Thoracotomy, en bloc chest wall resection, lobectomy, chest wall with reconstruction Figure 19-25. Treatment algorithm for Pancoast’s tumors. CT = computed tomography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; NSCLC = non–small cell lung cancer; PET = positron emission tomography. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 1. 2. 3. 4. 5. 6. 7. The tumor’s blood supply is still intact, allowing better chemotherapy delivery and avoiding tumor cell hypoxia (in any residual microscopic tumor remaining postoperatively), which would increase radioresistance. The primary tumor may be downstaged, enhancing resectability. Patients are better able to tolerate chemotherapy before surgery and are more likely to complete the prescribed regimen than after surgery. It functions as an in vivo test of the primary tumor’s sensitivity to chemotherapy. Response to chemotherapy can be monitored and used to guide decisions about additional therapy. Systemic micrometastases are treated. It identifies patients with progressive disease/non-responders and spares them a pulmonary resection. Potential disadvantages include: 1. 2. There is a possible increase in the perioperative complication rate in patients requiring right pneumonectomy after induction chemotherapy. While the patient is receiving chemotherapy, potentially curative resection is delayed; if the patient does not respond, this delay could result in tumor spread. In stage IIIA N2 disease, the response rates to induction chemotherapy are high, in the range of 70%. The treatment is generally safe, as it does not cause a significant increase in perioperative morbidity. Two randomized trials have now compared surgery alone for patients with N2 disease to preoperative chemotherapy followed by surgery. Both trials were stopped before complete accrual because of a significant increase in survival for the chemotherapy arm. The initially observed survival differences have been maintained for up to 3 years and beyond (5-year data not shown). Given these results, induction chemotherapy with cisplatin-based regimens (two to three cycles) has become standard for patients with N2 disease. Table 19-15 summarizes the findings of a systematic review and meta-analysis reporting response rates, progression-free survival, and overall survival after induction chemotherapy followed by surgical resection. Postoperative (Adjuvant) Chemotherapy for NSCLC. Postoperative adjuvant chemotherapy was previously thought to confer no benefit based on multiple prospective randomized trials, in part because patients who had undergone thoracotomy and lung resection had difficulty tolerating the adjuvant regimens. More recently, however, newer, more effective agents have shown promise and adjuvant therapy is better tolerated after minimally invasive lung resection (i.e., VATS or robotic anatomic resection). Targeted therapies, which have been shown to be beneficial in advanced-stage lung cancer, are of particular interest. Any patient with nodal metastasis (N1 or N2) or with T3 tumors (defined as tumors >7 cm; invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or main bronchus tumor <2 cm distal to the carina; causing atelectasis or obstructive pneumonitis; or with separate nodules in the same lobe of the lung) should receive adjuvant chemotherapy if they are able to tolerate the regimens. In the situation where the margins of resection are positive, re-resection is recommended. If not possible, concurrent chemoradiation is recommended for macroscopic residual tumor and sequential chemoradiation for microscopic residual tumor. Definitive Nonsurgical Treatment for NSCLC. Recent advances in targeted therapies have changed the management of advanced NSCLC from a generalized, platinum-based approach to one in which molecular analysis and targeted, personalized therapies are now standard of care. It is now mandatory that the pathologist clearly differentiate between squamous cell carcinoma and adenocarcinoma because the therapeutic options are different and use of bevacizumab, while beneficial in patients with adenocarcinoma, has been found to cause excessive pulmonary hemorrhage in patients with squamous histology. For the surgeon, this requirement translates into a much more aggressive approach to tissue diagnosis. At our institution, the cytopathologist provides onsite rapid assessment of the fine-needle aspirate to determine whether tumor cells are present and confirm that sufficient tumor cells are present to enable molecular testing. This has increased the number of passes performed during an EBUS-guided FNA or during CT-guided aspiration of a pulmonary or intrathoracic lesion; typically, an additional two passes are made for cell block material after confirming the presence of tumor cells in the target area. When insufficient cells are obtained for molecular testing, despite having a diagnosis, additional sampling is warranted; this is mandatory in patients with adenocarcinoma and likely to become necessary for other non–small cell histologic types as advances in targeted therapies become available for clinical use. Acquiring adequate tissue for diagnosis may require mediastinoscopy or VATS; close communication between the oncologist, surgeon, pathologist, and patient is needed to ensure that the benefits to the patient clearly outweigh the risks and that results obtained through more aggressive diagnostic measures are needed to direct subsequent care. Once a treatment plan has been devised, two strategies for delivery are available. “Sequential” chemoradiation involves full-dose systemic chemotherapy (i.e., cisplatin combined with a second agent) followed by standard radiotherapy (approximately 60 Gy). The combination of chemotherapy followed by radiation has improved 5-year survival from 6% with radiotherapy alone to 17%.89 An alternative approach, referred to as “concurrent chemoradiation,” administers chemotherapy and radiation at the same time. Certain chemotherapeutic agents sensitize tumor cells to radiation and, thus, enhance the radiation effect. The advantages of this approach are improved primary tumor and locoregional lymph node control and elimination of the delay in administering radiotherapy that occurs with sequential treatment. A disadvantage, however, is the necessary reduction in chemotherapy dosage in order to diminish overlapping toxicities; this can potentially lead to undertreatment of systemic micrometastases. Randomized trials have shown a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 643 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura For small rib resections or those posterior to the scapula, chest wall reconstruction is usually unnecessary. Larger defects (two rib segments or more) are usually reconstructed with Gore-Tex to provide chest wall contour and stability. En bloc resection is also used for other locally advanced tumors (T3) with direct invasion of the adjacent chest wall, diaphragm, or pericardium. If a large portion of the pericardium is removed, reconstruction with thin Gore-Tex membrane will be required to prevent cardiac herniation and venous obstruction. Preoperative (Induction) Chemotherapy for NSCLC. The use of chemotherapy before anatomic surgical resection has a number of potential advantages: UNIT II PART 644 SPECIFIC CONSIDERATIONS Table 19-15 Selected randomized trials of neoadjuvant chemotherapy for stage III non–small cell lung cancer Trial (Reference) No. of Patients (Stage III) Chemotherapy Response Rate (%) pCR (%) Complete Resection PFS OS 5-Year Survival Rosell et al 60 (60) Mitomycin Ifosfamide Cisplatin 60 4 85% 12 vs. 5 mo (DFS; P = .006) 22 vs. 10 mo (P = .005) 16% vs. 0% Roth et al90 60 (60) Cyclophosph amide Etoposide Cisplatin 35 NR 39% vs. 31% Not reached vs. 9 mo (P = .006) 64 vs. 11 mo (P = .008) 56% vs. 15%a Pass et al91 27 (27) Etoposide Cisplatin 62 8 85% vs. 86% 12.7 vs. 5.8 mo (P = .083) 28.7 vs. 15.6 mo (P = .095) NR Nagai et al92 62 (62) Cisplatin Vindesine 28 0 65% vs. 77% NR 17 vs. 16 mo (P = .5274) 10% vs. 22% Gilligan et al93 519 (80) Platinum basedb 49 4 82% vs. 80% NR 54 vs. 55 mo (P = .86) 44% vs. 45% Depierre et al 355 (167) Mitomycin Ifosfamide Cisplatin 64 11 92% vs. 86% 26.7 vs. 12.9 mo (P = .033) 37 vs. 26 mo (P = .15) 43.9% vs. 35.3%c Pisters et al95 354 (113)d Carboplatin Paclitaxel 41 NR 94% vs. 89% 33 vs. 21 mo (P = .07) 75 vs. 46 mo (P = .19) 50% vs. 43% Sorensen et al96 90 (NR) Paclitaxel Carboplatin 46 0 79% vs. 70% NR 34.4 vs. 22.5 mo (NS) 36% vs. 24% (NS) Mattson et al97 274 (274) Docetaxel 28 NR 77% vs. 76%e 9 vs. 7.6 mo (NS) 14.8 vs. 12.6 mo (NS) NR 85 94 3-year survival. Options included MVP (mitomycin C, vindesine, and platinum), MIC (mitomycin, ifosfamide, and cisplatin), NP (cisplatin and vinorelbine), PacCarbo (paclitaxel and carboplatin), GemCis (gemcitabine and cisplatin), and DocCarbo (docetaxel and carboplatin). c 4-year survival. d 113 patients (32%) were reported to have stage IIB or IIIA disease. e 22 patients in the chemotherapy arm and 29 patients in the control arm had resectable disease. DFS = disease-free survival; NR = not recorded; NS = not significant; OS = overall survival; pCR = pathologic complete response; PFS = progression-free survival. Source: Reproduced with permission from JNCCN—Journal of the National Comprehensive Cancer Network. a b VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Open and altered fractionation. Such poor results for patients with stage III lung cancer reflect the limitations of locoregional treatment in a disease where death results from systemic metastatic spread. VATS 645 Options for Thoracic Surgical Approaches p<0.001 None Mild Moderate Severe modest 5-year survival benefit as compared with chemotherapy. In a systematic review of 47 trials and six meta-analyses, an absolute survival benefit of 4% at 2 years was seen when concurrent platinum-based chemoradiation was given compared to sequential radiation.98 Definitive radiotherapy is predominantly used for palliation of symptoms in patients with poor performance status; cure rates with radiation as a single modality in patients with N2 or N3 disease is less than 7%. Recent improvement has been seen with three-dimensional conformal radiotherapy Video-Assisted Thoracoscopic Surgery. VATS has become the recommended approach to diagnosis and treatment of pleural effusions, recurrent pneumothoraces, lung biopsies, lobectomy or segmental resection, resection of bronchogenic and mediastinal cysts, and intrathoracic esophageal mobilization for esophagectomy.99 It is also utilized for pneumonectomy in some centers of excellence with very high volumes of VATS lung resection. VATS is performed via two to four incisions measuring 0.5 to 1.2 cm in length to allow insertion of the thoracoscope Table 19-16 Special circumstances under which lobectomy by video-assisted thoracic surgery may be preferable Condition Examples Pulmonary compromise Poor FEV1/Dlco, heavy smoking, sleep apnea, recent pneumonia Cardiac dysfunction Congestive heart failure, severe coronary artery disease, recent myocardial infarction, valvular disease Extrathoracic malignancy Solitary brain metastasis from lung cancer, deep pulmonary metastases requiring lobectomy Poor physical performance Performance status equivalent to a Zubrod score of 2 or 3, morbid obesity Rheumatologic/orthopedic condition Spinal disease, severe rheumatoid arthritis, severe kyphosis, lupus erythematosus, osteomyelitis Advanced age Age >70 years Vascular problems Aneurysm, severe peripheral vascular disease Recent or impending major operation Urgent abdominal operation, joint replacement requiring use of crutches, need for contralateral thoracotomy Psychological/neurologic conditions Substance abuse, poor command following, pain syndromes Immunosuppression/ impaired wound healing Recent transplantation, diabetes Dlco = carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second. Source: Reproduced with permission from Demmy TL, Nwogu C. Is video-assisted thoracic surgery lobectomy better? Quality of life considerations. Ann Thorac Surg. 2008;85:S719. Copyright © Elsevier. Copyright Elsevier. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Figure 19-26. Pie chart comparison of pain control at 3 weeks after lobectomy by standard thoracotomy or video-assisted thoracic surgery (VATS). The pie charts show that patients undergoing VATS have significantly less pain (P < .01) as measured by the most potent analgesic still required: severe—schedule II narcotic; moderate—schedule III or lower narcotic; mild—nonsteroidal antiinflammatory drug (NSAID) or acetaminophen. (Reproduced with permission from Demmy TL, Nwogu C. Is video-assisted thoracic surgery lobectomy better? Quality of life considerations. Ann Thorac Surg. 2008;85:S719. Copyright Elsevier.) Thoracic surgical approaches have changed over recent years with advancements in minimally invasive surgery. A surgeon trained in advanced minimally invasive techniques can now perform pleural-based, pulmonary and mediastinal procedures through multiple thoracoscopic ports without the need for a substantial, rib-spreading incision. Subjective measures of quality of life after VATS, such as pain (Fig. 19-26) and perceived functional recovery, consistently and reproducibly favor VATS over thoracotomy. Objective measures such as functional status as measured by 6-minute walk, return to work, and ability to tolerate chemotherapy also favor VATS over thoracotomy. Finally, recovery of respiratory function occurs earlier in VATS patients. These findings are pronounced in patients with chronic obstructive pulmonary disease and in the elderly—populations whose quality of life can be dramatically impacted by changes in their respiratory symptoms and function, thoracic pain, and physical performance. Table 19-16 provides a summary of populations that may benefit from VATS approaches. 646 and instruments. An access incision, typically in the fourth or fifth intercostal space in the anterior axillary line, is used for dissection of the hilum during lung resection. The incision location varies according to the procedure. With respect to VATS lobectomy, port placement varies according to the lobe being resected and is highly variable among surgeons.100 The basic principle is to position the ports high enough on the thoracic cage to have access to the hilar structures Endoscopic staplers are used to divide the major vascular structures and bronchus (Fig. 19-27). Open approaches to Thoracic Surgery. When video-assisted thoracoscopic approach is not possible, an open approach, most frequently the posterolateral thoracotomy, is used to gain access to the intrathoracic space.101,102 The posterolateral thoracotomy UNIT II PART Retract Dissect SPECIFIC CONSIDERATIONS View View Retract A B Dissect Retract Hold View View C D Retract Retract View E Figure 19-27. Selected video-assisted thoracic surgery lobectomy maneuvers. All the maneuvers are shown with the patient positioned in the left lateral decubitus position. The same maneuvers can be performed in mirror image for left-sided work. A. Medial viewing and inferior holding of lung to allow dissection through the access incision. Example shows dissection of the apical hilum. B. Medial viewing and access holding of lung to allow stapling of hilar structures from below. Example shows division of the apical pulmonary artery trunk to the right upper lobe (upper lobe branch of vein divided and reflected away). C. Standard viewing and use of working port to dissect and divide structures while lung is retracted through access incision. Example shows use of stapler to divide pulmonary artery to right lower lobe. D. Standard viewing and use of working port to retract lung and access incision to dissect structures. This method is commonly used to dissect the pulmonary artery in the major fissure. Example shows inferior pulmonary vein after the pulmonary ligament was divided using this maneuver. E. Standard viewing and use of access incision to deliver stapler to divide fissures. Example shows division of the posterior fissure between the right lower lobe and the upper lobe. (Reproduced with permission from Demmy et al.100 Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ centers. A partial median sternotomy can also be added to an anterior thoracotomy (“trap-door” or “hemiclamshell” thoracotomy) for access to mediastinal structures. A hypesthetic nipple is a frequent complication of this approach. The median sternotomy incision allows exposure of anterior mediastinal structures and is principally used for cardiac operations. Although the surgeon has access to both pleural cavities, incision into the pleural cavity can be avoided if entry is unnecessary (Fig. 19-29). Postoperative Care Chest Tube Management. At the conclusion of most thoracic operations, the pleural cavity is drained with a chest tube(s). If the visceral pleura has not been violated and there is no concern Latissimus dorsi divided Trapezius A B Latissimus dorsi Scapula retracted Rhomboid major Serratus anterior 5th rib Incision 6th rib Trapezius C 647 D Figure 19-28. The posterolateral thoracotomy incision. A. Skin incision from the anterior axillary line to the lower extent of the scapula tip. B and C. Division of the latissimus dorsi and shoulder girdle musculature. D. The pleural cavity is entered after dividing the intercostal muscles along the lower margin of the interspace, taking care not to injure the neurovascular bundle lying below each rib. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura incision can be used for most pulmonary resections, esophageal operations, and operations in the posterior mediastinum and vertebral column (Fig. 19-28). The anterolateral thoracotomy has traditionally been used in trauma victims. This approach allows quick entry into the chest with the patient supine. In the face of hemodynamic instability, the lateral decubitus position significantly compromises control over the patient’s cardiopulmonary system and resuscitation efforts, whereas the supine position allows the anesthesiologist full access to the patient. A bilateral anterior thoracotomy incision with a transverse sternotomy (“clamshell” thoracotomy) is a standard operative approach to the heart and mediastinum in certain elective circumstances. It is the preferred incision for double-lung transplantation in many 648 UNIT II PART A SPECIFIC CONSIDERATIONS Thymus Aortic arch R. atrial appendage Innominate v. Pulmonary a. L. atrial appendage R. ventricle Preperitoneal fat Diaphragm B Figure 19-29. The median sternotomy incision. A. Skin incision from the suprasternal notch to the xiphoid process. B. Exposure of the pleural space. a. = artery; v. = vein. for pneumo- or hemothorax (e.g., after VATS sympathectomy), a chest tube is unnecessary. After chest tube placement, the lung is re-expanded with positive-pressure ventilation. There are two reasons for the use of pleural tubes in this setting: first, the tube allows evacuation of air if an air leak is present; second, blood and pleural fluid can be drained, thereby preventing accumulation within the pleural space that would compromise the patient’s respiratory status. The tube is removed when the air leak is resolved and when the volume of drainage decreases below an acceptable level over 24 hours. Historically, many surgeons have somewhat arbitrarily required less than 150 mL of drainage volume over 24 hours prior to removing a chest tube to minimize risk of reaccumulation. The pleural lymphatics, however, can absorb up to 0.40 mL/kg per hour in a healthy individual, which may be as much as 500 mL over a 24-hour period. In fact, studies have shown that pleural tubes can be removed after VATS lobectomy or thoracotomy with 24-hour drainage volumes as high as 400 mL, without subsequent development of pleural effusions.103 It is our current practice to remove chest tubes with 24-hour outputs of 400 mL or less after lobectomy or lesser pulmonary resections. In settings where normal pleural fluid dynamics have been altered, such as malignant pleural effusion, pleural space infections or inflammation, and pleurodesis, strict adherence to a volume requirement before tube removal is appropriate (typically 100–150 mL over 24 hours). For operations involving lung resection or parenchymal injury, suction levels of –20 cm H2O are routinely used to eradicate residual air spaces and to control postoperative parenchymal air leaks for the first 12 to 24 hours. The following day, however, the decision to continue suction or place the patient to water seal (off suction) must be made. Applying suction to an air leak has been shown to prolong the duration of the air leak and extend the time frame during which tube thoracostomy is needed.104 The main guidelines for the continued use of suction if an air leak is present depend on the expansion of the remaining lung as determined by CXR. If the lung is wellexpanded, the chest tube can remain to water seal drainage. If an undrained pneumothorax is present on CXR, the chest tube and its attached tubing should be examined to ensure that the chest tube is patent and the attached tubing is not kinked or mechanically obstructed, such as occurs when the patient is lying on the tube. If the tube is a small caliber tube (aka pigtail catheter), it should be flushed with sterile saline through a three-way stopcock that has been cleaned with alcohol because these tubes tend to become clogged with fibrin. These catheters are also prone to kinking at the insertion site into the skin. Once the surgeon has confirmed that the chest tube is patent, the patient is asked to voluntarily cough or perform the Valsalva maneuver. This maneuver increases the intrathoracic pressure and will push air that is contained within the hemithorax out of the chest tube. During the voluntary cough, the fluid level in the water seal chamber should move up and down with the cough and with deep respiration, reflecting the pleural pressure changes occurring with these maneuvers. A stationary fluid level implies either a mechanical blockage (e.g., due to external tube compression or to a clot/debris within the tube) or pleurodesis of the pleural space. If bubbles pass through the water seal chamber, an air leak is presumed. If the leak is significant enough to induce atelectasis or collapse of the lung during use of water seal, suction should be used to achieve lung re-expansion. Pain Control. Good pain control after intrathoracic procedures is critical; it permits the patient to actively clear and manage secretions and promotes ambulation and a feeling of well-being. The most common techniques of pain management are epidural, paravertebral, and intravenous. Epidural catheters are commonly used, although we prefer to use paravertebral catheters in our center. To maximize efficacy, epidural catheters should be inserted at about the T6 level, roughly at the level of the scapular tip. Lower placement risks inadequate pain control, and higher placement may provoke hand and arm numbness. Typically, combinations of fentanyl at 0.3 μg/mL with either bupivacaine (0.125%) or ropivacaine (0.1%) are used. Ropivacaine has less cardiotoxicity than bupivacaine; thus, the potential for refractory complete heart block, in the case of inadvertent intravenous injection, is significantly less with ropivacaine. Paravertebral blocks can be placed using the same epidural catheter kit 2.5 cm lateral to the spinous process at T4 to T6. Combinations of narcotic and topical analgesia are then infused as with the epidural catheter. When properly placed, a well-managed epidural can provide outstanding pain control without significant systemic sedation.105 Thoracic epidurals do not commonly cause urinary retention, although a low thoracic epidural may block the sensory fibers to the bladder. Motor function, however, remains VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Respiratory Care. The best respiratory care is achieved when the patient is able to deliver an effective cough to clear secretions and results from the commitment and proper training of all involved healthcare providers. The process begins preoperatively, with clear instructions on using pillows (or other support techniques) over the wound and then applying pressure. Postoperatively, proper pain control (as outlined earlier) is essential, without oversedation. Daily morning rounds should include a careful assessment of the patient’s pulmonary status, reminders to the patient and family about the importance of coughing and deep breathing, including use of adjunctive respiratory equipment if ordered, and mobilization of the patient. Early transition to a chair and to ambulation is the best respiratory therapy and should be strongly encouraged. When available, physical and/ or cardiopulmonary rehabilitation services are vital additional members of the care team. In patients whose pulmonary function is significantly impaired preoperatively, generating an effective cough postoperatively may be nearly impossible. In this setting, routine nasotracheal suctioning can be employed, but is uncomfortable for the patient. A better alternative is placement of a percutaneous transtracheal suction catheter at the time of surgery. This catheter is well-tolerated by most patients and allows regular and convenient suctioning. Postoperative Complications Postoperative complications after pulmonary resection range from minor to life-threatening. Strict attention to volume status, early and aggressive pulmonary toilet, and good pain control can reduce the risk of most complications, but does not completely eliminate them, even in centers of excellence. The most devastating complication after pulmonary resection is postpneumonectomy pulmonary edema, which occurs in 1% to 5% of patients undergoing pneumonectomy and more often after right compared to left pneumonectomy. Clinically, symptoms of respiratory distress manifest hours to days after surgery. Radiographically, diffuse interstitial infiltration or frank alveolar edema is seen. The pathophysiologic causes are related to factors that increase permeability and filtration pressure and decrease lymphatic drainage from the affected lung. Judicious use of intravenous fluids perioperatively, including use of vasopressors rather than fluid boluses for hypotension intraoperatively and postoperatively, is critical to minimizing the risk of this syndrome. Treatment consists of ventilatory support, fluid restriction, and diuretics. Extracorporeal membrane oxygenation may be life-saving in centers where this option is available. The syndrome reportedly has a nearly 100% mortality rate despite aggressive therapy. Other postoperative complications include air leak and bronchopleural fistula. Although these are two very different problems, distinguishing between them may be difficult. Postoperative air leaks are common after pulmonary resection, particularly in patients with emphysematous lung, because the fibrosis and destroyed blood supply impairs healing of surface injuries. Prolonged air leaks (i.e., those lasting >5 days) may be treated by diminishing or discontinuing suction (if used), by continuing chest drainage, or by instilling a pleurodesis agent, usually doxycycline or talcum powder, which will cause pleurodesis of the lung within the chest cavity and minimize the possible collapse of the lung due to persistent air leak. This is useful only in patients in whom full lung expansion is achieved, either with suction or on water seal, as patients with a persistent pneumothorax on CXR will not have adequate lung-to-parietal pleural apposition to achieve adequate pleurodesis. If the leak is moderate to large, a high index of suspicion for bronchopleural fistula from the resected bronchial stump should be maintained, particularly if the patient is immunocompromised or had induction chemotherapy and/or radiation therapy. If a bronchopleural fistula is suspected, flexible bronchoscopy is performed to evaluate the bronchial stump. Management options include continued prolonged chest tube drainage, reoperation, and reclosure (with stump reinforcement with an intercostal muscle flap or a pedicled serratus muscle flap). If the fistula is very small (<4 mm), bronchoscopic fibrin glue application has been used successfully to seal the hole in some patients. Patients often have concomitant empyema, and open drainage may be necessary. Spontaneous Pneumothorax Spontaneous pneumothorax is secondary to intrinsic abnormalities of the lung and can be classified as primary and secondary. Primary spontaneous pneumothorax is defined as a spontaneous pneumothorax without underlying lung disease. The most common cause is rupture of an apical subpleural bleb. The cause of these blebs is unknown, but they occur more frequently in smokers and males, and they tend to predominate in young postadolescent males with a tall thin body habitus. Treatment is generally chest tube insertion with water seal. If a leak is present and persists for greater than 3 days, thoracoscopic management (i.e., bleb resection with pleurodesis by talc or pleural abrasion) is performed. Recurrences or complete lung collapse with the first episode are generally indications for thoracoscopic intervention.107 Additional indications for intervention on the first VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 649 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura intact. In some patients who are having difficulty voiding, it may be possible to avoid Foley catheterization by simply reminding the patient to void on a regular basis. In male patients with voiding difficulty prior to surgery, urinary catheterization may be required. In addition, the use of local anesthetics may cause sympathetic outflow blockade, leading to vasodilation and hypotension often requiring intravenous vasoconstrictors (an α-agonist such as phenylephrine) and/or fluid administration. In such circumstances, fluid administration for hypotension may be undesirable in pulmonary surgery patients, particularly after pneumonectomy. Paravertebral catheters provide equivalent pain control with less effect on hemodynamics.106 Alternatively, intravenous narcotics via patient-controlled analgesia can be used, often in conjunction with ketorolac and intravenous Tylenol. Dosing must be titrated to balance the degree of pain relief with the degree of sedation. Oversedated patients are as ominous as patients without adequate pain control, because of the significant risk of secretion retention, atelectasis/pneumonia, and pulmonary aspiration. These concerns are particularly relevant in elderly patients who should be carefully assessed for aspiration risk when ordered for dietary advancement. Proper pain control with intravenous narcotics requires a carefully regulated balance between pain relief and sedation; maximizing the benefits of pain control while minimizing these very real and potentially life-threatening complications. Whether on epidural, paravertebral, or intravenous pain control, the patient is typically transitioned to oral pain medication on the third or fourth postoperative day. During both the parenteral and oral phase of pain management, a standardized regimen of stool softeners and laxatives is advisable in order to prevent severe constipation. 650 UNIT II PART SPECIFIC CONSIDERATIONS episode include occupational hazards such as air travel, deep-sea diving, or travel to remote locations. CT findings of multiple small bullae or a large bleb are associated with an increased risk of recurrent pneumothorax.108 Many surgeons are now using screening CT scan to recommend VATS bleb resection with pleurodesis for first-episode spontaneous pneumothorax. Secondary spontaneous pneumothorax occurs in the setting of underlying lung disease, such as emphysema (rupture of a bleb or bulla), cystic fibrosis, acquired immunodeficiency syndrome (AIDS), metastatic cancer (especially sarcoma), asthma, lung abscess, and occasionally primary lung cancer. Catamenial pneumothorax, a rare but interesting cause of spontaneous pneumothorax in women in their second and third decades, occurs within 72 hours of the onset of menses and is possibility related to endometriosis. Management of pneumothorax in these circumstances is similar to that of primary spontaneous pneumothorax in that drainage and lung re-expansion are required. Additional therapy, however, is often tied to therapy of the specific disease process and may involve lung resection, thoracoscopic pleurectomy, or talc pleurodesis. Pulmonary Infections Lung Abscess. A lung abscess is a localized area of pulmonary parenchymal necrosis caused by an infectious organism; tissue destruction results in a solitary or dominant cavity measuring at least 2 cm in diameter. Less often, there may be multiple, smaller cavities (<2 cm). In that case, the infection is typically referred to as a necrotizing pneumonia. An abscess that is present for more than 6 weeks is considered chronic. Based on the etiology (Table 19-17), lung abscesses are further classified as primary or secondary. A primary lung abscess occurs, for example, in immunocompromised patients, as a result of highly virulent organisms inciting a necrotizing pulmonary infection, or in patients who have a predisposition to aspirate oropharyngeal or gastrointestinal secretions. A secondary lung abscess occurs in patients with an underlying condition such as a partial bronchial obstruction, a lung infarct, or adjacent suppurative infections (subphrenic or hepatic abscesses).109 Pathogenesis. Lung abscesses result when necrotizing microorganisms infect the lower respiratory tract via inhalation of aerosolized particles, aspiration of oropharyngeal secretions, or hematogenous spread from distant sites. Direct extension from a contiguous site is less frequent. Most primary lung abscesses are suppurative bacterial infections secondary to aspiration. Risk factors for pulmonary aspiration include advanced age, conditions of impaired consciousness, suppressed cough reflex, dysfunctional esophageal motility, laryngopharygeal reflux disease, and centrally acting neurologic diseases (e.g., stroke). At the time of aspiration, the composition of the oropharyngeal flora determines the etiologic organisms. With increasing use of proton pump inhibitors to suppress acid secretion in the stomach, the oropharyngeal flora has shifted and the risk of developing bacterial lung infections after an aspiration event has increased.110 Secondary lung abscesses occur most often distal to an obstructing bronchial carcinoma. Infected cysts or bullae are not considered true abscesses. Microbiology. Normal oropharyngeal secretions contain many more Streptococcus species and more anaerobes (approximately 1 × 108 organisms/mL) than aerobes (approximately 1 × 107 organisms/mL). Pneumonia that follows from aspiration, with or without abscess development, is typically polymicrobial. Table 19-17 Causes of lung abscess I. Primary A. Necrotizing pneumonia 1. Staphylococcus aureus, Klebsiella, Pseudomonas, Mycobacterium 2. Bacteroides, Fusobacterium, Actinomyces 3. Entamoeba, Echinococcus B. Aspiration pneumonia 1. Anesthesia 2. Stroke 3. Drugs or alcohol C. Esophageal disease 1. Achalasia, Zenker’s diverticulum, gastroesophageal reflux D. Immunodeficiency 1. Cancer (and chemotherapy) 2. Diabetes 3. Organ transplantation 4. Steroid therapy 5. Malnutrition II. Secondary A. Bronchial obstruction 1. Neoplasm 2. Foreign body B. Systemic sepsis 1. Septic pulmonary emboli 2. Seeding of pulmonary infarct C. Complication of pulmonary trauma 1. Infection of hematoma or contusion 2. Contaminated foreign body or penetrating injury D. Direct extension from extraparenchymal infection 1. Pleural empyema 2. Mediastinal, hepatic, subphrenic abscess Source: Adapted with permission from Rusch VW, et al. Chest wall, pleura, and mediastinum. In: Schwartz SI, et al, eds. Principles of Surgery. 7th ed. New York: McGraw-Hill; 1999:735. An average of two to four isolates present in large numbers have been cultured from lung abscesses sampled percutaneously. Overall, at least 50% of these infections are caused by purely anaerobic bacteria, 25% are caused by mixed aerobes and anaerobes, and 25% or fewer are caused by aerobes only. In nosocomial pneumonia, 60% to 70% of the organisms are gram-negative bacteria, including Klebsiella pneumoniae, Haemophilus influenzae, Proteus species, Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, and Eikenella corrodens. Immunosuppressed patients may develop abscesses because of the usual pathogens as well as less virulent and opportunistic organisms such as Salmonella species, Legionella species, Pneumocystis carinii, atypical mycobacteria, and fungi. Clinical Features and Diagnosis. The typical presentation may include productive cough, fever (>38.9°C), chills, leukocytosis (>15,000 cells/mm3), weight loss, fatigue, malaise, pleuritic chest pain, and dyspnea. Lung abscesses may also present in a more indolent fashion, with weeks to months of cough, malaise, weight loss, low-grade fever, night sweats, leukocytosis, and anemia. After aspiration pneumonia, 1 to 2 weeks typically elapse before cavitation occurs; 40% to 75% of such patients produce putrid, foul-smelling sputum. Severe complications VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ enteral intake. Oral therapy can then be used to complete the course of therapy. For community-acquired infections secondary to aspiration, likely pathogens are oropharyngeal streptococci and anaerobes. Penicillin G, ampicillin, and amoxicillin are the main therapeutic agents, but a β-lactamase inhibitor or metronidazole should be added to cover the increasing prevalence of gram-negative anaerobes that produce β-lactamase. Clindamycin is also a primary therapeutic agent. For hospital-acquired infections, Staphylococcus aureus and aerobic gram-negative bacilli are common organisms of the oropharyngeal flora. Piperacillin or ticarcillin with a β-lactamase inhibitor (or equivalent alternatives) provide better coverage of likely pathogens. Surgical drainage of lung abscesses is uncommon since drainage usually occurs spontaneously via the tracheobronchial tree. Indications for intervention are listed in Table 19-18. Drainage and resection may be required for actinomycosis and nocardiosis; diagnosis is often delayed because the bacteria are difficult to culture; invasion of the infection into surrounding structures is, therefore, common. Once identified, long-term antibiotics (months to years) are typically required along with drainage, debridement, and resection as needed. While penicillin derivatives are effective against most Actinomyces species, the infections are typically polymicrobial, and broad-spectrum parenteral antibiotics may be required. Nocardia species, in contrast, are highly variable; specific identification of the infecting species with antibiotic sensitivities is needed to direct appropriate therapy. Evaluation for malignant spread, particularly to the brain, is also required in the management of nocardiosis, as systemic dissemination occurs early and frequently. External drainage may be accomplished with tube thoracostomy, percutaneous drainage, or surgical cavernostomy. The choice between tube thoracostomy versus radiographically guided catheter placement depends on the treating physician’s preference and the availability of interventional radiology. Surgical resection is required in fewer than 10% of lung abscess patients. Lobectomy is the preferred intervention for bleeding from a lung abscess or pyopneumothorax. An important intraoperative consideration is to protect the contralateral lung with a double-lumen tube, bronchial blocker, or contralateral main stem intubation. Surgical treatment has a 90% success rate, with an associated mortality of 1% to 13%. Bronchiectasis. Bronchiectasis is defined as a pathologic and permanent dilation of bronchi with bronchial wall thickening. This condition may be localized to certain bronchial segments, or it may be diffuse throughout the bronchial tree, typically affecting the medium-sized airways. Overall, this is a rare clinical entity in the United States with a prevalence of less than 1 in 10,000, although the incidence has increased in recent years and noncystic fibrosis–related bronchiectasis is now thought to affect 27.5 out of every 10,000 persons over age 75. Pathogenesis. Development of bronchiectasis can be attributed to either congenital or acquired causes. The principal congenital diseases that lead to bronchiectasis include cystic fibrosis, primary ciliary dyskinesia, and immunoglobulin deficiencies (e.g., selective IgA deficiency). Congenital causes tend to produce a diffuse pattern of bronchial involvement. Acquired causes are categorized broadly as infectious and inflammatory. Bronchial obstruction from cancer, inhaled objects, extrinsic airway compression, or inspissated sputum promotes localized infection and subsequent medium airway destruction. Diffuse pneumonic processes from pathogens including necrotizing bacterial VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 651 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura such as massive hemoptysis, endobronchial spread to other portions of the lungs, rupture into the pleural space and development of pyopneumothorax, or septic shock and respiratory failure are rare in the modern antibiotic era. The mortality rate is about 5% to 10%, except in the presence of immunosuppression, where rates range from 9% to 28%. The CXR is the primary tool for diagnosing a lung abscess (Fig. 19-30). Its distinguishing characteristic is a density or mass with a relatively thin-walled cavity. An air-fluid level observed within the abscess indicates communication with the tracheobronchial tree. CT scan of the chest clarifies the diagnosis when CXR is equivocal and identifies endobronchial obstruction and/ or an associated mass and other pathologic anomalies. A cavitating lung carcinoma is frequently mistaken for a lung abscess. Differential diagnosis also includes loculated or interlobar empyema, infected lung cysts or bullae, tuberculosis, bronchiectasis, fungal infections, and noninfectious inflammatory conditions (e.g., Wegener’s granulomatosis). Ideally, the specific etiologic organism is identified before antibiotic administration. Bronchoscopy, which is essential to rule out endobronchial obstruction due to tumor or foreign body, is ideal for obtaining uncontaminated cultures using bronchoalveolar lavage. Culture samples can also be obtained by percutaneous, transthoracic FNA under ultrasound or CT guidance. Routine sputum cultures are often of limited usefulness because of contamination with upper respiratory tract flora. Actinomycosis and nocardiosis, although rare, are particularly virulent infections associated with lung abscess, and diagnosis can be difficult.111 Both frequently masquerade as other clinical syndromes; thus, it is important for the surgeon to keep these bacteria in mind when considering the differential diagnosis for cavitary lung lesions. Actinomyces, a normal oropharyngeal bacterium, causes extensive pulmonary damage as the result of aspiration. Actinomycosis lung infection typically begins as acute pneumonitis after an aspiration. The symptoms mimic pulmonary tuberculosis, including chronic cough, night sweats, weight loss, and hemoptysis. Ongoing infection leads to chronic inflammation and fibrosis; cavitation occurs due to destruction of the pulmonary tissues. Without treatment, the infection continues to destroy surrounding structures, which can result in fistula formation into the adjacent structures, including the adjacent lung, interlobar fissures, pleural space, chest wall, and mediastinum. Actinomyces israelii is the most common cause of disease among the Actinomyces species. Nocardiosis is also a rare opportunistic infection that usually occurs in an immunocompromised host (human immunodeficiency virus [HIV] or cancer patients) and causes both local and systemic suppurative infections. The most common site is pulmonary, caused by Nocardia asteroides in 90% of cases; one series, however, reported a high prevalence of the particularly virulent species, Nocardia farcinica. Similar to actinomycosis, infection is slowly progressive, with weight loss, fatigue, cough, and hemoptysis. An acute pulmonary infection is common, with necrotizing pneumonia and cavitation or slowly enlarging pulmonary nodule(s). In some cases, empyema also develops. Management of Lung Abscess. Systemic antibiotics directed against the causative organism represent the mainstay of therapy. The duration of antimicrobial therapy varies from 3 to 12 weeks for necrotizing pneumonia and lung abscess. It is likely best to treat until the cavity is resolved or until serial radiographs show significant improvement. Parenteral therapy is generally used until the patient is afebrile and able to demonstrate consistent 652 UNIT II PART SPECIFIC CONSIDERATIONS A B C Figure 19-30. Lung abscess resulting from emesis and aspiration after an alcoholic binge. A. Chest x-ray showing an abscess cavity in the left upper lobe. B. A coronal tomogram highlights the thin wall of the abscess. C. Healing of the abscess cavity after 4 weeks of antibiotic therapy and postural drainage. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 653 Table 19-18 Indications for surgical drainage procedures for lung abscesses pneumonia, pertussis and measles pneumonia, severe influenza, or varicella pneumonia can lead to widespread bronchiectasis. Chronic granulomatous disease, immunodeficiency disorders, and hypersensitivity disorders can also lead to diffuse bronchiectasis. Noninfectious causes of bronchiectasis include inhalation of toxic gases such as ammonia, which results in severe and destructive airway inflammatory responses. Allergic bronchopulmonary aspergillosis, Sjögren’s syndrome, and α1-antitrypsin deficiency are some additional examples of presumed immunologic disorders that may be accompanied by bronchiectasis. In addition, recent studies have suggested an association between chronic gastroesophageal reflux disease, acid suppression, and nontuberculous mycobacterial infection with bronchiectasis.112,113 This interaction is thought to be related to 10 chronic aspiration of colonized gastric secretions in the setting of acid suppression; while not proven to be causative, these findings suggest a role for gastroesophageal reflux disease in the pathogenesis of bronchiectasis. The process shared by all causes of bronchiectasis is impairment of airway defenses or deficits in immunologic mechanisms, which permit bacterial colonization and chronic infection. Common organisms include Haemophilus species (55%), Pseudomonas species (26%), and Streptococcus pneumoniae (12%).114 Both the bacterial organisms and the inflammatory cells recruited to thwart the bacteria elaborate proteolytic and oxidative molecules, which progressively destroy the muscular and elastic components of the airway walls; those components are then replaced by fibrous tissue. Thus chronic airway inflammation is the essential pathologic feature of bronchiectasis. The dilated airways are usually filled with thick purulent material; more distal airways are often occluded by secretions or obliterated by fibrous tissue. Bronchial wall vascularity increases, bronchial arteries become hypertrophied, and abnormal anastomoses form between the bronchial and pulmonary arterial circulation. There are three principal types of bronchiectasis, based on pathologic morphology: cylindrical—uniformly dilated bronchi; varicose—an irregular or beaded pattern of dilated bronchi; and saccular (cystic)—peripheral balloon-type bronchial dilation. The saccular type is the most common after bronchial obstruction or infection (Fig. 19-31). Clinical Manifestations and Diagnosis. Typical symptoms are a daily persistent cough and purulent sputum production; the quantity of daily sputum production (10 mL to >150 mL) correlates with disease extent and severity. Other patients Figure 19-31. Multiple cystic-type bronchiectatic cavities can be seen on a cut section of right lower lobe lung. may appear asymptomatic or have a dry nonproductive cough (“dry bronchiectasis”). These patients are prone to have involvement of the upper lobes. The clinical course is characterized by progressive symptoms and respiratory impairment. Increasing resting and exertional dyspnea are the result of progressive airway obstruction. Acute exacerbations may be triggered by viral or bacterial pathogens. Bleeding attributable to chronically inflamed, friable airway mucosa causes increasingly more frequent hemoptysis with disease progression. Massive bleeding may result from erosion of the hypertrophied bronchial arteries. Both mild and severe forms of bronchiectasis are readily demonstrated with chest CT scanning because it provides a highly detailed, cross-sectional view of bronchial architecture. CXRs, although less sensitive, may reveal characteristic signs of bronchiectasis such as lung hyperinflation, bronchiectatic cysts, and dilated, thick-walled bronchi forming track-like patterns radiating from the lung hila. Sputum culture may identify characteristic pathogens. Sputum acid-fast bacillus smears and cultures should be performed to evaluate for the presence of nontuberculous mycobacteria, which is common in this setting. Spirometry provides an assessment of the severity of airway obstruction and can be followed to track the course of disease. Management of Bronchiectasis. Standard therapy includes optimizing airway clearance, use of bronchodilators to reverse any airflow limitation, and correction of reversible underlying causes whenever possible.115 Chest physiotherapy based on vibration, percussion, and postural drainage is widely accepted, although randomized trials demonstrating efficacy are lacking. Acute exacerbations should be treated with a 2- to 3-week course of broad-spectrum intravenous antibiotics tailored to culture and sensitivity profiles, followed by an oral regimen; this will result in a longer-lasting remission. Macrolide antibiotics have been shown to decrease sputum production, inhibit cytokine release, and inhibit neutrophil adhesion and formation of reactive oxygen species. They also inhibit migration of Pseudomonas, disrupt biofilm, and prevent release of virulence factors.116 While macrolide therapy does appear to be efficacious, it is important to remember that macrolides have significant activity against nontuberculous mycobacteria, and widespread prophylactic use for patients with bronchiectasis may lead to multidrug-resistant nontuberculous mycobacterial species. It has also been suggested that inhaled antibiotics, such VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura 1. Failure of medical therapy 2. Abscess under tension 3. Abscess increasing in size during appropriate treatment 4. Contralateral lung contamination 5. Abscess >4–6 cm in diameter 6. Necrotizing infection with multiple abscesses, hemoptysis, abscess rupture, or pyopneumothorax 7. Inability to exclude a cavitating carcinoma 654 UNIT II PART SPECIFIC CONSIDERATIONS as tobramycin and colistin, improve rates of bacterial clearance and slow the decline in pulmonary function associated with bronchiectasis, but large, randomized trials showing overall clinical benefit have not yet been published.117,118 In addition to antibiotics, daily nebulized hypertonic saline appears to be effective. A recent randomized crossover study comparing lung function and quality of life has shown that 7% normal saline, compared to isotonic saline, results in a statistically significant 15% increase in FEV1 and an 11% increase in forced vital capacity (compared to 1.8% and 0.7%, respectively, with isotonic saline). Antibiotic use and emergency room utilization were significantly decreased; from this, hypertonic saline appears to be a reasonable adjunct to maintaining quality of life and decreasing exacerbations by reducing sputum volume, improving mucociliary clearance, and slowing the decline in lung function.119 Studies supporting mucolytics such as DNase and N-acetylcysteine for non-cystic fibrosis bronchiectasis have shown either no change or a worsening of pulmonary status and require further study in the non-cystic fibrosis population. Surgical resection of a localized bronchiectatic segment or lobe, preserving as much functional lung as possible, may benefit patients with refractory symptoms while on maximal medical therapy. Multifocal disease must be excluded before any attempt at surgery; any uncorrectable predisposing factor (e.g., ciliary dyskinesia) must also be excluded. Patients with end-stage lung disease from bronchiectasis may be potential candidates for a bilateral lung transplant. Surgical resection is also indicated in patients with significant hemoptysis, although bronchial artery embolization is the preferred first option. Antireflux surgery may also prove beneficial in patients with chronic aspiration, but further studies are required. It is particularly important to recognize that antireflux surgery in patients with severe underlying pulmonary dysfunction has higher risk for perioperative adverse outcomes than in the general population. It should be undertaken only by very experienced surgeons with direct involvement of the pulmonary medicine physicians to minimize postoperative pulmonary compromise. Mycobacterial Infections Epidemiology. Tuberculosis is a widespread problem that affects nearly one third of the world’s population. Between 8.3 and 9 million new cases of tuberculosis and 12 million prevalent cases (range 10–13 million) were estimated worldwide in 2011 according to the World Health Organization. Only 10,521 new cases were reported to the World Health Organization in the United States in 2011. HIV infection is the strongest risk factor for developing active tuberculosis. The elderly, minorities, and recent immigrants are the most common populations to have clinical manifestations of infection, yet no age group, sex, or race is exempt from infection. In most large urban centers, reported cases of tuberculosis are more numerous among the homeless, prisoners, and drug-addicted populations. Immunocompromised patients additionally contribute to an increased incidence of tuberculosis infection, often developing unusual systemic as well as pulmonary manifestations.120 As compared with past decades, presently surgical intervention is required more frequently in patients with multidrug-resistant tuberculosis organisms (MDRTB) who do not respond to medical treatment and in selected patients with nontuberculous mycobacterial infections (NTM). Microbiology. Mycobacterial species are obligate aerobes. They are primarily intracellular parasites with slow rates of growth. Their defining characteristic is the property of acid-fastness, which is the ability to withstand decolorization by an acid-alcohol mixture after being stained. Mycobacterium tuberculosis is the highly virulent bacillus of this species that produces invasive infection among humans, principally pulmonary tuberculosis.121 Infections with M. tuberculosis are primary when they are the first infection in a previously unsensitized host and secondary or postprimary when reactivation of a previous infection occurs. Because of improper application of antimycobacterial drugs and multifactorial interactions, MDRTB organisms, defined by their resistance to at least two of the first-line antimycobacterial drugs (isoniazid and rifampin), have emerged. It is estimated that 1.4% of new tuberculosis cases and 7.6% of retreatment cases in the United States in 2011 are from MDRTB organisms. In addition, there is another rare variant termed extensively drug-resistant tuberculosis, which is resistant to isoniazid and rifampin, all fluoroquinolones, and at least one of the injectable second-line drugs (e.g., capreomycin, amikacin, kanamycin). It is estimated that 9% of all MDRTB cases are extensively drug resistant. The more important NTM organisms include Mycobacterium kansasii, M. avium and M. intracellulare complex (MAC), and M. fortuitum. The highest incidence of M. kansasii infection is in midwestern U.S. cities among middle-aged males from good socioeconomic surroundings. MAC organisms are important infections in elderly and immunocompromised patient groups. M. fortuitum infections are common complications of underlying severe debilitating disease. None of these organisms are as contagious as M. tuberculosis. Pathogenesis and Pathology. The main route of transmission is via airborne inhalation of viable mycobacteria. Three stages of primary infection have been described. In the first stage, alveolar macrophages become infected through ingesting the bacilli. In the second stage, from days 7 to 21, the patient typically remains asymptomatic while the bacteria multiply within the infected macrophages. The third stage is characterized by the onset of cell-mediated immunity (CD4+ helper T cells) and delayed-type hypersensitivity. Activated macrophages acquire an increased capacity for bacterial killing. Macrophage death increases, resulting in the formation of a granuloma, the characteristic lesion found on pathologic examination. Tuberculous granulomas are composed of blood-derived macrophages, degenerating macrophages or epithelioid cells, and multinucleated giant cells (fused macrophages with nuclei around the periphery; also known as Langerhans cells). The low oxygen content of this environment inhibits macrophage function and bacillary growth, with subsequent central caseation as macrophage death occurs. A Ghon complex is a single, small lung lesion that is often the only remaining trace of a primary infection. The primary infection is usually located in the peripheral portion of the middle zone of the lungs. Reactivation tuberculosis may occur after hydrolytic enzymes liquefy the caseum. Typically, the apical and posterior segments of the upper lobes and the superior segments of the lower lobes are involved. Edema, hemorrhage, and mononuclear cell infiltration are also present. The tuberculous cavity may become secondarily infected with other bacteria, fungi, or yeasts, all of which may contribute to enhanced tissue destruction. The pathologic changes caused by NTM organisms are similar to those produced by M. tuberculosis. M. intracellulare complex infections commonly occur, not only in immunocompromised patients, but also in patients with previously damaged lungs. Caseous necrosis is uncommon and is characterized by VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ clusters of tissue macrophages filled with mycobacteria. It has a poor granulomatous response and confinement of immune cell infiltration to the interstitium and alveolar walls. Cavitary disease is infrequent, although nodules may be noted. Management. Medical therapy is the primary treatment of pulmonary tuberculosis and is often initiated before a mycobacterial pathogen is definitively identified. Combinations of two or more drugs are routinely used in order to minimize resistance, which inevitably develops with only single-agent therapy. A current treatment algorithm is outlined in Fig. 19-32. Generally, therapy lasts about 18 months. The overall response rate is satisfactory in 70% to 80% of patients with M. kansasii infection. Surgical intervention is rarely required in the 20% to 30% of patients who are not responsive to medical therapy. In contrast, pulmonary M. intracellulare complex infections respond poorly, even to combinations of four or more drugs, and most of the patients will eventually require surgical intervention. Overall, sputum conversion is achieved in only 50% to 80% of NTM infections, and relapses occur in up to 20% of patients. In the United States, surgical intervention is most often required in order to treat patients with MDRTB organisms Pulmonary Fungal Infections. The incidence of fungal infections has increased significantly, with many new opportunistic fungi emerging. This increase is attributed to the growing population of immunocompromised patients (e.g., organ transplant recipients, cancer patients undergoing chemotherapy, HIV patients, and young and elderly patients) who are more likely to become infected with fungi.123 Clinically significant examples include species of Aspergillus, Cryptococcus, Candida, and Mucor. Other at-risk patient populations include those who are malnourished, severely debilitated, or diabetic or who have hematologic disorders. Patients receiving high-dose, intensive antibiotic therapies are also susceptible. There are, however, some fungi that are primary or true pathogens, able to cause infections in otherwise healthy patients. Some endemic examples in the United States include species of Histoplasma, Coccidioides, and Blastomyces.124 Direct identification of the organism in body exudates or tissues, preferably as growth in culture, provides definitive diagnosis. Serologic testing to identify mycotic-specific antibodies may also be useful. Several new classes of antifungal agents have proven effective against many life-threatening fungi and are less toxic than older agents. In addition, thoracic surgery may be a useful therapeutic adjunct for patients with pulmonary mycoses. Aspergillosis. The genus Aspergillus comprises over 150 species and is the most common cause of mortality due to invasive mycoses in the United States. It is typically acute in onset and life-threatening and occurs in the setting of neutropenia, chronic steroid therapy, or cytotoxic chemotherapy. It can also occur in the general intensive care unit population of critically ill patients, including patients with underlying chronic obstructive pulmonary disease (COPD), postoperative patients, patients with cirrhosis or alcoholism, and postinfluenza patients, without any of these factors present. The species most commonly responsible for clinical disease include A. fumigatus, A. flavus, A. niger, and A. terreus. Aspergillus is a saprophytic, filamentous fungus with septate hyphae. Spores (2.5–3 μm in diameter) are released and easily inhaled by susceptible patients; because the spores are microns in size, they are able to reach the distal bronchi and alveoli. Aspergillosis can manifest as one of three clinical syndromes: Aspergillus hypersensitivity lung disease, aspergilloma, or invasive pulmonary aspergillosis. Overlap occurs between these syndromes, depending on the patient’s immune status.125 Aspergillus hypersensitivity manifests as a productive cough, fever, wheezing, pulmonary infiltrates, eosinophilia, and elevation of IgE antibodies to Aspergillus, whereas aspergilloma (fungal ball) is a matted sphere of hyphae, fibrin, and inflammatory cells that tends to colonize pre-existing intrapulmonary cavities. Grossly, aspergilloma appears as a round or oval, friable, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 655 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Clinical Presentation and Diagnosis. The clinical course of infection and the presentation of symptoms are influenced by many factors, including the site of primary infection, the stage of disease, and the degree of cell-mediated immunity. About 80% to 90% of tuberculosis patients present with clinical disease in the lungs. In 85% to 90% of these patients, involution and healing occur, leading to a dormant phase that may last a lifetime. The only evidence of tuberculosis infection may be a positive skin reaction to tuberculin challenge or a Ghon complex observed on CXR. Within the first 2 years of primary infection, reactivation may occur in up to 10% to 15% of infected patients. In 80%, reactivation occurs in the lungs; other reactivation sites include the lymph nodes, pleura, and the musculoskeletal system. After primary infection, pulmonary tuberculosis is frequently asymptomatic. Systemic symptoms of low-grade fever, malaise, and weight loss are subtle and may go unnoticed. A productive cough may develop, usually after tubercle cavitation. Many radiographic patterns can be identified at this stage, including local exudative lesions, local fibrotic lesions, cavitation, bronchial wall involvement, acute tuberculous pneumonia, bronchiectasis, bronchostenosis, and tuberculous granulomas. Hemoptysis often develops from complications of disease such as bronchiectasis or erosion into vascular malformations associated with cavitation. Extrapulmonary involvement is due to hematogenous or lymphatic spread from pulmonary lesions. Virtually any organ can become infected, giving rise to the protean manifestations of tuberculosis. The pleura, chest wall, and mediastinal organs may all be involved. More than one third of immunocompromised patients have disseminated disease, with hepatomegaly, diarrhea, splenomegaly, and abdominal pain. The definitive diagnosis of tuberculosis requires identification of the mycobacterium in a patient’s bodily fluids or involved tissues. Skin testing using purified protein derivative is important for epidemiologic purposes and can help exclude infection in uncomplicated cases. For pulmonary tuberculosis, sputum examination is inexpensive and has a high diagnostic yield. Bronchoscopy with alveolar lavage may also be a useful diagnostic adjunct and has high diagnostic accuracy. Chest CT scan can delineate the extent of parenchymal disease. whose lungs have been destroyed and who have persistent thick-walled cavitation.122 The indications for surgery related to mycobacterial pulmonary infections are presented in Table 19-19. The governing principle of mycobacterial surgery is to remove all gross disease while preserving any uninvolved lung tissue. Scattered nodular disease may be left intact, given its low mycobacterial burden. Antimycobacterial medications should be given preoperatively (for about 3 months) and continued postoperatively for 12 to 24 months. Overall, more than 90% of patients who were deemed good surgical candidates are cured when appropriate medical and surgical therapy is used. 656 INH/RIF 2-month culture negative INH/RIF Cavitation on CXR or positive AFB smear at 2 months UNIT II PART High clinical suspicion for active tuberculosis INH/RIF 2-month culture positive No cavitation Cavitation INH/RIF/EMB*/PZA† SPECIFIC CONSIDERATIONS No cavitation on CXR and negative AFB smear at 2 months INH/RIF INH/RIF INH/RPT‡§ 0 1 2 3 4 6 9 Time (months) Figure 19-32. Treatment algorithm for tuberculosis. Patients in whom tuberculosis is proven or strongly suspected should have treatment initiated with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph (CXR) or the acid-fast bacillus (AFB) smear results are positive at completion of 2 months of treatment, the continuation phase of treatment should consist of INH and RIF daily or twice daily for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial CXR and the culture results at the time of completion of 2 months of therapy are positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4+ cell count is <100/μL, the continuation phase should consist of daily or three times weekly INH and RIF. In HIV-uninfected patients with no cavitation on CXR and negative results on AFB smears at completion of 2 months of treatment, the continuation phase may consist of either once weekly INH and rifapentine (RPT) or daily or twice weekly INH and RIF to complete a total of 6 months of treatment (bottom). For patients receiving INH and RPT whose 2-month culture results are positive, treatment should be extended by an additional 3 months (total of 9 months). *EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. †PZA may be discontinued after it has been taken for 2 months (56 doses). ‡RPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. §Therapy should be extended to 9 months if results of 2-month culture are positive. (Reproduced with permission of the American Thoracic Society. Copyright © American Thoracic Society. Blumberg HM, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603.) Table 19-19 Indications for surgery to treat mycobacterial pulmonary infections 1. Complications resulting from previous thoracic surgery to treat tuberculosis 2. Failure of optimized medical therapy (e.g., progressive disease, lung gangrene, or intracavitary aspergillosis superinfection) 3. Need for tissue acquisition for definitive diagnosis 4. Complications of pulmonary scarring (e.g., massive hemoptysis, cavernomas, bronchiectasis, or bronchostenosis) 5. Extrapulmonary thoracic involvement 6. Pleural tuberculosis 7. Nontuberculous mycobacterial infection gray (or red, brown, or even yellow), necrotic-looking mass (Fig. 19-33). This form is the most common presentation of noninvasive pulmonary aspergillosis. The most common symptoms are hemoptysis, chronic and productive cough, clubbing, malaise, or weight loss. CXR can suggest the diagnosis by the finding of a crescentic radiolucency above a rounded radiopaque lesion (Monad sign). The natural history varies greatly between patients and, therefore, treatment is individualized. Factors associated with poor prognosis include severe underlying pul11 monary disease, growth in the number or size of the aspergilloma(s) during observation, immunosuppression or HIV infection, history of lung transplantation, chronic pulmonary sarcoidosis, and increasing Aspergillus-specific IgG titers. Asymptomatic patients can be observed without any additional therapy. Antifungals have limited utility due to the poor blood supply to the aspergilloma. Amphotericin B is the drug of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 657 B C Figure 19-33. Pulmonary aspergilloma. A. The chest x-ray shows a solid mass within a cavity surrounded by a rim of air between the mass and cavity wall (Monad sign, arrows). B. A cut section shows the “fungus ball” occupying an old, fibrotic cavity. C. Histologic stain reveals characteristic Aspergillus hyphae invading the wall of the cavity. choice, although voriconazole has recently been used for treatment of aspergillosis, with fewer side effects and equivalent efficacy. Hemoptysis is a harbinger of erosion of the disease into adjacent bronchial arteries and typically requires intervention. In the setting of very mild hemoptysis (e.g., bloodstreaked sputum), cough suppression is warranted while further therapeutic evaluation is performed. Bronchial artery embolization is the first-line therapy for massive hemoptysis and may be definitive therapy.126 This is particularly important to consider for patients with severely impaired pulmonary function who may not have sufficient reserve to tolerate even a very small pulmonary resection. Operative intervention may be required for recurrent hemoptysis, particularly after bronchial artery embolization, chronic cough with systemic symptoms, progressive infiltrate around the mycetoma, and a pulmonary mass of unknown cause.127 When operative intervention is indicated, the surgeon must remain cognizant of the goals of the procedure. As this disease typically occurs in patients with significantly impaired pulmonary function, attempts should be made to excise all diseased tissue with as limited a resection as possible. Once resection is completed, the postresection space in the hemithorax should be obliterated with a pleural tent, pneumoperitoneum, decortication of the remaining lung, intrathoracic rotation of a muscle or omental flap, or thoracoplasty. Long-term follow-up is necessary, given that the recurrence rate after surgery is about 7%. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura A 658 UNIT II PART SPECIFIC CONSIDERATIONS Invasive pulmonary aspergillosis typically affects immunocompromised patients who have dysfunctional cellular immunity, namely defective polymorphonuclear leukocytes. Invasion of pulmonary parenchyma and blood vessels by a necrotizing bronchopneumonia may be complicated by thrombosis, hemorrhage, and then dissemination. Patients present with fever that is nonresponsive to antibiotic therapy in the setting of neutropenia. They may also have pleuritic chest pain, cough, dyspnea, or hemoptysis. Characteristic signs on CT scan include the halo sign and cavitary lesions. Treatment with voriconazole must be prompt and aggressive, including reversal of neutropenia, if there is to be any chance for recovery. Mortality ranges from 93% to 100% in bone marrow transplant recipients, to approximately 38% in kidney transplant recipients, although this improves to approximately 60% at 12 weeks with voriconazole therapy. Several other advances in diagnosis and treatment, including CT scans in high-risk populations and development of additional triazoles and echinocandins, have improved the early identification and response to therapy in this patient population. Additional treatment considerations include the use of hematopoietic growth factors to minimize the neutropenic period, which contributes to uncontrolled disease. Surgical removal of the infectious nidus is advocated by some groups because medical treatment has such poor outcomes. Treatment continues until microbiologic clearance is achieved and clinical signs and radiographic imaging indicate resolution of disease. In addition, the patient should no longer be immunosuppressed. If continuation of immunosuppressive medications is required, antifungal therapy should also continue to prevent recurrence of invasive disease. Cryptococcosis. Cryptococcosis is a subacute or chronic infection caused by Cryptococcus neoformans, a round, budding yeast (5–20 μm in diameter) that is sometimes surrounded by a characteristic wide gelatinous capsule. Cryptococci are typically present in soil and dust contaminated by pigeon droppings. When inhaled, such droppings can cause a nonfatal disease primarily affecting the pulmonary and central nervous systems. At present, cryptococcosis is the fourth most common opportunistic infection in patients with HIV infection, affecting 6% to 10% of that population. Four basic pathologic patterns are seen in the lungs of infected patients: granulomas; granulomatous pneumonia; diffuse alveolar or interstitial involvement; and proliferation of fungi in alveoli and lung vasculature. Symptoms are nonspecific, as are the radiographic findings. Cryptococcus may be isolated from sputum, bronchial washings, percutaneous needle aspiration of the lung, or cerebrospinal fluid. If disease is suspected, serum cryptococcal antigen titers should be obtained; if positive or if the patient has persistent fever, evidence of progression, physiologic compromise, or dissemination, treatment should be promptly initiated. Multiple antifungal agents are effective against C. neoformans, including amphotericin B and the azoles. The choice of antifungal and duration of treatment depend on the severity of disease. Duration of therapy is longer in patients who are immunocompromised. Candidiasis. Candida organisms are oval, budding cells (with or without mycelial elements) that colonize the oropharynx of many healthy individuals. The fungi of this genus are common hospital and laboratory contaminants. Usually, Candida albicans causes disease in the oral or bronchial mucosa, among other anatomic sites. Other potentially pathogenic Candida species include C. tropicalis, C. glabrata, and C. krusei. Historically, C. albicans was the most common pathogen to cause invasive candidal infection. However, more recent reports suggest that other Candida species, particularly C. glabrata and C. krusei, are becoming more prevalent and now account for between 40% and 50% of all cases. These species are relatively resistant to fluconazole, and the shift is likely related to the widespread use of this antifungal agent.128 The incidence of Candida infections has increased and is no longer confined to immunocompromised patients. Increasing incidence of infection has been identified in patients with any of the following risk factors: critical illness of long duration; use of long-term antibiotics, particularly multiple; indwelling urinary or vascular catheter; gastrointestinal perforation; or burn wounds.129 With respect to the thorax, such patients commonly have candidal pneumonia, pulmonary abscess, esophagitis, and mediastinitis. Pulmonary candidal infections typically result in an acute or chronic granulomatous reaction. Because Candida can invade blood vessel walls and a variety of tissues, systemic or disseminated infections can occur, but are less common. Treatment for candidal infection includes both fungicidal and fungistatic agents. The fungicidal medications include polyenes (amphotericin B deoxycholate [AmB-D] and various lipid-associated amphotericin B preparations) and the echinocandins (caspofungin, micafungin, and anidulafungin). Fungistatic drugs include the triazoles (fluconazole, itraconazole, voriconazole, and posaconazole).128 The availability of multiple effective therapies allows for specific tailoring of treatment, including combination regimens, based on the patient’s ability to tolerate associated toxicities, the microbiologic information for the specific candidal species, and the route of administration. While demonstrated efficacy is similar, the triazoles and echinocandins appear to have fewer side effects and are better tolerated than the other classes of antifungal drugs. In addition to prompt institution of antifungal therapy, it is advisable to remove all central venous catheters. For fungemia, an eye examination should be performed. Treatment should continue for at least 2 weeks after the last positive blood culture. For patients with Candida mediastinitis (which has a mortality rate of >50%), surgical intervention to debride all infected tissues is required, in addition to prolonged administration of antifungal drugs. Mucormycosis. The Mucor species, rare members of the class Zygomycetes, are responsible for rapidly fatal disease in immunocompromised patients. Other disease-causing species of the class Zygomycetes include Absidia, Rhizopus, and Mortierella.130 Characteristic of these fungi are nonseptate, branching hyphae that are difficult to culture. Infection occurs via inhalation of spores. Immunocompromised patients, including patients with neutropenia, acidosis, diabetes, and hematologic malignancy all predispose to clinical susceptibility. In the lungs, disease consists of blood vessel invasion, thrombosis, and infarction of infected organs. Tissue destruction is significant, along with cavitation and abscess formation. Initial treatment is to correct underlying risk factors and administer antifungal therapies, although the optimal duration and optimal total dose are unknown. Lipid formulations of amphotericin B are recommended at this time. Surgical resection of any localized disease should be performed after initial medical treatment attempts fail. Primary Fungal Pathogens Histoplasma capsulatum. Histoplasma capsulatum is a dimorphic fungus existing in mycelial form in soil contaminated by VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ silicone stents may be needed for airway compromise, although this should be directed by a surgeon with expertise in mediastinal and airway disease management. Chronic pulmonary histoplasmosis occurs in about 10% of patients who become symptomatic after infection. Most such patients have pre-existing lung pathology, particularly emphysema, which becomes colonized. Subsequent pneumonitis and necrosis, cavity enlargement, new cavity formation, and pulmonary dissemination occur. Nonspecific symptoms, such as cough, sputum production, fever, weight loss, weakness, and hemoptysis are common. Chest radiography may reveal intrapulmonary cavitation and scarring. Occasionally, partial resolution of the inflammatory changes may be observed. Itraconazole provides effective therapy, but must be given for 12 to 24 months. It is superior to ketoconazole and fluconazole; these should only be used if itraconazole is not tolerated. Voriconazole and posaconazole have been found to be useful for salvage therapy. Serum itraconazole levels should be monitored to ensure that the drug is being absorbed. Occasionally, lipidassociated amphotericin B is necessary for more severe infections. Surgical excision should be considered in patients with adequate pulmonary reserve and localized, thick-walled cavities that have been unresponsive to antifungal therapy. Disseminated histoplasmosis occurs most frequently in patients who are severely immunocompromised, such as posttransplantation patients, patients with HIV, and patients using immunosuppressive medications. Presentation ranges from nonspecific signs of fever, weight loss, and malaise, to shock, respiratory distress, and multiorgan failure. Diagnosis can be made with a combination of Histoplasma urine antigen, serologic assay, and fungal culture and should be suspected in patients with the above symptoms in any endemic area, particularly if the patient is immunosuppressed.133 Any of the antifungal therapies can be used in treatment of disseminated histoplasmosis. Use of amphotericin B has decreased the mortality rate to less than 25% in this type of serious infection. Coccidioides immitis. Coccidioides immitis is an endemic fungus found in soil and dust of the southwestern United States. Agricultural workers, military personnel, and other occupations with extensive exposure to soil, especially in areas of endemic growth, are at highest risk, as are immunocompromised individuals.134 Spores (arthroconidia) are inhaled, swell into spherules, and subdivide into endospores, and subsequent infection develops. Diagnosis can be achieved through serum analysis for anticoccidioidal antibody, spherule identification in tissue, or by isolating the fungus in cultures from sputum, other body fluid, or tissue. Inhalation of the fungus causes pulmonary involvement in 95% of patients with symptomatic disease. Three main categories of pulmonary involvement, based on the associated signs and symptoms, are possible: primary; complicated; and residual pulmonary coccidioidomycosis. Primary pulmonary coccidioidomycosis occurs in about 40% of people who inhale spores. The other 60% will remain asymptomatic and develop life-long immunity. The constellation of symptoms of “valley fever,” including fever, chills, headache, erythema multiforme, erythema nodosum, polyarthralgias, nonproductive cough, and chest pain, and a CXR showing hilar and paratracheal adenopathy are highly suggestive of pulmonary coccidioidomycosis. In many patients, initial diagnosis is community-acquired pneumonia, and it is only when the patient fails to respond to appropriate antibiotic therapy that pulmonary coccidioidomycosis VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 659 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura fowl or bat excreta and in yeast form in human hosts. The most common of all fungal pulmonary infections, histoplasmosis primarily affects the respiratory system after spores are inhaled. It is endemic in the Midwest and Mississippi River Valley of the United States, where about 500,000 new cases arise each year. In immunocompromised patients, the infection becomes systemic and more virulent; because cell-mediated immunity is impaired, uninhibited fungal proliferation occurs within pulmonary macrophages and then spreads. Acute forms of the disease present as primary or disseminated pulmonary histoplasmosis; chronic forms present as pulmonary granulomas (histoplasmomas), chronic cavitary histoplasmosis, mediastinal granulomas, fibrosing mediastinitis, or bronchiolithiasis. Histoplasmosis is definitively diagnosed by fungal smear, culture, direct biopsy of infected tissues, or serologic testing. The clinical presentation depends on the inoculum size and on host factors. Symptoms of acute pulmonary histoplasmosis are fever, chills, headache, chest pain, musculoskeletal pain, and nonproductive cough. CXRs may be normal or may show mediastinal lymphadenopathy and patchy parenchymal infiltrates. Most patients improve in a few weeks; mild to moderate disease can be treated with itraconazole. Amphotericin B is the treatment of choice if moderate symptoms persist for 2 to 4 weeks or if the illness is extensive, including dyspnea and hypoxia, and if patients are immunosuppressed.131 As the pulmonary infiltrates from acute histoplasmosis heal, consolidation into an asymptomatic solitary nodule or histoplasmoma may occur and is usually seen incidentally on radiographs as a coin-shaped lesion. Central and concentric calcification may occur; if so, no further treatment is required. Noncalcification of the lesion requires further diagnostic workup including chest CT scan, needle biopsy, or surgical excision to rule out a malignancy. Figure 19-34 demonstrates the differences in pathologic findings between infections in normal and immunocompromised hosts.132 When lymph nodes and pulmonary granulomas calcify over time, pressure atrophy on the bronchial wall may result in erosion and migration of the granulomatous mass into the bronchus, causing bronchiolithiasis. Typical symptoms include cough, hemoptysis, and dyspnea. Life-threatening complications include massive hemoptysis or bronchoesophageal fistula. In addition to radiography, bronchoscopy should be performed to aid in diagnosis. Definitive treatment requires surgical excision of the bronchial mass and repair of the airway and contiguous structures. Endobronchial debridement is not advised as this can result in massive, fatal bleeding. Fibrosing mediastinitis is an uncommon manifestation of histoplasmosis but can be fatal due to progressive distortion and compression of the major vessels and central airways. Diagnosis can be difficult and symptoms may be present for extended periods, even years, before the diagnosis is made. The differential diagnosis for the disease process includes granulomatous mediastinitis related to recent infection, malignancy, and chronic pulmonary thromboembolism. A trial of itraconazole is worthwhile, although it is not proven to be effective. In cases where radiographic or physiologic improvement is achieved after a trial of 12 week of therapy, continuation of therapy is considered for a full 12 months. In the majority of patients, however, antifungal therapy has not been proven effective. There is no role for corticosteroids at this time or for antifibrotics. Occasionally, intravascular stents have been helpful for severe vascular compromise. Balloon dilatation and endobronchial 660 UNIT II PART SPECIFIC CONSIDERATIONS Figure 19-34. Pathologic findings of infection in normal and immunocompromised hosts. Histopathologic preparations are shown contrasting acute diffuse pulmonary involvement in a lung segment of a normal host with a probable primary infection (A through D) with pulmonary granulomas from an immunocompromised patient who had an opportunistic reinfection with Histoplasma capsulatum (E, F). A. Diffuse interstitial pneumonitis in an adult (normal host) with recent heavy environmental exposure and subsequent development of progressive pulmonary disease. There is an inflammatory cell infiltrate primarily involving the interalveolar interstitial spaces but present within many alveolar spaces as well. The exudate consists mostly of mononuclear phagocytes, lymphocytes, and occasional plasma cells. Many of the alveolar walls are markedly thickened (hematoxylin and eosin stain [H&E], ×50). B. Another area from the same lung as in A showing focal vasculitis with an infiltrate of lymphocytes and macrophages (H&E, ×25). C. Relatively large alveolar macrophages packed with single and budding yeasts 2 to 4 μm in diameter (same lung as in A and B). The basophilic cytoplasm of these yeasts is retracted from their thin outer cell walls, leaving halo-like clear areas that can be confused with capsules (H&E, ×500). D. Intracellular and extracellular yeasts, 2 to 4 μm in diameter, some of which are single, budding, or in short chains (Gomori methenamine silver stain, ×500). E. Nonnecrotizing (sometimes called epithelioid cell or noncaseating) granuloma from a patient who had recently received chemotherapy for a germ cell tumor (different patient than in A through D). This lesion consists of a focal collection of macrophages (sometimes referred to as histiocytes or epithelioid cells) plus lymphocytes and occasional plasma cells. A few multinucleated macrophages are present. A thin layer of fibroblasts circumscribes the lesion. Yeasts of H. capsulatum, probably present within macrophages of this lesion at an earlier stage, were not identified in this granuloma or in any of several other nonnecrotizing granulomas within the specimen. Lesions of this type often undergo necrosis to become necrotizing granulomas (H&E, ×50). F. Necrotizing (sometimes referred to as caseating) granuloma from the same lung as in E. This lesion has a necrotic center surrounded by macrophages, encapsulating fibroblasts, fibrous connective tissue in the periphery, and scattered lymphocytes. A prominent giant cell is present in the lower left of the granuloma (at approximately 8 o’clock). Microorganisms are usually present only in relatively small numbers in these types of lesions. They are most frequently detected within the most central necrotic material in these granulomas (H&E, ×25). (Reproduced with permission from Hage et al.132) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Once a patient manifests symptoms of chronic blastomycosis, antifungal treatment is required to achieve resolution. Mortality approaches 60% if untreated.135 While controversial, a short course of triazole therapy (oral itraconazole 200 mg daily) for 6 months is the treatment of choice for most patients with mild to moderate forms of the disease. Because itraconazole has poor CNS penetration, the most common site of recurrence after apparently successful therapy is in the CNS. In the absence of therapy, close follow-up is warranted for evidence of progression to chronic or extrapulmonary disease. Amphotericin B is warranted for patients with severe or life-threatening disease, CNS involvement, disseminated disease, or extensive lung involvement and in immunocompromised patients. After adequate drug therapy, surgical resection of known cavitary lesions should be considered because viable organisms are known to persist in such lesions. Massive Hemoptysis Massive hemoptysis is generally defined as expectoration of over 600 mL of blood within a 24-hour period. It is a medical emergency associated with a mortality rate of 30% to 50%. Most clinicians would agree that losing over a liter of blood via the airway within 1 day is significant, yet use of an absolute volume criterion presents difficulties. First, it is difficult for the patient or caregivers to quantify the volume of blood being lost. Second, and most relevant, the rate of bleeding necessary to incite respiratory compromise is highly dependent on the individual’s prior respiratory status. For example, the loss of 100 mL of blood over 24 hours in a 40-year-old male with normal pulmonary function would be of little immediate consequence, because his normal cough would ensure his ability to clear the blood and secretions. In contrast, the same amount of bleeding in a 69-year-old male with severe COPD, chronic bronchitis, and an FEV1 of 1.1 L may be life-threatening. Anatomy. The lungs have two sources of blood supply: the pulmonary and bronchial arterial systems. The pulmonary system is a high-compliance, low-pressure system, and the walls of the pulmonary arteries are very thin and delicate. The bronchial arteries, part of the systemic circulation, have systemic pressures and thick walls; most branches originate from the proximal thoracic aorta. Most cases of massive hemoptysis involve bleeding from the bronchial artery circulation or from the pulmonary circulation pathologically exposed to the high pressures of the bronchial circulation. In many cases of hemoptysis, particularly those due to inflammatory disorders, the bronchial arterial tree becomes hyperplastic and tortuous. The systemic pressures within these arteries, combined with a disease process within the airway and erosion, lead to bleeding. Causes. Significant hemoptysis occurs as a result of pulmonary, extrapulmonary, and iatrogenic causes. Table 19-20 summarizes the most common causes of hemoptysis. Most are secondary to inflammatory processes. Aneurysms of the pulmonary artery (referred to as Rasmussen’s aneurysm) can develop within pulmonary cavities and can result in massive bleeding. Hemoptysis due to lung cancer is usually mild, resulting in blood-streaked sputum. Massive hemoptysis in patients with lung cancer is typically caused by malignant invasion of pulmonary artery vessels by large central tumors. Although rare, it is often a terminal event. Management. Life-threatening hemoptysis is best managed by a multidisciplinary team of intensive care physicians, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 661 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura is considered. The disease is self-limited in the majority of patients, and treatment is not required in these cases. Therapy should be considered for (a) patients with impaired cellular immunity; (b) comorbid illnesses that are adversely impacted by the infection, including chronic pulmonary dysfunction, renal failure, and congestive heart failure; and (c) when symptoms and radiographic findings persist for more than 6 to 8 weeks, at which time the disease is considered to be persistent coccidioidal pneumonia and occurs in approximately 1% of patients. Progression to caseous nodules, cavities, and calcified, fibrotic, or ossified lesions indicates complicated or residual stages of coccidioidomycosis. There are several relative indications for surgery in pulmonary coccidioidomycosis. A rapidly expanding (>4 cm) cavity that is close to the visceral pleura is a high risk for rupture into the pleural space and subsequent empyema. Other indications for operative intervention include life-threatening hemoptysis; hemoptysis that is persistent despite medical therapy; symptomatic fungus ball; bronchopleural fistula; cavitary lesions with persistent positive sputum; and pulmonary nodules that degenerate over time. Finally, any nodule with signs that are concerning for malignancy should undergo further evaluation, including biopsy or resection, to determine the underlying etiology. Diagnosis of coccidioidomycosis is confirmed by histopathologic, mycologic, and serologic evaluation. Extrapulmonary disease may develop in approximately 0.5% of infected patients, with involvement of meninges, bones, joints, skin, or soft tissues. Immunocompromised patients are especially susceptible to disseminated coccidioidomycosis, which carries a mortality rate over 40%. Treatment options for this disease vary depending on the severity of the disease as well as the stage. Amphotericin B deoxycholate or the triazoles continue to be the primary antifungal medications. If meningeal involvement is identified, fluconazole or itraconazole therapy is required for the remainder of the patient’s life. Intrathecal amphotericin B can also be administered in some cases. Blastomyces dermatitidis. Blastomyces dermatitidis is a round, single-budding yeast with a characteristic thick, refractile cell wall. It resides in the soil as a nonmotile spore called conidia. Exposure occurs when contaminated soil is disturbed and the conidia are aerosolized. The spore is inhaled and transforms into a yeast phase at body temperature.135 Infection is typically self-limited. A small minority of patients will develop chronic pulmonary infection or disseminated disease, including cutaneous, osteoarticular, and genitourinary involvement. B. dermatitidis has a worldwide distribution; in the United States, it is endemic in the central states.136 With chronic infection, the organism induces a granulomatous and pyogenic reaction with microabscesses and giant cells; caseation, cavitation, and fibrosis may also occur. Symptoms are nonspecific and consistent with chronic pneumonia in 60% to 90% of patients. They include cough, mucoid sputum production, chest pain, fever, malaise, weight loss, and, uncommonly, hemoptysis. In acute disease, radiographs are either completely negative or have nonspecific findings; in chronic disease, fibronodular lesions (with or without cavitation) similar to tuberculosis are noted. Pulmonary parenchymal abnormalities in the upper lobe(s) may be noted. Mass lesions similar to carcinoma are frequent, and lung biopsy is frequently used. Over 50% of patients with chronic blastomycosis also have extrapulmonary manifestations, but less than 10% of patients present with severe clinical manifestation.135 662 Table 19-20 Pulmonary and extrapulmonary causes of massive hemoptysis UNIT II PART SPECIFIC CONSIDERATIONS Pulmonary Extrapulmonary Iatrogenic Pulmonary parenchymal disease Bronchitis Bronchiectasis Tuberculosis Lung abscess Pneumonia Cavitary fungal infection (e.g., aspergilloma) Lung parasitic infection (ascariasis, schistosomiasis, paragonimiasis) Pulmonary neoplasm Pulmonary infarction or embolism Trauma Arteriovenous malformation Pulmonary vasculitis Pulmonary endometriosis Wegener’s granulomatosis Cystic fibrosis Pulmonary hemosiderosis Congestive heart failure Coagulopathy Mitral stenosis Medications Intrapulmonary catheter interventional radiologists, and thoracic surgeons. Treatment priorities begin with respiratory stabilization; intubation with isolation of the bleeding lung may be required to prevent asphyxiation. This can be done with main-stem intubation into the nonbleeding lung, endobronchial blockers into the bleeding lung, or double-lumen endotracheal intubation, depending on the urgency of the situation and the expertise of the providers. Once adequate ventilation has been achieved, the bleeding site should be localized; bronchoscopy can often provide direct visualization of blood coming from a specific area of the tracheobronchial anatomy. Control of the hemorrhage is then achieved endobronchially with laser or bronchial occlusion, endovascularly with bronchial and/or pulmonary artery embolization, or surgically with resection of the involved area.137 The order of priorities in management is detailed in Table 19-21. The clinically pragmatic definition of massive hemoptysis is a degree of bleeding that threatens respiratory stability. Therefore, clinical judgment of respiratory compromise is the first step in evaluating a patient.138,139 Two scenarios are possible: (1) bleeding is significant and persistent, but its rate allows a rapid, sequential diagnostic and therapeutic approach, or (2) bleeding is so rapid that emergency airway control and therapy are necessary. Table 19-21 Treatment priorities in the management of massive hemoptysis 1. Achieve respiratory stabilization and prevent asphyxiation. 2. Localize the bleeding site. 3. Control the hemorrhage. 4. Determine the cause. 5. Definitively prevent recurrence. Scenario 1: Significant, Persistent, but Nonmassive Bleeding. Although bleeding is brisk in scenario 1, the patient may be able to maintain clearance of the blood and secretions with his or her own respiratory reflexes. Immediate measures are admission to an intensive care unit; strict bed rest; Trendelenburg positioning with the affected side down (if known); administration of humidified oxygen; cough suppression; monitoring of oxygen saturation and arterial blood gases; and insertion of large-bore intravenous catheters. Strict bed rest with sedation may lead to slowing or cessation of bleeding, and the judicious use of intravenous narcotics or other relaxants to mildly sedate the patient and diminish some of the reflexive airway activity is often necessary. Also recommended are administration of aerosolized adrenaline, intravenous antibiotic therapy if needed, and correction of abnormal blood coagulation study results. Finally, unless contraindicated, intravenous vasopressin (20 U over 15 minutes, followed by an infusion of 0.2 U/min) can be given. A CXR is the first test and often proves to be the most revealing. Localized lesions may be seen, but the effects of blood soiling of other areas of the lungs may predominate, obscuring the area of pathology. Chest CT scan provides more detail and is nearly always performed if the patient is stable. Pathologic areas may be obscured by blood soiling. Flexible bronchoscopy is the next step in evaluating the patient’s condition. Some clinicians argue that rigid bronchoscopy should always be performed. However, if the patient is clinically stable and the ongoing bleeding is not imminently threatening, flexible bronchoscopy is appropriate. It allows diagnosis of airway abnormalities and will usually permit localization of the bleeding site to either a lobe or even a segment. The person performing the bronchoscopy must be prepared with excellent suction and must be able to perform saline lavage with a dilute solution of epinephrine. Most cases of massive hemoptysis arise from the bronchial arterial tree; therefore, the next therapeutic option frequently is selective bronchial arteriography and embolization. Bronchoscopy VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Scenario 2: Significant, Persistent, and Massive Bleeding. Life-threatening bleeding requires emergency airway control and preparation for potential surgery. Such patients are best cared for in an operating room equipped with rigid bronchoscopy. Immediate orotracheal intubation may be necessary to gain control of ventilation and suctioning. However, rapid transport to the operating room with rigid bronchoscopy should be facilitated. Rigid bronchoscopy allows adequate suctioning of bleeding with visualization of the bleeding site; the nonbleeding side can be cannulated with the rigid scope and the patient ventilated. After stabilization, ice-saline lavage of the bleeding site can then be performed (up to 1 L in 50-mL aliquots); bleeding stops in up to 90% of patients.142 Alternatively, blockade of the main stem bronchus of the affected side can be accomplished with a double-lumen endotracheal tube, with a bronchial blocker, or by intubation of the nonaffected side by an uncut standard endotracheal tube. Placement of a double-lumen endotracheal tube is challenging in these circumstances, given the bleeding and secretions. Proper placement and suctioning may be difficult, and attempts could compromise the patient’s ventilation. The best option is to place a bronchial blocker in the affected bronchus with inflation. Endovascular embolization can be performed to stop the bleeding after control has been achieved with the bronchial blocker. The blocker is left in place for 24 hours; after 24 hours, the area is re-examined bronchoscopically. Surgical Intervention. In most patients, bleeding can be stopped, recovery can occur, and plans to definitively treat the underlying cause can be made. In scenario 1 (significant, persistent, but nonmassive bleeding), the patient may undergo further evaluation as an inpatient or outpatient. A chest CT scan and Table 19-22 663 General indications for urgent operative intervention for massive hemoptysis 1. 2. 3. 4. Presence of a fungus ball Presence of a lung abscess Presence of significant cavitary disease Failure to control the bleeding pulmonary function studies should be obtained preoperatively. In scenario 2 (patients with significant, persistent, and massive bleeding), surgery, if appropriate, will usually be performed during the same hospitalization as the rigid bronchoscopy or main stem bronchus blockade. In a small number of patients (<10%), immediate surgery will be necessary due to the extent of bleeding. The bleeding site in these patients is localized using rigid bronchoscopy with immediate thoracotomy or sternotomy to follow. Surgical treatment is individualized according to the source of bleeding and the patient’s medical condition, prognosis, and pulmonary reserve. General indications for urgent surgery are presented in Table 19-22. In patients with significant cavitary disease or with fungus balls, the walls of the cavities are eroded and necrotic; rebleeding will likely ensue. In addition, bleeding from cavitary lesions may be due to pulmonary artery erosion, which requires surgery for control. End-Stage Lung Disease Lung Volume Reduction Surgery. The ideal patient for lung volume reduction surgery (LVRS) has heterogeneous emphysema with apical predominance, meaning the worst emphysematous changes are in the apex (seen on chest CT scan) of the lungs. The physiologic lack of function of these areas is demonstrated by quantitative perfusion scan, which shows minimal or no perfusion. By surgically excising these nonfunctional areas, the volume of the lung is reduced, theoretically restoring respiratory mechanics. Diaphragm position and function are improved, and there may be an improvement in the dynamic small airway collapse in the remaining lung. Operative mortality in the initial experience was 16.9%, with a 1-year mortality of 23%. In response, the National Emphysema Treatment Trial (NETT) performed a randomized trial of 1218 patients in a noncrossover design to medical vs. surgical management after a 10-week pretreatment pulmonary rehabilitation program. Subgroup analysis demonstrated that in patients with the anatomic changes delineated by Cooper and colleagues, LVRS significantly improved exercise capacity, lung function, quality of life, and dyspnea compared to medical therapy. After 2 years, functional improvements began to decline toward baseline. Similar parameters in medically treated patients steadily decline below baseline. LVRS was associated with increased short-term morbidity and mortality and did not confer a survival benefit over medical therapy.143 Lung Transplantation. The most common indications for lung transplant are COPD and idiopathic pulmonary fibrosis (IPF). Most patients with IPF and older patients with COPD are offered a single-lung transplant. Younger COPD patients and patients with α1-antitrypsin deficiency and severe hyperinflation of the native lungs are offered a bilateral-lung transplant. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura prior to arteriogram is extremely useful to direct the angiographer. However, if bronchoscopy fails to localize the bleeding site, then bilateral bronchial arteriograms can be performed. More recently, use of multidetector CT angiography in patients with hemoptysis that is not immediately life-threatening has been shown to facilitate endovascular intervention; reformatting of the images in multiple projections allows clear delineation of the pulmonary vascular anatomy.126 With this approach, abnormal bronchial and nonbronchial arteries can be visualized and subsequently targeted for therapeutic arterial embolization.140 Once the targeted arterial system has been embolized, immediate control and cessation of the hemoptysis is achieved in more than 80% of patients. If bleeding persists after bronchial artery embolization, a pulmonary artery source should be suspected and a pulmonary angiogram performed at the same setting. Recurrence is seen in 30% to 60% of cases and is very common in the setting of invasive fungal infections such as aspergilloma. Recurrence after bronchial artery embolization is less common in the setting of malignancy and active tuberculosis but does occur and can ultimately result in patient death.141 Repeat embolization can be effective and is warranted for initial management of recurrent hemoptysis, but early surgical intervention should be considered, particularly in the setting of aspergilloma or other cavitary lesions.126 If respiratory compromise is impending, orotracheal intubation should be performed. After intubation, flexible bronchoscopy should be performed to clear blood and secretions and to attempt localization of the bleeding site. Depending on the possible causes of the bleeding, bronchial artery embolization or (if appropriate) surgery can be considered. BOS-free survival 1.0 Survival 0.8 0.6 0.4 0.2 1 2 3 Years posttransplant SPECIFIC CONSIDERATIONS Figure 19-36. The survival rate after lung transplantation in the absence of bronchiolitis obliterans syndrome (BOS) at the University of Minnesota. injury to the lung(s) (Fig. 19-37). Reperfusion injury is characterized radiographically by interstitial and alveolar edema and clinically by hypoxia and ventilation-perfusion mismatch. Donor neutrophils and recipient lymphocytes probably play an important role in the pathogenesis of reperfusion injury. The most important impediment to longer-term survival after a lung transplant is the development of BOS, a manifestation of chronic rejection. Episodes of acute rejection are the major risk factors for developing BOS. Other injuries to the lung (including early reperfusion injury and chronic gastroesophageal reflux disease) may also adversely affect long-term outcomes of patients.146,147 CHEST WALL Chest Wall Mass Clinical Approach. Surgeons confronted with a patient with a chest wall mass must be cognizant that their approach to diagnosis Primary graft failure 1.0 Overall survival 1.0 No PGF 0.8 0.8 Survival UNIT II PART Most patients with primary pulmonary hypertension and almost all patients with cystic fibrosis are treated with a bilateral-lung transplant. A heart-lung transplant is reserved for patients with irreversible ventricular failure or uncorrectable congenital cardiac disease. Patients with COPD are considered for placement on the transplant waiting list when their FEV1 has fallen to below 25% of its predicted value. Patients with significant pulmonary hypertension should be listed earlier. IPF patients should be referred when their forced vital capacity has fallen to less than 60% or their Dlco has fallen to less than 50% of their predicted values. In the past, patients with primary pulmonary hypertension and New York Heart Association (NYHA) class III or IV symptoms were listed for a lung transplant. However, treatment of such patients with intravenous prostacyclin and other pulmonary vasodilators has now markedly altered that strategy. Virtually all patients with primary pulmonary hypertension are now treated with intravenous epoprostenol. Several of these patients have experienced a marked improvement in their symptoms associated with a decrease in their pulmonary arterial pressures and an increase in exercise capacity. Listing of these patients is deferred until they develop NYHA class III or IV symptoms or until their mean pulmonary artery pressure rises above 75 mmHg. Medium-term and bronchiolitis obliterans syndrome (BOS)-free survival rates of patients who underwent a lung transplant during a recent 5-year period at the University of Minnesota are shown in Figs. 19-35 and 19-36. The mortality of patients while waiting for transplants is about 10%. In an effort to expand the number of lung donors, many transplant groups have liberalized their criteria for donor selection. Still, the partial pressure of arterial oxygen (Pao2) should be greater than 300 mmHg on a fraction of inspired oxygen (Fio2) of 100%. In special circumstances, lungs may be used from donors with a smoking history; from donors older than 50 years of age; and from donors with positive Gram stains or infiltrates on CXR.144,145 The use of two living donors, each donating a single lower lobe, is another strategy for increasing the donor pool. Recipient outcomes are similar to those with cadaver donors in carefully selected patients. Most of the early mortality after lung transplant is related to primary graft failure resulting from a severe ischemia-reperfusion Survival 664 0.6 0.6 PGF 0.4 0.4 0.2 0.2 1 1 2 2 3 Years posttransplant 3 Years posttransplant Figure 19-35. The overall survival rate after lung transplantation at the University of Minnesota. Figure 19-37. The survival rate after lung transplantation at the University of Minnesota as a function of primary graft failure (PGF). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Chest wall mass Chest wall mass 665 CT or MRI or both CT or MRI or both Diagnosis is NOT clear Needle biopsy or incisional biopsy Lesion <2.0 cm Benign Tumors Fibrous dysplasia Chondroma Osteochondroma Eosinophilic granuloma Malignant Tumors Chondrosarcoma Nonrhabdosarcoma Fibrosarcoma Malignant fibrous histiocytoma Liposarcoma Synovial cell sarcoma Desmoid Nonrhabdomyosarcoma PNET/ Ewing’s sarcoma Preoperative chemotherapy Wide surgical excision Figure 19-38. Systematic approach for evaluating a chest wall mass when the clinical scenario is uncomplicated and initial imaging studies suggest a clear diagnosis. CT = computed tomography; MRI = magnetic resonance imaging. and treatment has significant impact on the patient’s chances for long-term survival. All chest wall tumors should be considered malignant until proven otherwise. It is critically important that the surgeon(s) be mindful of this tenet and well-versed in the diagnostic and treatment principles for chest wall malignancies. These tenets must be applied from the initial biopsy, as the placement of the incision can impact significantly on the successful complete resection and reconstruction of the chest wall. Complete resection is imperative if there is any hope for cure and/or long-term survival. A general approach is outlined in Figs. 19-38 and 19-39. Patients with chest wall tumors, regardless of etiology, typically complain of a slowly enlarging palpable mass (50%–70%), chest wall pain (25%–50%), or both. Interestingly, growing masses are often not noticed by the patient until they suffer a trauma to the area. Pain from a chest wall mass is typically localized to the area of the tumor; it occurs more often and more intensely with malignant tumors, but it can also be present in up to one third of patients with benign tumors. With Ewing’s sarcoma, fever and malaise may also be present. Benign chest wall tumors tend to occur in younger patients (average age 26 years), whereas malignant tumors tend to be found in older patients (average age 40 years). Overall, between 50% and 80% of chest wall tumors are malignant. Evaluation and Management. Laboratory evaluations are useful in assessing chest wall masses for the following: 1. Osteosarcoma Rhabdomyosarcoma Plasmacytoma: Serum protein electrophoresis demonstrates a single monoclonal spike, which is measuring the overproduction of one immunoglobulin from the malignant plasma cell clone. Wide surgical excision Figure 19-39. Systematic approach for evaluating a chest wall mass for which the diagnosis is not unequivocal. A tissue diagnosis is critical for effective management of chest wall masses. CT computed tomography; MRI magnetic resonance imaging; PNET primitive neuroectodermal tumor. 2. Osteosarcoma: Alkaline phosphatase levels may be elevated. 3. Ewing’s sarcoma: Erythrocyte sedimentation rates may be elevated. Radiography. CXR may reveal rib destruction, calcification within the lesion, and if old films are available, a clue to growth rate. CT scanning, however, is necessary to determine the relationship of the chest wall mass to contiguous structures (e.g., mediastinum, lung, soft tissues, and other skeletal elements), evaluate for pulmonary metastases, and assess for extraosseous bone formation and bone destruction, both typically seen with osteosarcoma. Because MRI provides multiple planes of imaging (coronal, sagittal, and oblique), better definition of the relationship between tumor and muscle, and tumor and contiguous or nearby neurovascular structures or the spine, it is an important radiographic adjunct for preoperative planning. Compared to CT scan alone, MRI may further delineate tissue abnormalities, potentially enhancing the ability to distinguish benign from malignant sarcoma. Biopsy. The first step in the management of all chest wall tumors is to obtain a tissue diagnosis. Inappropriate or misguided attempts at tissue diagnosis through casual open biopsy techniques have the potential (if the lesion is a sarcoma) to seed surrounding tissues and contiguous body cavities (e.g., the pleural space) with tumor cells, potentially compromising local tumor control and patient survival. Tissue diagnosis is accomplished using one of three methods: needle biopsy (typically VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Diagnosis is clear; a surgical resection is the primary treatment 666 CT-guided FNA or a core biopsy), incisional biopsy, or excisional biopsy in limited and specific situations. 1. 2. UNIT II PART SPECIFIC CONSIDERATIONS 3. Needle biopsy: Pathologists experienced with sarcomas can accurately diagnose approximately 90% of patients using FNA cytology. A needle biopsy (FNA or core) has the advantage of avoiding wound and body cavity contamination (a potential complication with an incisional biopsy). Incisional biopsy: If a needle biopsy is nondiagnostic, an incisional biopsy may be performed, with caveats. First, the skin incision must be placed directly over the mass and oriented to allow subsequent scar excision; skin flaps and drains should be avoided. However, if the surgeon believes a hematoma is likely to develop, a drain is useful for limiting soft tissue contamination by tumor cells. At the time of definitive surgical resection, the en bloc resection includes the biopsy scar and the drain tract along with the tumor. Excisional biopsy: Any lesion less than 2.0 cm can be excised as long as the resulting wound is small enough to close primarily. Otherwise, excisional biopsy is performed only when the initial diagnosis (based on radiographic evaluation) indicates that the lesion is benign or when the lesion has the classic appearance of a chondrosarcoma (in which case, definitive surgical resection can be undertaken). Benign Chest Wall Neoplasms 1. 2. 3. 4. Chondroma. Chondromas, seen primarily in children and young adults, are one of the more common benign tumors of the chest wall. They usually occur at the costochondral junction anteriorly and may be confused with costochondritis, except that a painless mass is present. Radiographically, the lesion is lobulated and radiodense; it may have diffuse or focal calcifications; and it may displace the bony cortex without penetration. Chondromas may grow to huge sizes if left untreated. Treatment is surgical resection with a 2-cm margin. Large chondromas may harbor well-differentiated chondrosarcoma and should be managed with a 4-cm margin to prevent local recurrence.148 Fibrous dysplasia. As with chondromas, fibrous dysplasia most frequently occurs in young adults and may be associated with trauma. Pain is an infrequent complaint, and the lesion is typically located in the posterolateral aspect of the rib cage. Radiographically, an expansile mass is present, with cortical thinning and no calcification. Local excision with a 2-cm margin is curative. Osteochondroma. Osteochondromas, often found incidentally as a solitary lesion on radiograph, are the most common benign bone tumor. Osteochondromas occur in the first two decades of life, and they arise at or near the growth plate of bones. Osteochondromas in the thorax arise from the rib cortex. They are one of several components to the autosomal dominant syndrome, hereditary multiple exostoses. When part of this syndrome, osteochondromas have a high rate of degeneration into chondrosarcomas. Any patient with hereditary multiple exostoses syndrome who develops new pain at the site of an osteochondroma or who notes gradual growth in the mass over time should be carefully evaluated for osteosarcoma. Local excision of a benign osteochondroma is sufficient. If malignancy is determined, wide excision is performed with a 4-cm margin. Eosinophilic granuloma. Eosinophilic granulomas are benign osteolytic lesions. Eosinophilic granulomas of the ribs can occur as solitary lesions or as part of a more generalized disease process of the lymphoreticular system termed Langerhans cell histiocytosis (LCH). In LCH, the involved tissue is infiltrated with large numbers of histiocytes (similar to Langerhans cells seen in skin and other epithelia), which are often organized as granulomas. The cause is unknown. Of all LCH bone lesions, 79% are solitary eosinophilic granulomas, 7% involve multiple eosinophilic granulomas, and 14% belong to other forms of more systemic LCH. Isolated single eosinophilic granulomas can occur in the ribs or skull, pelvis, mandible, humerus, and other sites. They are diagnosed primarily in children between the ages of 5 and 15 years. Because of the associated pain and tenderness, they may be confused with Ewing’s sarcoma or with an inflammatory process such as osteomyelitis. Healing may occur spontaneously, but the typical treatment is limited surgical resection with a 2-cm margin. 5. Desmoid tumors. Soft tissue neoplasms arising from fascial or musculoaponeurotic structures, desmoid tumors consist of proliferations of benign-appearing fibroblastic cells, abundant collagen, and few mitoses. Desmoid tumors possess alterations in the adenomatous polyposis coli (APC)/β-catenin pathway. Cyclin D1 dysregulation is thought to play a significant role in their pathogenesis.149 Associations with other diseases and conditions are well documented, especially those with similar alterations in the APC pathway, such as familial adenomatous polyposis (Gardner’s syndrome). Other conditions with increased risk of desmoid tumor formation include increased estrogen states (pregnancy) and trauma. Surgical incisions (abdominal and thorax) have been the site of desmoid development, either in or near the scar.   Clinically, patients are usually in the third to fourth decade of life and have pain, a chest wall mass, or both. The tumor is usually fixed to the chest wall, but not to the overlying skin. There are no typical radiographic findings, but MRI may delineate muscle or soft tissue infiltration. Desmoid tumors do not metastasize, but they have a significant propensity to recur locally, with reported rates ranging from 5% to 50%, sometimes despite complete initial resection with histologically negative margins.150 Such locally aggressive behavior is secondary to microscopic tumor infiltration of muscle and surrounding soft tissues and prompts some to consider them a low-grade form of fibrosarcoma.   Because the lesions have low cellularity and poor yield with FNA, an open incisional biopsy for lesions over 3 to 4 cm is often necessary, following the caveats listed earlier (see biopsy section). Surgery consists of wide local excision with a 2- to 4-cm margin and intraoperative frozen section assessment of resection margins. Typically, chest wall resection, including the involved rib(s) and one rib above and below the tumor with a 4- to 5-cm margin of rib, is required. A margin of less than 1 cm results in much higher local recurrence rates. If a major neurovascular structure would have to be sacrificed, leading to high morbidity, then a margin of less than 1 cm would have to suffice. Survival after wide local excision with negative margins is 90% at 10 years.151 Primary Malignant Chest Wall Tumors Malignant tumors of the chest wall are either metastatic lesions from another primary tumor or sarcoma. Soft tissue sarcomas of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 667 the chest wall include fibrosarcomas, liposarcomas, malignant fibrous histiocytomas (MFHs), rhabdomyosarcomas, angiosarcomas, and other extremely rare lesions (Fig. 19-40). Despite the prevalence of localized disease, soft tissue sarcomas of the chest wall have significantly worse survival than similar tumors located on the extremities or the head and neck region. The factors impacting on risk of death from soft tissue sarcomas of the chest wall are presented in Table 19-23. All sarcomas have a propensity to spread to the lungs. While many varieties of sarcoma exist, the primary features affecting prognosis are histologic grade and responsiveness to chemotherapy (Table 19-24). Preoperative (neoadjuvant) chemotherapy offers the ability to: (a) assess tumor chemosensitivity by the degree of tumor size reduction and microscopic necrosis; (b) determine tumor sensitivity to specific chemotherapeutic agents; and (c) improve resectability by reducing tumor size. Patients whose tumors are responsive to preoperative chemotherapy have a much better prognosis than those with a poor response. Information about tumor response to chemotherapy, the patient’s physiologic state and capacity to receive treatment, and metastatic disease status is used to determine optimal therapy. The initial treatment is either: (a) preoperative chemotherapy (for patients with osteosarcoma, rhabdomyosarcoma, primitive neuroectodermal tumor, or Ewing’s sarcoma) followed by surgery and postoperative chemotherapy; (b) primary surgical resection and reconstruction (for patients with nonmetastatic MFH, fibrosarcoma, liposarcoma, or synovial sarcoma); or (c) preoperative chemotherapy followed by surgical resection if indicated in patients presenting with metastatic soft tissue sarcomas. Contiguous involvement of underlying lung or other soft tissues or the presence of pulmonary metastases does not preclude successful surgery. In fact, patients receiving surgical intervention have significantly better overall survival. Median survival with surgical resection is 25 months compared to 8 months without resection Additional prognostic variables that are important for long-term survival include tumor size, grade, stage, and negative re-resection margin.152 With the exception of rhabdomyosarcomas, the primary treatment of these lesions is wide surgical resection with 4-cm margins and reconstruction.153 The following is an overview of several chest wall sarcomas. 1. 2. Chondrosarcoma. Chondrosarcomas are the most common primary chest wall malignancy. As with chondromas, they usually arise anteriorly from the costochondral arches. CT scan shows a radiolucent lesion often with stippled calcifications pathognomonic for chondrosarcomas (Fig. 19-41). The involved bony structures are also destroyed. Most chondrosarcomas are slow-growing, lowgrade tumors; these often painful masses can reach massive proportions.148 For this reason, any lesion in the anterior chest wall likely to be a low-grade chondrosarcoma should be treated with wide (4-cm) resection after metastatic disease to the lungs or bones is ruled out. Chondrosarcomas are not sensitive to radiation or chemotherapy. Prognosis is determined by tumor grade and extent of resection. With a low-grade tumor and wide resection, patient survival at 5 to 10 years can be as high as 60% to 80%. Osteosarcoma. While osteosarcomas are the most common bone malignancy, they represent only 10% to 15% of all malignant chest wall tumors.154,155 They primarily occur in young adults as rapidly enlarging, painful masses; however, osteosarcomas can occur in older patients as well, sometimes in association with previous radiation, Paget’s disease, or chemotherapy. Radiographically, the typical appearance consists of spicules of new periosteal bone formation producing a sunburst appearance. Osteosarcomas have a propensity to spread to the lungs, and up to one third of patients present with metastatic disease. Osteosarcomas are potentially sensitive to chemotherapy. Currently, preoperative chemotherapy is common. After chemotherapy, complete resection is performed with wide (4-cm) margins, followed by reconstruction. In patients presenting with lung metastases that are potentially amenable to surgical resection, induction chemotherapy may be given, followed by surgical resection of the primary tumor and of the pulmonary metastases. Following surgical treatment of known disease, additional maintenance chemotherapy is usually recommended. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Figure 19-40. Chest computed tomography scan showing a right chest wall tumor (arrow). Tissue diagnosis revealed that this mass was a leiomyosarcoma. 668 Table 19-23 Cox proportional hazards model for risk of death from soft tissue sarcoma UNIT II PART SPECIFIC CONSIDERATIONS N Hazard Ratio 95% CI P Value Gender Male Female 3937 4113 Reference group 0.897 Reference group 0.843–0.955 Reference group .001 Age 50 years 51–70 years >70 years 1837 3099 3114 Reference group 1.131 1.538 Reference group 1.026–1.247 1.395–1.697 Reference group .013 <.001 Race Caucasian Non-Caucasian 7152 898 Reference group 1.212 Reference group 1.093–1.344 Reference group <.001 Histologic type Fibrosarcoma MFH Liposarcoma LMS/GIST 489 2529 1534 3498 Reference group 1.281 0.894 1.204 Reference group 1.097–1.495 0.759–1.054 1.033–1.403 Reference group .002 .182 .018 Location Head and neck Trunk Extremity Retroperitoneum 576 4054 2474 946 Reference group 1.255 1.003 1.276 Reference group 1.096–1.438 0.875–1.151 1.093–1.489 Reference group .001 .960 .002 Stage Localized Regional Distant 5006 1724 1320 Reference group 1.575 2.897 Reference group 1.458–1.702 2.660–3.155 Reference group <.001 <.001 Surgical treatment Yes No 6754 1296 Reference group 1.562 Reference group 1.443–1.691 Reference group <.001 Radiation therapy Yes No 2175 5875 Reference group 1.151 Reference group 1.070–1.239 Reference group <.001 Chemotherapy Yes No 1062 6988 Reference group 0.909 Reference group 0.829–0.996 Reference group .041 CI = confidence interval; GIST = gastrointestinal stromal tumor; LMS = leiomyosarcoma; MFH = malignant fibrous histiocytoma. Source: Reproduced with permission from Gutierrez et al.152 Copyright Elsevier. 3. Table 19-24 Classification of sarcomas by therapeutic response Tumor Type Chemotherapy Sensitivity Osteosarcoma + Rhabdomyosarcoma + Primitive neuroectodermal tumor + Ewing’s sarcoma + Malignant fibrous histiocytoma ± Fibrosarcoma ± Liposarcoma ± Synovial sarcoma ± 4. Malignant fibrous histiocytoma. Originally thought to derive from histiocytes because of the microscopic appearance of cultured tumor cells, these tumors likely originate from the fibroblast. MFHs are generally the most common soft tissue sarcoma of late adult life, although they are rare on the chest wall. The typical age at presentation is between age 50 and 70 years. Presentation is pain, with or without a palpable mass. Radiographically, a mass is usually evident, with destruction of surrounding tissue and bone. Treatment is wide resection with a margin of 4 cm or more and reconstruction. Over two thirds of patients suffer from distant metastasis or local recurrence. Liposarcoma. Liposarcomas make up 15% of chest wall sarcomas. Most liposarcomas are low-grade tumors that have a propensity to recur locally, given their infiltrative nature. They typically present as a painless mass. Treatment is wide resection and reconstruction. Intraoperative VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 669 5. 6. margins should be evaluated (as with all sarcomas) and resection continued, if feasible, until margins are negative. Local recurrence can be treated with re-excision, with occasional use of radiotherapy. Fibrosarcoma. Often presenting as a large, painful mass, these lesions are visible on plain radiograph or CT, with surrounding tissue destruction. Treatment is wide local excision with intraoperative frozen-section analysis of margins, followed by reconstruction. Local and systemic recurrence is frequent. Patient survival at 5 years is about 50% to 60%. Rhabdomyosarcoma. Rhabdomyosarcomas are rare tumors of the chest wall. Microscopically, they are a spindle cell tumor. The diagnosis often depends on immunohistochemical staining for muscle markers. Rhabdomyosarcomas are sensitive to chemotherapy. Treatment consists of preoperative chemotherapy with subsequent surgical resection. Other Tumors of the Chest Wall 1. Primitive neuroectodermal tumors (PNETs) and Ewing’s sarcoma. PNETs (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) derive from primordial neural crest cells that migrate from the mantle layer of the developing spinal cord. Histologically, PNETs and Ewing’s sarcomas are small, round cell tumors; both possess a translocation between the long arms of chromosomes 11 and 22 within their genetic makeup. They also share a consistent pattern of proto-oncogene expression and have been found to express the product of the MIC2 gene. Ewing’s sarcoma occurs in adolescents and young adults who present with progressive chest wall pain, but without the presence of a mass. Systemic symptoms of malaise and fever are often present. Laboratory studies reveal an elevated erythrocyte sedimentation rate and mild white blood cell elevation. Radiographically, the characteristic onion peel appearance is produced by multiple layers of periosteum in the bone formation. Evidence of bony destruction is also common. The diagnosis can be made by a percutaneous needle biopsy or an incisional biopsy.   These tumors have a strong propensity to metastasize to the lungs and skeleton; patient survival rates are thus only 50% or less at 3 years. Increasing tumor size is associated with decreasing survival. Treatment has improved significantly and now consists of multiagent chemotherapy, radiation therapy, and surgery. Patients are typically treated preoperatively with chemotherapy and re-evaluated with radiologic imaging. When residual disease is identified, surgical resection and reconstruction are performed followed by maintenance chemotherapy. 2. Plasmacytoma. Solitary plasmacytomas of the chest wall are very rare, with approximately 25 to 30 cases per year in the United States.154 The typical presentation is pain without a palpable mass. Plain radiographs show an osteolytic lesion in the region of the pain. As with other chest wall tumors, a needle biopsy under CT guidance is performed for diagnosis. Histologically, the lesion is identical to multiple myeloma, with sheets of plasma cells. It occurs at an average age of 55 years. Evaluation for systemic myeloma is performed with bone marrow aspiration, testing of calcium levels, and measurement of urinary Bence Jones proteins. If the results of these studies are negative, then a solitary plasmacytoma is diagnosed. Surgery is usually limited to a biopsy only, which may be excisional.155 Treatment consists of radiation with doses of 4000 to 5000 cGy. Up to 75% of patients develop systemic multiple myeloma with 10-year survival of approximately 20%. Chest Wall Reconstruction The primary determinant of long-term freedom from recurrence and overall survival is margin status; therefore, adequate margins of normal tissue must be included in the en bloc resection. En bloc resection should include involved ribs, sternum, superior sulcus, or spine if necessary; invasion of these structures should not be considered a contraindication to surgery in an otherwise fit patient. The resection should include at least one normal adjacent rib above and below the tumor, with all intervening intercostal muscles and pleura. In addition, an en bloc resection of overlying chest wall muscles is often necessary, such as of the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Figure 19-41. Chest computed tomography scan showing a right posterior lung tumor. In the appropriate clinical setting, stippled calcifications (white streaks in right lung mass) are highly indicative of chondrosarcomas. 670 UNIT II PART SPECIFIC CONSIDERATIONS B A Figure 19-42. Principles of reconstruction after resection of a chest wall tumor (osteogenic sarcoma) are shown. A. En bloc resection of the involved chest wall, including normal ribs above and below the tumor as well as pulmonary parenchyma, must be performed. The resected specimen is shown. B. A prosthesis has been sewn in place. In the lower third of the prosthesis, the line of diaphragm reattachment is seen. The skin defect was closed with a myocutaneous flap from the ipsilateral rectus muscle. pectoralis minor or major, serratus anterior, or latissimus dorsi. When the periphery of the lung is involved with the neoplasm, it is appropriate to resect the adjacent part of the pulmonary lobe in continuity (Fig. 19-42). Involvement of the sternum by a malignant tumor requires total resection of the sternum with the adjacent cartilage. Techniques for postoperative respiratory support are now good enough that resection should not be compromised because of any concern about the patient’s ability to be adequately ventilated in the early postoperative period. The extent of resection depends on the tumor’s location and on any involvement of contiguous structures. Laterally based lesions often require simple wide excision, with resection of any contiguously involved lung, pleura, muscle, or skin. Anteriorly based lesions contiguous with the sternum require partial sternectomy. Primary malignant tumors of the sternum may require complete sternectomy. Posterior lesions involving the rib heads over their articulations with the vertebral bodies may, depending on the extent of rib involvement, require partial en bloc vertebrectomy. Optimal management of larger tumors includes careful preoperative planning and execution of the surgery by the thoracic surgeon and an experienced plastic surgeon, in order to ensure optimal physiologic and cosmetic results. With this, reconstruction at the same operation can be accomplished.156 Reconstruction of a large defect in the chest wall requires the use of some type of material to prevent lung herniation and to provide stability for the chest wall (see Fig. 19-42). Mild degrees of paradoxical motion are often well tolerated if the area of instability is relatively small. Historically, a wide variety of materials have been used to re-establish chest wall stability, including rib autografts, steel struts, acrylic plates, and numerous synthetic meshes. The current preference is either a 2-mm polytetrafluoroethylene (Gore-Tex) patch or a double-layer polypropylene (Marlex) mesh sandwiched with methylmethacrylate. There are several properties that make Gore-Tex an excellent material for use in chest wall reconstruction: (a) it is impervious to fluid, which prevents pleural fluid from entering the chest wall and minimizes the formation of seromas, which can compromise the myocutaneous flap viability and provide a nidus for infection; and (b) it provides excellent rigidity and stability when secured taut to the surrounding bony structure and, as a result, provides a firm platform for myocutaneous flap reconstruction. Except for smaller lesions, tissue coverage requires the use of myocutaneous flaps (latissimus dorsi, serratus anterior, rectus abdominis, or pectoralis major muscles).157,158 MEDIASTINUM Anatomy and Pathologic Entities The mediastinum can be divided into compartments for classification of anatomic components and disease processes, which, despite substantial overlap, facilitates understanding of general concepts of surgical interest. Several classification schemes exist, but for the purposes of this chapter, the three-compartment model is used (Fig. 19-43). The anterior compartment lies between the sternum and the anterior surface of the heart and great vessels. The visceral or middle compartment is located between the great vessels and the trachea. As the name implies, the posterior compartment lies posterior and includes the paravertebral sulci, bilaterally, and the paraesophageal area. The normal content of the anterior compartment includes the thymus gland or its remnant, the internal mammary artery and vein, lymph nodes, and fat. The thymus gland is large during childhood, occupying the entire anterior mediastinum (Fig. 19-44) but decreases in both thickness and length after adolescence and takes on a more fatty content, with only residual islands of thymic cellular components (Fig. 19-45). The middle mediastinal compartment contains the pericardium and its contents, the ascending and transverse aorta, the superior and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Anterosuperior mediastinum Figure 19-43. Anatomic division of the mediastinum. inferior venae cavae, the brachiocephalic artery and vein, the phrenic and upper vagus nerves, the trachea and main bronchi and corresponding lymph nodes, and the central portions of the pulmonary arteries and veins. The posterior compartment contains the descending aorta, esophagus, thoracic duct, azygos and hemiazygos veins, and lymph nodes. Numerous pathologic variants may be present in the various compartments, with much overlap. Table 19-25 includes the most common pathologic entities listed by compartment.159,160 History and Physical Examination Mediastinal pathology varies significantly by patient age. In children, neurogenic tumors of the posterior mediastinum are most common, followed by lymphoma, which is usually located in the anterior or middle compartment. Thymoma in childhood is rare (Table 19-26). In adults, the most common tumors include neurogenic tumors of the posterior compartment, benign cysts occurring in any compartment, and thymomas of the anterior mediastinum (Table 19-27). In both age groups, about 25% Imaging and Serum Markers Chest CT or MRI is required to fully delineate the anatomy.161 A contrast-enhanced CT scan enables clear delineation of the soft tissue structures from the vasculature and is preferred over noncontrast studies. If there is concern for invasion of vascular structures or spinal involvement, MRI is more accurate than CT scan and provides important information regarding respectability. Thymus Figure 19-44. Normal appearance of the thymus gland in childhood. Ao = aorta; PA = pulmonary artery; VC = vena cava. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 671 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Posterior mediastinum Middle mediastinum of mediastinal tumors are malignant. Pediatric tumors will be discussed in Chapter 39. Up to two thirds of mediastinal tumors in adults are discovered as asymptomatic abnormalities on radiologic studies ordered for other problems, particularly now that screening CT examinations are more prevalent. When symptomatic, these tumors are significantly more likely to be malignant. Characteristics such as size, location, rate of growth, and associated inflammation are important factors that correlate with symptoms. Large, bulky tumors, expanding cysts, and teratomas can cause compression of mediastinal structures, in particular the trachea, and lead to cough, dyspnea on exertion, or stridor. Chest pain or dyspnea may be reported secondary to associated pleural effusions, cardiac tamponade, or phrenic nerve involvement. Occasionally, a mediastinal mass near the aortopulmonary window may be identified in a workup for hoarseness because of left recurrent laryngeal nerve involvement. The patient in Fig. 19-46 presented with hoarseness due to nodal compression of the left recurrent laryngeal nerve from a primary lung cancer with metastases to the level 5 and 6 lymph nodes in the region of the aortopulmonary window. The history and physical examination in conjunction with the imaging findings may suggest a specific diagnosis (Table 19-28). In one recent series, systemic symptoms were present in 50% of patients with a mediastinal mass and a lymphoproliferative disorder, as compared with only 29% of patients with other masses (such as thymic or neurogenic). Laboratory signs of inflammation were also noted; the erythrocyte sedimentation rate and C-reactive protein levels were elevated and leukocytosis was present in 86% of patients with a lymphoproliferative disorder, as compared with only 58% of patients with other types of mediastinal masses. 672 UNIT II PART SPECIFIC CONSIDERATIONS Figure 19-45. Computed tomography scan showing the normal appearance of an involuted thymus gland in an adult. Note the near-total fatty appearance of the gland with only tiny islands of soft tissue scattered within it (small arrows). If an endocrine origin is suspected, several other imaging modalities are available (Table 19-29). Single-photon emission CT (SPECT) technology may be used to improve image contrast and give information on three-dimensional localization, largely replacing conventional two-dimensional nuclear imaging studies. If a thyroid origin is suspected, a thyroid scan using 131I or 123I can identify most intrathoracic goiters and identify the extent of functioning thyroid tissue. If indicated, the thyroid scan should precede other scans requiring iodine-containing contrast agents, because they would subsequently interfere with iodine tracer uptake by thyroid tissue. If a pheochromocytoma or neuroblastoma is suspected, the octreotide scan or 123 I-metaiodobenzylguanidine (MIBG) scans are helpful in diagnosis and localization. The sestamibi scan may be useful for diagnosing and localizing a mediastinal parathyroid gland. PET is useful for distinguishing malignant from benign tumors and may help detect distant metastases in some patients. However, the role of routine PET imaging for staging surgically resectable lesions of the mediastinum has not been established. The use of serum markers to evaluate a mediastinal mass can be invaluable in some patients. For example, nonseminomatous and seminomatous germ cell tumors can frequently be diagnosed and often distinguished from one another by the levels of α-fetoprotein (AFP) and human chorionic gonadotropin (hCG). In over 90% of nonseminomatous germ cell tumors, either the AFP or the hCG level will be elevated. Results are close to 100% specific if the level of either AFP or hCG is greater than 500 ng/mL. Some centers institute chemotherapy based on this result alone, without biopsy confirmation of the diagnosis. In contrast, the AFP level in patients with mediastinal seminoma is always normal; only 10% will have elevated hCG, which is usually less than 100 ng/mL. Other serum markers, such as intact parathyroid hormone level for ectopic parathyroid adenomas, may be useful for diagnosing and also for intraoperatively confirming complete resection. After successful resection of a parathyroid adenoma, this hormone level should rapidly normalize. Diagnostic Nonsurgical Biopsies of the Mediastinum The treatment of up to 60% of patients with anterior mediastinal masses is ultimately nonsurgical, so it is essential to Table 19-25 Usual location of the common primary tumors and cysts of the mediastinum Anterior Compartment Visceral Compartment Paravertebral Sulci Thymoma Enterogenous cyst Neurilemoma-schwannoma Germ cell tumor Lymphoma Neurofibroma Lymphoma Pleuropericardial cyst Malignant schwannoma Lymphangioma Mediastinal granuloma Ganglioneuroma Hemangioma Lymphoid hamartoma Ganglioneuroblastoma Lipoma Mesothelial cyst Neuroblastoma Fibroma Neuroenteric cyst Paraganglioma Fibrosarcoma Paraganglioma Pheochromocytoma Thymic cyst Pheochromocytoma Fibrosarcoma Parathyroid adenoma Thoracic duct cyst Lymphoma Source: Reproduced with permission from Shields TW. The mediastinum and its compartments. In: Shields TW, ed. Mediastinal Surgery. Philadelphia: Lea & Febiger; 1991:5. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 673 Table 19-26 Mediastinal tumors in children Percentage of Total Location Neurogenic tumors 40 Posterior Lymphomas 18 Anterior/middle Cysts 18 All Germ cell tumors 11 Anterior Mesenchymal tumors 9 All Thymomas Rare Anterior Source: Reproduced with permission from Silverman NA, Sabiston DC Jr. Mediastinal masses. Surg Clin North Am. 1980;60:760. Copyright Elsevier. understand all options for obtaining adequate tissue for a definitive diagnosis using the least invasive approach. CT-guided needle biopsy, and EUS-guided FNA, and even core-needle biopsy (either CT-guided EBUS-guided, or EUS-guided) have proven most useful for cytologic and tissue diagnosis of mediastinal masses and lymphadenopathy. When FNA and core-needle biopsy were combined, the accuracy was 98%, compared to 79% for each modality independently. In addition, core-needle biopsy changed the diagnosis in nine cases that had been missed by FNA due to inadequate specimens. Finally, core-needle biopsy was better at diagnosis for benign diseases compared to FNA. Accessible nodal stations include subcarinal (level 7), aortopulmonary (level 5), paraesophageal (level 8), and inferior pulmonary ligament (level 9) as well as paratracheal (level 4).162 Technical expertise in these modalities should be pursued by thoracic and general surgeons. Historically, needle biopsies of anterior mediastinal masses were reportedly sensitive and specific for most carcinomatous tumors, but there were questions regarding accuracy for diagnosing lymphomas.163 However, advances in cytopathology as well as needle biopsy technology have substantially improved diagnostic accuracy such that most centers are reporting yields Table 19-27 Mediastinal tumors in adults Tumor Type Percentage of Total Location Neurogenic tumors 21 Posterior Cysts 20 All Thymomas 19 Anterior Lymphomas 13 Anterior/middle Germ cell tumors 11 Anterior Mesenchymal tumors 7 All Endocrine tumors 6 Anterior/middle Source: Data from Shields TW. Primary lesions of the mediastinum and their investigation and treatment. In: Shields TW, ed. General Thoracic Surgery, 4th ed. Baltimore: Lippincott Williams & Wilkins; 1994:1731. Figure 19-46. Computed tomography scan of a patient who presented with hoarseness due to compression of the left recurrent laryngeal nerve caused by mediastinal lymph node metastases to the aortopulmonary window area (arrow) from a primary lung cancer. ranging from 75% to 80% for the diagnosis of lymphoma as well. To achieve maximal diagnostic yield for mediastinal masses suggestive of a lymphoma, it is necessary to obtain multiple fine-needle aspirates, preferably with immediate onsite rapid cytologic analysis to confirm sampling of the target tissue and adequate cellularity. This also facilitates processing of the sample to ensure that proper studies for lymphoma, including flow cytometry, are obtained. If the needle biopsy is inconclusive, surgical biopsy can be performed.164,165 If the lesion is accessible by CT-guided or EUS-guided core-needle biopsy, intraoperative frozen section or immediate cytologic smear of a core biopsy can also be performed. Recently, core-needle biopsy with EBUS became possible with release of a EBUS-core needle device. This addition to the surgeon’s armamentarium will greatly facilitate tissue sampling for evaluation of mediastinal masses. The authors perform their own endobronchial, endoscopic, and CT-guided transbronchial and transthoracic biopsies and, in our experience, lack of cellularity in the aspirate is readily apparent. In general, plans to proceed with surgical biopsy are made in combination with the image-guided aspiration and, as such, are performed in the same setting. This enables the authors to avoid a more invasive surgical procedure when FNA or core-needle biopsy is sufficient without contributing to delays in diagnosis by having multiple attempts from multiple providers (such as interventional radiology and pulmonology) before involvement of the surgeon in the diagnostic workup. Surgical Biopsies and Resection of Mediastinal Masses For tumors of the mediastinum that are not amenable to an endoscopic or CT-guided needle biopsy or that do not yield sufficient tissue for diagnosis, a surgical biopsy is indicated. The definitive approach to a surgical biopsy of the anterior mediastinum is through a median sternotomy. At the time of sternotomy, if the lesion is easily resectable, it should be completely removed. Given the invasiveness of the procedure and the inability in some patients to obtain a definitive diagnosis by frozen section, less invasive procedures are preferable if the lesion is large or if the CT scan or history suggests that surgery is not the best definitive treatment. Masses in the paratracheal region are easily biopsied by mediastinoscopy. For tumors of the anterior or VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Tumor Type 674 Table 19-28 Signs and symptoms suggestive of various diagnoses in the setting of a mediastinal mass Compartment Location of Mass UNIT II PART Diagnosis History and Physical Findings Lymphoma Night sweats, weight loss, fatigue, extrathoracic adenopathy, elevated erythrocyte sedimentation rate or C-reactive protein level, leukocytosis Any compartment Thymoma with myasthenia gravis Fluctuating weakness, early fatigue, ptosis, diplopia Anterior Mediastinal granuloma Dyspnea, wheezing, hemoptysis Visceral (middle) Germ cell tumor Male gender, young age, testicular mass, elevated levels of human chorionic gonadotropin and/or α-fetoprotein Anterior SPECIFIC CONSIDERATIONS posterior mediastinum, a left or right VATS approach often allows safe and adequate surgical biopsies. In some patients, an anterior mediastinotomy (i.e., Chamberlain procedure) may be ideal for an anterior tumor or a tumor with significant parasternal extension. Before a surgical biopsy is pursued, a discussion should be held with the pathologist regarding routine histologic assessment, special stains and markers, and requirements for lymphoma workup. Surgical resection using minimally invasive approaches, including video-assisted and robotic thoracoscopic surgery and transcervical, are now routine for the vast majority of middle and posterior tumors and for moderate sized (<5 to 6 cm) anterior mediastinal tumors.166-169 Outcomes comparing VATS to open thymectomy in patients with myasthenia gravis without thymoma were prospectively evaluated by Chang and colleagues in 2005, and no differences were seen in terms of response to therapy and recurrence of symptoms. Pain scores were significantly better in the VATS approach.170 These reports and others support application of VATS for the majority of anterior mediastinal masses. Other minimally invasive approaches are under study. For example, good results have been reported using a cervical incision with a sternal retractor for thymus removal. The upward lift allows the surgeon reasonable access to the anterior mediastinum and has proven adequate in some centers for definitive resection of the thymus gland for myasthenia gravis.171 For larger anterior mediastinal masses or in centers where expertise in thoracoscopy is not available, median sternotomy and thoracotomy remain excellent options for resection of anterior mediastinal masses. Occasionally, a lateral thoracotomy with sternal extension (hemi-clamshell) provides excellent exposure for extensive mediastinal tumors that have a lateral component. Most surgeons would agree that if a larger anterior mediastinal tumor is seen or malignancy is suspected, a median sternotomy with a more radical resection should be performed. Mediastinal Neoplasms Thymic Hyperplasia. Diffuse thymic hyperplasia was first described in children after successful chemotherapy for lymphoma. It has now been described in adults and is referred to as Table 19-29 Nuclear imaging relevant to the mediastinum Radiopharmaceutical, Radionuclide, or Radiochemical Label Disease of Interest Iodine 131 I, Monoclonal antibodies 111 In, Octreotide 111 In Gallium 67 Sestamibi 99m Thallium 201 Tl See sestamibi MIBG 131 I, 123I Pheochromocytoma, neuroblastoma; see also octreotide Fluorodeoxyglucose 18 F General oncologic imaging, breast and colon cancer, melanoma 123 I 99m Ga Tc Retrosternal goiter, thyroid cancer Tc NSCLC, colon and breast cancer, prostate cancer metastases Amine precursor uptake decarboxylation tumors: carcinoid, gastrinoma, insulinoma, small cell lung cancer, pheochromocytoma, glucagonoma, medullary thyroid carcinoma, paraganglioma Lymphoma, NSCLC, melanoma Medullary thyroid carcinoma, nonfunctional papillary or follicular thyroid carcinoma, Hürthle cell thyroid carcinoma, parathyroid adenoma or carcinoma MIGB = metaiodobenzylguanidine; NSCLC = non–small cell lung cancer. Source: Reproduced with permission from McGinnis KM, et al. Markers of the mediastinum. In: Pearson FG, et al, eds. Thoracic Surgery. 2nd ed. New York: Churchill Livingstone; 2002:1675. Copyright Elsevier. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ anterior mediastinum in adults (seen most frequently between 40 and 60 years of age), thymoma is rare in children. Between 10% and 50% of patients with thymoma will have symptoms suggestive of myasthenia gravis or have circulating antibodies to acetylcholine receptor, but less than 10% of patients with myasthenia gravis have a thymoma. Most patients with thymoma are asymptomatic. Thymectomy leads to improvement or resolution of symptoms of myasthenia gravis in only about 25% of patients with thymomas. In contrast, in patients with myasthenia gravis and no thymoma, thymectomy results are superior: up to 50% of patients have a complete remission and 90% improve. In 5% of patients with thymomas, other paraneoplastic syndromes, including red cell aplasia, hypogammaglobulinemia, systemic lupus erythematosus, Cushing’s syndrome, or SIADH, may be present. Large thymic tumors may present with symptoms related to a mass effect, which may include cough, chest pain, dyspnea, or SVC syndrome. The diagnosis may be suspected based on CT scan and history, but imaging alone is not diagnostic. In most centers, the diagnosis is made after surgical resection because of the relative difficulty of obtaining a needle biopsy and the likelihood that removal will ultimately be recommended. Biopsy should be avoided in cases where imaging is highly suggestive of thymoma. In most patients, the distinction between lymphomas and thymomas can be made on CT scan, since most lymphomas have marked lymphadenopathy and thymomas most frequently appear as a solitary encapsulated mass. PET scan may have a role in differentiating thymic cancer from thymoma, as thymic cancer tends to be very FDG avid.174 In addition, PET scan may facilitate identification of low-risk and minimally invasive thymoma; a standardized uptake value (SUV) <5 was associated with Masaoka stage I or II thymoma, whereas invasive thymoma and mediastinal lymphoma were more likely when the SUV was >5.175 In cases where the diagnosis is unclear, transmediastinal, not transpleural, CT-guided FNA biopsy has a diagnostic sensitivity of 87% and a specificity of 95% in specialized centers. The most commonly accepted staging system for thymoma is that of Masaoka.176 It is based on the presence or absence of gross or microscopic invasion of the capsule and of surrounding structures, as well as on the presence or absence of metastases (Table 19-30). Histologically, thymomas are characterized by a mixture of epithelial cells and mature lymphocytes. Grossly, many thymomas remain well encapsulated. Even those with capsular invasion often lack histologic features of malignancy; Masaoka staging system for thymoma Stage I Encapsulated tumor with no gross or microscopic evidence of capsular invasion Stage II Gross capsular invasion or invasion into the mediastinal fat or pleura or microscopic capsular invasion Stage III Gross invasion into the pericardium, great vessels, or lung Stage IVA Pleural or pericardial dissemination Stage IVB Lymphogenous or hematogenous metastasis they appear cytologically benign and identical to early-stage tumors. This lack of classic cellular features of malignancy is why most pathologists use the term “thymoma” or “invasive thymoma” rather than “malignant thymoma.” Thymic tumors with malignant cytologic features are classified separately and referred to as “thymic carcinoma.” The definitive treatment for thymoma is complete surgical removal; local recurrence rates and survival vary according to stage (Fig. 19-47). In centers with significant experience with VATS procedures, thymoma is not a contraindication to VATS approach, provided the principles of resection are adhered to, such as a complete resection without disrupting the capsule.177 Otherwise, resection is generally accomplished by median sternotomy with extension to hemi-clamshell in more advanced cases. Even advanced tumors with local invasion of resectable structures such as the pericardium, SVC, or innominate vessels should be considered for resection with reconstruction. A multidisciplinary approach to nonresectable and more advanced lesions (stage ≥II) is mandatory to optimize patient care. The goal for surgical resection should be complete excision of the mass with total thymectomy. All contiguous and noncontiguous disease is removed at the same setting; this may include resection of the pericardium or pleura, adjacent adherent lung, phrenic nerve, major vascular structures, and pleural metastasis. Bilateral phrenic nerve resection should be avoided, however, due to the major respiratory morbidity associated with bilateral paralyzed hemidiaphragms. The role of adjuvant or neoadjuvant therapies for advanced-stage tumors remains unclear. Traditionally, stage II 1.0 Stage I Proportion surviving Thymoma. The most frequently encountered neoplasm of the 675 Table 19-30 P=.002 .8 Stage IV .6 Stage II .4 Stage III .2 0 0 10 Years Figure 19-47. Stage-specific survival for thymomas. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 20 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura “rebound thymic hyperplasia.”172 It is most frequently reported after chemotherapy for lymphoma or germ cell tumors. Initially, atrophy of the thymic gland is seen with subsequent thymic gland enlargement, which can be dramatic. The usual time course for thymic hyperplasia is about 9 months after cessation of chemotherapy (range 2 weeks–12 months). Benign hyperplasia must be clearly distinguished from recurrent lymphoma or germ cell tumors, which may be difficult since thymic hyperplasia is dramatic in some patients; careful follow-up with serial CT scans is the minimum requirement. The role of PET scanning is unclear. Thymic hyperplasia is a known cause of false-positive PET scans; in many patients, CT scan will show a triangular soft tissue density in the retrosternal space that has a characteristic bilobed anatomic appearance consistent with thymus gland.173 In addition, a low standardized uptake value of tracer on PET scan suggests a benign tumor.174 Biopsies may be required if the clinical index of suspicion is high. 676 UNIT II PART SPECIFIC CONSIDERATIONS thymomas have been treated by complete surgical resection followed by mediastinal radiation, but randomized trials have not been done. A recent retrospective review of a single-institution series of stage II thymoma patients showed no difference in survival or local recurrence after complete surgical resection alone, as compared with surgical resection with radiotherapy. Advanced thymomas have been shown to respond to platinumbased chemotherapy and to corticosteroids.178 One summary of chemotherapy trials showed an overall response rate of about 70%. Cisplatin/doxorubicin-based regimens appear to yield the best results. The combination radiotherapy and chemotherapy for local progression appears to prolong survival in some small series.179 Radiation therapy in surgically resected stage III thymoma is likely beneficial in extending disease-specific survival; a recent analysis of the Surveillance, Epidemiology, and End Results (SEER) database identified 476 patients with stage III thymoma treated with primary surgery. Postoperative radiation was given to 322 patients with a significant improvement in survival (127 months compared to 105 months, P = .038) despite the fact that these patients were more likely to have had debulking rather than curative resection. In multivariate analysis, disease-specific survival was better in the adjuvant radiation group.180 Therefore, it is imperative that all patients with thymomas undergo a thorough evaluation for potential resection. Current guidelines recommend radiation for patients with unresectable thymoma who have failed induction chemotherapy or for patients with incompletely resected invasive thymoma or thymic cancer. Planning the radiation ports requires input from the surgeon; it is important for the surgeon to carefully document areas of adherence between the thymoma and adjacent structures during the operation, with clips or other radiopaque markers placed to guide radiation therapy postoperatively. Extracapsular extension and positive surgical margins should be noted by the pathologist and correlated anatomically so that the surgeon and radiation oncologist can ensure appropriate radiation treatment. Thymic Carcinoma. Thymic carcinomas are unequivocally malignant at the microscopic level. Suster and Rosai classified thymic carcinomas into low-grade and high-grade tumors.181 Low-grade tumors are well differentiated with squamous cell, mucoepidermoid, or basaloid features. High-grade thymic carcinomas include those with lymphoepithelial, small cell neuroendocrine, sarcomatoid, clear cell, and undifferentiated or anaplastic features. Care must be taken to differentiate thymic carcinoma from lung cancer metastatic to the thymus gland as the histologic features can be similar between the two. Compared with thymomas, they are a more heterogeneous group of malignancies with a propensity for early local invasion and widespread metastases. Malignant pleural and pericardial effusions occur frequently. Five-year survival rates are between 30% and 50%. Complete resection is occasionally curative and leads to improved survival, but most thymic carcinomas will recur and are refractory to chemotherapy.178 Management, therefore, depends on the completeness of the resection. Postoperative care includes radiation therapy, guided by residual gross disease or microscopically positive margins from the resection specimen. Chemotherapy may also be given, with carboplatin/paclitaxel recommended based on the best response rates with the least toxicity in clinical trials. The prognosis of patients with thymic cancer remains poor. Thymolipoma. Thymolipomas are rare benign tumors that may grow to a very large size prior to diagnosis. On CT scan, their appearance can be dramatic, with a characteristic fat density dotted by islands of soft tissue density representing islands of thymic tissue (Fig. 19-48). Thymolipomas are generally well-encapsulated, soft, and pliable masses that do not invade Figure 19-48. Massive thymolipoma that was asymptomatic in an 18-year-old female. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 677 Table 19-31 Classification of neurogenic tumors of the mediastinum Benign Malignant Nerve sheath Neurilemoma, neurofibroma, melanotic schwannoma, granular cell tumor Neurofibrosarcoma Ganglion cell Ganglioneuroma Ganglioneuroblastoma, neuroblastoma Paraganglionic cell Chemodectoma, pheochromocytoma Malignant chemodectoma, malignant pheochromocytoma Source: Reproduced with permission from Bousamra.182 Copyright Elsevier. surrounding structures. Resection is recommended for large masses. Neurogenic Tumors. Most neurogenic tumors of the mediastinum arise from the cells of the nerve sheath, from ganglion cells, or from the paraganglionic system (Table 19-31). The incidence, cell types, and risk of malignancy strongly correlate with patient age. Tumors of nerve sheath origin predominate in adults. Most present as asymptomatic incidental findings, and most are benign. In children and young adults, tumors of the autonomic ganglia predominate, with up to two thirds being malignant.182 Nerve Sheath Tumors. Nerve sheath tumors account for 20% of all mediastinal tumors. More than 95% of nerve sheath tumors are benign neurilemomas or neurofibromas. Malignant neurosarcomas are much less common. Neurilemoma. Neurilemomas, also called schwannomas, arise from Schwann cells in intercostal nerves. They are firm, wellencapsulated, and generally benign. Two characteristic histologic components are referred to as Antoni type A and Antoni type B regions. Antoni type A regions contain compact spindle cells with twisted nuclei and nuclear palisading. Antoni type B regions contain loose and myxoid connective tissue with haphazard cellular arrangement. These characteristics distinguish neurilemoma from malignant, fibrosarcomatous tumors, which lack encapsulation and have no Antoni features. If routine CT scan suggests extension of a neurilemoma into the intervertebral foramen, MRI is used to evaluate the extent of this “dumbbell” configuration (Fig. 19-49). Such a configuration may lead to cord compression and paralysis and requires a more complex surgical approach. Resection is recommended; VATS has been established as safe and effective for simple and, in experienced centers, even the more complex operations.183 It is reasonable to follow small, asymptomatic paravertebral tumors in older patients or in patients at high risk for surgery. In children, ganglioneuroblastomas or neuroblastomas are more common; therefore, all neurogenic tumors should be completely resected. Neurofibroma. Neurofibromas consist of both nerve sheath and nerve cells and account for up to 25% of nerve sheath tumors. Up to 40% of patients with mediastinal fibromas have generalized neurofibromatosis (von Recklinghausen’s disease). About 70% of neurofibromas are benign, but malignant degeneration to neurofibrosarcoma occurs in 25% to 30% of patients.184 The risk of malignant degeneration increases with advancing age, Figure 19-49. Magnetic resonance image of a neurogenic tumor with extension into the spinal canal via the foramen, giving a typical dumbbell appearance. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Tumor Origin 678 UNIT II PART SPECIFIC CONSIDERATIONS von Recklinghausen’s disease, and exposure to previous radiation. Neurofibrosarcomas carry a poor prognosis because of rapid growth and aggressive local invasion along nerve bundles. Complete surgical resection is the mainstay of treatment. Adjuvant radiotherapy or chemotherapy does not confer a significant benefit, but may be added if complete resection is not possible.185 The 5-year survival rate is 53%, but drops to 16% in patients with neurofibromatosis or with large tumors (>5 cm). Ganglion Cell Tumors. Ganglion cell tumors (ganglioneuromas, ganglioneuroblastomas, and neuroblastomas) arise from the sympathetic chain or from the adrenal medulla. Ganglioneuroma. Well-differentiated, benign tumors characterized histologically by well-differentiated ganglion cells with a background of Schwann cells, these are most often found incidentally in asymptomatic young adults. Diarrhea related to secretion of a vasoactive intestinal peptide has been described in some patients. These tumors have a propensity for intraspinal canal extension, although they remain well-encapsulated; complete resection is curative, with a low risk of local recurrence. Ganglioneuroblastoma. Ganglioneuroblastomas contain a mixture of benign ganglion cells and malignant neuroblasts. The distribution of these cells within the tumor is predictive of the clinical course. The nodular pattern has a high incidence of metastatic disease, whereas the diffuse pattern rarely metastasizes. Gross examination typically reveals encapsulated tumor; histologically, there are focal calcifications around regions of neuroblasts. Ganglioneuroblastomas arise most frequently in infants and children <3 years old. The majority are resectable, with 80% 5-year survival. Neuroblastoma. Highly malignant, neuroblastomas are the most common extracranial solid malignancy of childhood. The primary site is intrathoracic malignancy in 14%; extension into the spinal canal and osseous invasion is commonly present. These thoracic tumors are not as recalcitrant to chemotherapy and surgical resection as other chest malignancies; they are more likely to be resectable, with less invasion of surrounding organs. More than half occur in children under 2 years old; 90% arise within the first decade of life, and thus, these malignancies are discussed in more detail in Chapter 39. Paraganglionic Tumors. Paraganglionic tumors arising in the thoracic cavity include chemodectomas and pheochromocytomas. Only 10% of all pheochromocytomas are located in an extra-adrenal site. Intrathoracic pheochromocytomas are one of the rarest tumors. Approximately 10% of thoracic pheochromocytomas are malignant, a rate similar to that of adrenal tumors. The most common thoracic location is within the costovertebral sulcus, but paraganglionic tumors also arise within the visceral compartment of the mediastinum. These catecholamine-producing lesions can lead to life-threatening hemodynamic problems, so complete removal is important. Diagnosis is generally confirmed by measuring elevated levels of urinary catecholamines and their metabolites. Localization is by CT scan, aided by MIBG scintigraphy. Preoperative care includes α- and β-adrenergic blockade to prevent intraoperative malignant hypertension and arrhythmias. These tumors tend to be highly vascular and should be approached with care. Chemodectomas are rare tumors that may be located around the aortic arch, vagus nerves, or aorticosympathetics. They rarely secrete catecholamines and are malignant in up to 30% of patients. Lymphoma. Overall, lymphomas are the most common malignancy of the mediastinum. In about 50% of patients who have both Hodgkin’s and non-Hodgkin’s lymphoma, the mediastinum may be the primary site. The anterior compartment is most commonly involved, with occasional involvement of the middle compartment and hilar nodes. The posterior compartment is rarely involved. Chemotherapy and/or radiation results in a cure rate of up to 90% for patients with early-stage Hodgkin’s disease and up to 60% with more advanced stages. Mediastinal Germ Cell Tumors. Germ cell tumors are uncommon neoplasms, with only about 7000 diagnosed each year. However, they are the most common malignancy in young men 15 to 35 years of age. Most germ cell tumors are gonadal in origin; primary mediastinal germ cell tumors comprise less than 5% of all germ cell tumors and less than 1% of all mediastinal tumors (usually occurring in the anterior compartment). If a malignant mediastinal germ cell tumor is found, it is important to exclude a gonadal primary tumor. Primary mediastinal germ cell tumors (including teratomas, seminomas, and nonseminomatous malignant germ cell tumors) are a heterogeneous group of benign and malignant neoplasms thought to originate from primitive pluripotent germ cells “misplaced” in the mediastinum during embryonic development. Previously, most mediastinal germ cell tumors were thought to be metastatic. However, two lines of evidence suggest that many mediastinal germ cell tumors are primary, developing from pluripotent primordial germ cells in the mediastinum: (a) several autopsy series showed that patients with extragonadal sites of germ cell tumors, presumed previously to have originated from the gonads, had no evidence of an occult primary tumor or of any residual scar of the gonads, even after an exhaustive search; and (b) patients treated by surgery or radiation for their mediastinal germ cell tumors had long-term survival with no late testicular recurrences.186 About one third of all primary mediastinal germ cell tumors are seminomatous. Two thirds are nonseminomatous tumors or teratomas. Treatment and prognosis vary considerably within these two groups. Mature teratomas are benign and can generally be diagnosed by the characteristic CT findings of multilocular cystic tumors, encapsulated with combinations of fluid, soft tissue, calcium, and/or fat attenuation in the anterior compartment. FNA biopsy alone may be diagnostic for seminomas, usually with normal serum markers, including hCG and AFP. In 10% of seminomas, hCG levels may be slightly elevated. FNA findings, along with high hCG and AFP levels, can accurately diagnose nonseminomatous tumors. If the diagnosis remains uncertain after assessment of FNA findings and serum marker levels, then core-needle biopsies or surgical biopsies may be required. Thoracoscopy is the most frequent diagnostic surgical approach. Seminoma. Most patients with seminomas have advanced disease at the time of diagnosis and present with symptoms of local compression, including SVC syndrome, dyspnea, or chest discomfort. With advanced disease, the preferred treatment is combination cisplatin-based chemotherapy regimens with bleomycin and either etoposide or vinblastine. Complete responses have been reported in over 75% of patients treated with these regimens. Surgical resection may be curative for small asymptomatic seminomas that are found incidentally with screening CT scans. Surgical resection of residual masses after chemotherapy may be indicated. Nonseminomatous germ cell tumors. Nonseminomatous germ cell tumors include embryonal cell carcinomas, choriocarcinomas, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Mediastinal Cysts Benign cysts account for up to 25% of mediastinal masses and are the most frequently occurring mass in the middle mediastinal compartment. A CT scan showing characteristic features of near water density in a typical location is virtually 100% diagnostic.188 Pericardial cyst. Usually asymptomatic and detected incidentally in the right costophrenic angle, pericardial cysts typically contain a clear fluid and are lined with a single layer of mesothelial cells. For most simple, asymptomatic pericardial cysts, observation alone is recommended. Surgical resection or aspiration may be indicated for complex cysts or large symptomatic cysts. Bronchogenic cyst. Developmental anomalies that occur during embryogenesis and occur as an abnormal budding of the foregut or tracheobronchial tree, bronchogenic cysts arise most often in the mediastinum just posterior to the carina or main stem bronchus. Approximately 15% occur within the pulmonary parenchyma. Thin-walled and lined with respiratory epithelium, they contain a protein-rich mucoid material and varying amounts of seromucous glands, smooth muscle, and cartilage. They may communicate with the tracheobronchial tree. In adults, over half of all bronchogenic cysts are found incidentally during workup for an unrelated problem or during screening. The natural history of an incidentally diagnosed, asymptomatic bronchogenic cyst is unknown, but it is clear that many such cysts do not lead to clinical problems. In one study of young military personnel, 78% of all bronchogenic cysts found on routine CXRs were asymptomatic. However, in other reports with more comprehensive follow-up, up to 67% of adults with incidentally found bronchogenic cysts eventually became symptomatic. Symptoms include chest pain, cough, dyspnea, and fever. If large (>6 cm) or symptomatic, resection is generally recommended since serious complications may occur if the cyst becomes larger or infected. Complications include airway obstruction, infection, rupture, and rarely, malignant transformation.189,190 Traditionally, complete removal of the cyst wall has been via posterolateral thoracotomy.191 Resection of infected cysts may be quite difficult because of dense adhesions; elective removal is often recommended before infection has a chance to occur. Thoracoscopic exploration and resection are possible for small cysts with minimal adhesions. With increasing experience using video-assisted or robotic-assisted thoracoscopy, a greater proportion of these lesions are amenable to minimally invasive resection. Enteric cyst. Most clinicians agree that in contrast to bronchogenic cysts, esophageal cysts should be removed, regardless of the presence or absence of symptoms. Esophageal cysts have a propensity for serious complications secondary to enlargement, leading to hemorrhage, infection, or perforation. Thus, surgical resection is the treatment of choice in both adults and children. As with bronchogenic cysts, experienced surgeons are approaching enteric cyst resections using minimally invasive techniques with great success. Thymic cyst. Generally asymptomatic, thymic cysts are often discovered incidentally. Simple cysts are of no consequence; however, the occasional cystic neoplasm must be ruled out. Cystic components occasionally are seen in patients with thymoma and Hodgkin’s disease. Ectopic endocrine glands. Up to 5% of all mediastinal masses are of thyroid origin; most are simple extensions of thyroid masses. Usually nontoxic, over 95% can be completely resected through a cervical approach. True ectopic thyroid tissue of the mediastinum is rare. About 10% to 20% of abnormal parathyroid glands are found in the mediastinum; most can be removed during exploration from a cervical incision. In cases of true mediastinal parathyroid glands, thoracoscopic or open resection may be indicated. Location can generally be pinpointed by a combination of CT scan and Sestamibi scans. Mediastinitis Acute Mediastinitis. Acute mediastinitis is a fulminant infectious process that spreads rapidly along the continuous fascial planes connecting the cervical and mediastinal compartments. Infections originate most commonly from esophageal perforations, sternal infections, and oropharyngeal or neck infections, but a number of less common etiologic factors can lead to this deadly process (Table 19-32). Clinical signs and symptoms include fever, chest pain, dysphagia, respiratory distress, and cervical and upper thoracic subcutaneous crepitus. In severe cases, the clinical course can rapidly deteriorate to florid sepsis, hemodynamic instability, and death. Thus, a high index of suspicion is required in the context of any infection with access to the mediastinal compartments. A chest CT scan illuminates the extent of spread and guides selection of the best approach to surgical drainage. Acute VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 679 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura endodermal sinus tumors, and mixed types. They are often bulky, irregular tumors of the anterior mediastinum with areas of low attenuation on CT scan because of necrosis, hemorrhage, or cyst formation. Frequently, adjacent structures have been involved, with metastases to regional lymph nodes, pleura, and lungs. Lactate dehydrogenase (LDH), AFP, and hCG levels are frequently elevated. Chemotherapy is the preferred treatment and includes combination therapy with cisplatin, bleomycin, and etoposide, followed by surgical resection of residual disease. With this regimen, survival is 67% at 2 years and 60% at 5 years. Surgical resection of residual masses is indicated, as it may guide further therapy. Up to 20% of residual masses contain additional tumors; in another 40%, mature teratomas; and the remaining 40%, fibrotic tissue. It is important to note that oxygen toxicity can occur in patients who have been exposed to bleomycin; high levels of oxygen supplementation in the perioperative setting should be avoided in these patients as respiratory failure and death can ensue.187 Factors independently predictive of survival after induction chemotherapy followed by resection are elevated serum tumor markers after resection, postchemotherapy pathologic findings (complete necrosis vs. teratoma), and persistent germ cell or non-germ cell cancer in the pathologic specimen.187 Teratoma. Teratomas are the most common type of mediastinal germ cell tumors, accounting for 60% to 70% of mediastinal germ cell tumors. They contain two or three embryonic layers that may include teeth, skin, and hair (ectodermal), cartilage and bone (mesodermal), or bronchial, intestinal, or pancreatic tissue (endodermal). Therapy for mature, benign teratomas is surgical resection, which confers an excellent prognosis. Rarely, teratomas may contain a focus of carcinoma; these malignant teratomas (or teratocarcinomas) are locally aggressive. Often diagnosed at an unresectable stage, they respond poorly to chemotherapy and in a limited manner to radiotherapy; prognosis is uniformly poor. 680 Table 19-32 Etiologic factors in acute mediastinitis UNIT II PART SPECIFIC CONSIDERATIONS Esophageal perforation Iatrogenic    Balloon dilatation (for achalasia)    Bougienage (for peptic stricture)   Esophagoscopy    Sclerotherapy (for variceal bleeding) Spontaneous    Postemetic (Boerhaave’s syndrome) Straining during:   Elimination   Weight lifting Seizure   Pregnancy   Childbirth Ingestion of foreign bodies Trauma   Blunt   Penetrating Postsurgical   Infection   Anastomotic leak Erosion by cancer Deep sternotomy wound infection Oropharynx and neck infections Ludwig’s angina Quinsy Retropharyngeal abscess Cellulitis and suppurative lymphadenitis of the neck Infections of the lung and pleura Subphrenic abscess Rib or vertebral osteomyelitis Hematogenous or metastatic abscess Source: Reproduced with permission from Razzuk MA, et al. Infections of the mediastinum. In: Pearson FG, et al, eds. Thoracic Surgery. 2nd ed. New York: Churchill Livingstone; 2002:1604. Copyright Elsevier. mediastinitis is a true surgical emergency; treatment must be instituted immediately and aimed at correcting the primary problem, such as the esophageal perforation or oropharyngeal abscess, and debridement and drainage of the spreading infectious process within the mediastinum, neck, pleura, and other tissue planes. Antibiotics, fluid resuscitation, and other supportive measures are also important. Debridement may need to be repeated and other planes and cavities explored depending on the patient’s clinical status. Blood cell counts and serial CT scans may also be required. Persistent sepsis or collections on CT scan may require further radical surgical debridement. Chronic Mediastinitis. Sclerosing or fibrosing mediastinitis results from chronic mediastinal inflammation that originates in the lymph nodes, most frequently from granulomatous infections such as histoplasmosis or tuberculosis. Chronic, low-grade inflammation leads to fibrosis and scarring, which can, in some patients, result in entrapment and compression of the lowpressure veins (including the SVC and innominate and azygos veins), the esophagus, and pulmonary arteries. There is no definitive treatment. Surgery is indicated only for diagnosis or in specific patients to relieve airway or esophageal obstruction or to achieve vascular reconstruction. Reports of palliative success with less invasive procedures (such as dilation and stenting of airways, the esophagus, or the SVC) are promising. In one series of 22 patients, ketoconazole was effective in controlling progression. In another series of 71 patients, 30% died during long-term follow-up. Chronic mediastinitis is similar to retroperitoneal fibrosis, sclerosing cholangitis, and Riedel’s thyroiditis. PLEURA AND PLEURAL SPACE Anatomy Each hemithorax has a mesothelial lining that invaginates at the hilum of each lung and continues on to cover each lung. The portion lining the bony rib cage, mediastinum, and diaphragm is called the parietal pleura, whereas the portion encasing the lung is known as the visceral pleura. Between these two surfaces is the potential pleural space, which is normally occupied by a thin layer of lubricating pleural fluid. A network of somatic, sympathetic, and parasympathetic fibers innervates the parietal pleura. Irritation of the parietal surface by inflammation, tumor invasion, trauma, and other processes can lead to a sensation of chest wall pain. The visceral pleura have no somatic innervation.192,193 Pleural Effusion Pleural effusion refers to any significant collection of fluid within the pleural space. Normally, between 5 and 10 L of fluid enters the pleural space each day by filtration through microvessels supplying the parietal pleura (located mainly in the less dependent regions of the cavity). The net balance of pressures in these capillaries leads to fluid flow from the parietal pleural surface into the pleural space, and the net balance of forces in the pulmonary circulation leads to absorption through the visceral pleura. Normally, 15 to 20 mL of pleural fluid is present at any given time. Any disturbance in these forces can lead to imbalance and accumulation of pleural fluid. Common pathologic conditions in North America that lead to pleural effusion include congestive heart failure, bacterial pneumonia, malignancy, and pulmonary emboli (Table 19-33).194 Access and Drainage of Pleural Fluid Collections Most patients with pleural effusions of unknown cause should undergo thoracentesis with only two exceptions: effusions in the setting of congestive heart failure or renal failure or small effusions associated with an improving pneumonia. If the clinical history suggests congestive heart failure as a cause, particularly in the setting of bilateral effusions, a trial of diuresis may be indicated (rather than thoracentesis). Up to 75% of effusions due to congestive heart failure resolve within 48 hours with diuresis alone. Similarly, thoracentesis can be avoided in patients with small effusions associated with resolving pneumonia. These patients typically present with cough, fever, leukocytosis, and unilateral infiltrate, and the effusion is usually a result of a reactive, parapneumonic process. If the effusion is small and the patient responds to antibiotics, a diagnostic thoracentesis may be unnecessary. If the effusion is large and compromising respiratory efforts, or if the patient has a persistent white blood cell count despite improving signs of pneumonia, an empyema of the pleural space must be considered. In these patients, early and aggressive drainage with chest tubes is required, possibly with surgical intervention. Once the decision is made to access a pleural effusion, the next step is to determine if a sample of the fluid or complete VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 681 Table 19-33 Leading causes of pleural effusion in the United States, based on data from patients undergoing thoracentesis Annual Incidence Transudate Exudate Congestive heart failure 500,000 Yes No Pneumonia 300,000 No Yes Cancer 200,000 No Yes Pulmonary embolus 150,000 Sometimes Sometimes Viral disease 100,000 No Yes Coronary artery bypass surgery 60,000 No Yes Cirrhosis with ascites 50,000 Yes No Source: Reproduced with permission from Light RW. Pleural effusion. N Engl J Med 2002;346:1971. Copyright © Massachusetts Medical Society. All rights reserved. Adapted from Light RW. Approach to the patient. In: Light RW, ed. Pleural Diseases. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:111. drainage of the pleural space is desired. This step is influenced by the clinical history, the type and amount of fluid present, the nature of the collection (such as free-flowing or loculated), the cause, and the likelihood of recurrence. For small, free-flowing effusions, an outpatient diagnostic and/or therapeutic thoracentesis with a relatively small-bore needle or catheter (14- to 16-gauge) can be performed (Fig. 19-50). The appearance of the fluid is informative: clear straw-colored fluid is often transudative; turbid or bloody fluid is often exudative. The site of entry for drainage of a pleural effusion or pneumothorax may be based on the CXR alone if the effusion is demonstrated to be free-flowing. For free-flowing effusions, a low approach at the eighth or ninth intercostal space in the posterior midclavicular line facilitates complete drainage. If the effusion is loculated, CT- or ultrasound-guided drainage may be indicated. If the goal is complete drainage of nonbloody and nonviscous fluid, a small-bore pigtail catheter is inserted and connected to a closed drainage system with applied suction (typically –20 cm H2O). If the fluid is bloody or turbid, a larger-diameter drainage tube (such as a 28F chest tube) may be required. In general, the smallest-bore drainage catheter that will effectively drain the pleural space should be chosen. Figure 19-50. Techniques for aspiration and drainage of a pleural effusion. A. Needle aspiration. With careful appraisal of the x-ray findings, the best interspace is selected, and fluid is aspirated with a needle and syringe. Large volumes of fluid can be removed with a little patience and a large-bore needle. B. Chest tube insertion. After careful skin preparation, draping, and administration of local anesthesia, a short skin incision is made over the correct interspace. The incision is deepened into the intercostal muscles, and the pleura is penetrated (usually with a clamp). When any doubt exists about the status of the pleural space at the site of puncture, the wound is enlarged bluntly to admit a finger, which can be swept around the immediately adjacent pleural space to assess the situation and break down any adhesions. The tube is inserted, with the tip directed toward the optimal position suggested by the chest x-rays. In general, a high anterior tube is best for air (pneumothorax), and a low posterior tube is best for fluid. A 28F to 32F tube is adequate for most situations. A 36F tube is preferred for hemothorax or for a viscous empyema. Many surgeons prefer a very small tube (16F–20F) for drainage of simple pneumothorax. C. The tube is connected to a water-seal drainage system. Suction is added, if necessary, to expand the lung; it usually will be required in a patient with a substantial air leak (bronchopleural fistula). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Cause 682 Smaller-diameter catheters significantly decrease the pain associated with the placement of chest tubes but are more prone to clogging and twisting.195,196 For clinical situations requiring biopsy or for potential interventions such as adhesiolysis or pleurodesis, minimally invasive surgery may be indicated, using a VATS approach. Complications of Pleural Drainage. The most common UNIT II PART SPECIFIC CONSIDERATIONS complications of invasive pleural procedures are inadvertent injury to adjacent organs, including lung, with air leakage and pneumothorax; subdiaphragmatic entry and damage to the liver, spleen, or other intra-abdominal viscera; intercostal vessel injury with subsequent bleeding or larger vessel injury; and even cardiac puncture. Sometimes bleeding may be the result of an underlying coagulopathy or anticoagulant therapy. Other technical complications include loss of a catheter, guidewire, or fragment in the pleural space and infections. Occasionally, rapid drainage of a large effusion can be followed by shortness of breath, clinical instability, and a phenomenon referred to as postexpansion pulmonary edema. For this reason, it is recommended to drain only up to 1500 mL initially. Most complications can be avoided by consulting with a clinician experienced in pleural drainage techniques. Pleural Fluid Analysis. Pleural fluid collections are generally classified as transudates and exudates (Table 19-34). Transudates are protein-poor ultrafiltrates of plasma that result from alterations in the systemic hydrostatic pressures or colloid osmotic pressures (for example, with congestive heart failure or cirrhosis). On gross visual inspection, a transudative effusion is generally clear or straw-colored. Exudates are protein-rich pleural fluid collections that generally result from inflammation or pleural invasion by tumor. Grossly, they are often turbid, bloody, or purulent. Absent trauma, grossly bloody effusions are frequently malignant, but may also occur in the setting of a pulmonary embolism or pneumonia. Transudates and exudates can be differentiated using Light’s criteria. An effusion is exudative if the pleural fluidto-serum ratio of protein is greater than 0.5 and the LDH ratio is greater than 0.6 or the absolute pleural LDH level is greater than two thirds of the normal upper limit for serum. If criteria suggest a transudate, a careful evaluation for congestive heart failure, cirrhosis, or conditions associated with transudates is undertaken. If criteria suggest an exudate, further diagnostic studies may be helpful. If total and differential cell counts reveal a predominance of neutrophils (>50% of cells), the effusion is likely associated with an acute inflammatory process (such as a parapneumonic effusion or empyema, pulmonary embolus, or pancreatitis). A predominance of mononuclear cells suggests a more chronic inflammatory process (such as cancer or tuberculosis). Gram stains and cultures should be obtained if possible, with inoculation into culture bottles at the bedside. Pleural fluid glucose levels are frequently decreased (<60 mg/dL) with complex parapneumonic effusions or malignant effusions. A pleural effusion occurring in association with pleuritic chest pain, hemoptysis, or dyspnea out of proportion to the size of the effusion should raise concern for pulmonary embolism. These effusions may be transudative, but if an associated infarct near the pleural surface occurs, an exudate may be seen. If a pulmonary embolism is suspected in a postoperative patient, most clinicians would obtain a spiral CT scan. Alternatively, duplex ultrasonography of the lower extremities may yield a diagnosis of deep vein thrombosis, thereby indicating anticoagulant therapy and precluding the need for a specific diagnosis of pulmonary embolism. In some patients, a blood test for levels of D-dimer may be helpful; if a sensitive D-dimer blood test is negative, pulmonary embolism may be ruled out. Malignant Pleural Effusion Malignant pleural effusions may occur in association with a number of different malignancies, most commonly lung cancer, breast cancer, and lymphomas, depending on the patient’s age and gender (Tables 19-35 and 19-36).197 Cytologic testing should be done on exudative effusions to rule out an associated malignancy; accuracy is 70% when associated with adenocarcinomas, but is less sensitive for mesotheliomas (<10%), squamous cell carcinomas (20%), or lymphomas (25%–50%). If the diagnosis remains uncertain after drainage and fluid analysis, thoracoscopy and direct biopsies are indicated.198,199 Malignant effusions are exudative and often tinged with blood. An effusion in the setting of a malignancy means a more advanced stage; mean survival ranges from 3 to 11 months, depending on the primary tumor location. Occasionally, effusions associated with a bronchogenic NSCLC are benign, and surgical resection may still be indicated. Effusion size and degree of associated dyspnea influence management. Symptomatic, moderate to large effusions should be drained by tunneled indwelling pleural catheter, tube thoracostomy (chest tube or pigtail catheter) with subsequent instillation of doxycycline as a sclerosing agent, or VATS with talc instillation. Management is based on patient preference, degree of known or anticipated lung re-expansion, and patient tolerance for operative intervention. Lung entrapment by tumor or adhesions limits re-expansion and generally predicts a poor result with pleurodesis; it is the primary indication for placement of indwelling pleural catheters. Patient preference is also considered, as is their life expectancy. Tunneled indwelling pleural catheters have dramatically changed the management of end-stage cancer treatment because they substantially shorten the amount of time patients spend in the hospital during their final weeks of life.200 If the lung is expected to 12 fully expand and the patient has a longer life expectancy (e.g., malignant effusions in the setting of breast cancer), drainage with sclerosis is the preferred option. The choice of sclerosant includes mechanical, talc, bleomycin, or doxycycline. Success rates range from 60% to 90% and are highest with talc. Typically, talc is administered as an aerosolized powder during video-assisted thoracoscopy, whereas doxycycline is infused at the bedside through a previously placed pigtail catheter or larger bore chest tube. Figure. 19-51 presents a decision algorithm for the management of malignant pleural effusion. Empyema Thoracic empyema is defined by a purulent pleural effusion. Patients of all ages can develop empyema, but the frequency is increased in older or debilitated patients. Common associated conditions include a pneumonic process in patients with pulmonary disorders and neoplasms, cardiac problems, diabetes mellitus, drug and alcohol abuse, neurologic impairments, postthoracotomy problems, and immunologic impairments. The mortality of empyema frequently depends on the degree of associated comorbid diseases, ranging from as low as 1% to over 40% in immunocompromised patients. Pathophysiology. The most common causes of empyema are parapneumonic, but postsurgical or posttraumatic empyema VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 683 Table 19-34 Differential diagnosis of pleural effusions 3. Postpartum pleural effusion 4. Megis’ syndrome 5. Endometriosis G. Collagen vascular diseases 1. Rheumatoid pleuritis 2. Systemic lupus erythematosus 3. Drug-induced lupus 4. Immunoblastic lymphadenopathy 5. Sjögren’s syndrome 6. Familial Mediterranean fever 7. Churg-Strauss syndrome 8. Wegener’s granulomatosis H. Drug-induced pleural disease 1. Nitrofurantoin 2. Dantrolene 3. Methysergide 4. Ergot alkaloids 5. Amiodarone 6. Interleukin-2 7. Procarbazine 8. Methotrexate 9. Clozapine I. Miscellaneous diseases and conditions 1. Asbestos exposure 2. After lung transplantation 3. After bone marrow transplantation 4. Yellow nail syndrome 5. Sarcoidosis 6. Uremia 7. Trapped lung 8. Therapeutic radiation exposure 9. Drowning 10. Amyloidosis 11. Milk of calcium pleural effusion 12. Electrical burns 13. Extramedullary hematopoiesis 14. Rupture of mediastinal cyst 15. Acute respiratory distress syndrome 16. Whipple’s disease 17. Iatrogenic pleural effusions J. Hemothorax K. Chylothorax Source: Reproduced with permission from Light RW. Approach to the patient. In: Light RW, ed. Pleural Diseases. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:110. is also common (Table 19-37). The spectrum of organisms involved in pneumonic processes that progress to empyema is changing. Pneumococci and staphylococci continue to be the most frequent causative organisms, but gram-negative aerobic bacteria and anaerobes are becoming more prevalent. Cases involving mycobacteria or fungi are rare. Multiple organisms may be found in up to 50% of patients. Cultures may be sterile, however, if antibiotics were initiated before the culture or if the culture process was not efficient. The choice of antibiotics, therefore, is guided by the clinical scenario and not just the organisms found on culture. Broad-spectrum coverage may be required even when cultures do not grow out an organism or if a single organism is grown when the clinical picture is more consistent with a multiorganism process. Common gram-negative organisms include Escherichia coli, Klebsiella, Pseudomonas, and Enterobacteriaceae. Anaerobic organisms may be fastidious and difficult to document by culture and are associated with periodontal diseases, aspiration syndromes, alcoholism, general VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura I. Transudative pleural effusions A. Congestive heart failure B. Cirrhosis C. Nephrotic syndrome D. Superior vena caval obstruction E. Fontan procedure F. Urinothorax G. Peritoneal dialysis H. Glomerulonephritis I. Myxedema J. Cerebrospinal fluid leaks to pleura K. Hypoalbuminemia L. Pulmonary emboli M. Sarcoidosis II. Exudative pleural effusions A. Neoplastic diseases 1. Metastatic disease 2. Mesothelioma 3. Body cavity lymphoma 4. Pyothorax-associated lymphoma B. Infectious diseases 1. Tuberculosis 2. Other bacterial infections 3. Fungal infections 4. Parasitic infections 5. Viral infections C. Pulmonary embolization D. Gastrointestinal disease 1. Pancreatic disease 2. Subphrenic abscess 3. Intrahepatic abscess 4. Intrasplenic abscess 5. Esophageal perforation 6. After abdominal surgery 7. Diaphragmatic hernia 8. Endoscopic variceal sclerosis 9. After liver transplantation E. Heart diseases 1. After coronary artery bypass graft surgery 2. Post-cardiac injury (Dressler’s) syndrome 3. Pericardial disease F. Obstetric and gynecologic diseases 1. Ovarian hyperstimulation syndrome 2. Fetal pleural effusion 684 Table 19-35 Table 19-36 Primary organ site or neoplasm type in male patients with malignant pleural effusions Primary organ site or neoplasm type in female patients with malignant pleural effusions Primary Site or Tumor Type No. of Male Patients Percentage of Male Patients 140 49.1 Lymphoma/leukemia 60 21.1 Breast 70 37.4 Gastrointestinal tract 20 7.0 Female genital tract 38 20.3 Genitourinary tract 17 6.0 Lung 28 15.0 4 1.4 Lymphoma 14 8.0 10 3.5 Gastrointestinal tract 8 4.3 Melanoma 6 3.2 Urinary tract 2 1.1 Miscellaneous less common tumors 3 1.6 17 9.1 187 100.0 Lung UNIT II PART Melanoma Miscellaneous less common tumors SPECIFIC CONSIDERATIONS Primary site unknown Total 31 10.9 285 100.0 Source: Reproduced with permission from Johnston WW. The malignant pleural effusion: a review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer. 1985;56:905. anesthesia, drug abuse, or other functional associations with gastroesophageal reflux. Organisms gain entry into the pleural cavity through contiguous spread from pneumonia, lung abscess, liver abscess, or another, adjacent infectious processes. Organisms may also enter the pleural cavity by direct contamination from thoracentesis, thoracic surgical procedures, esophageal injuries, or trauma. As organisms enter the pleural space, an influx of polymorphonuclear cells and fluid occurs, with subsequent release of inflammatory mediators and toxic oxygen radicals. These mechanisms lead to variable degrees of endothelial injury and capillary instability. This process overwhelms the normal pleural lymphatic drainage. This early effusion is watery and No. of Female Patients Percentage of Female Patients Primary Site or Tumor Type Primary site unknown Total Source: Reproduced with permission from Johnston WW. The malignant pleural effusion: a review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer. 1985;56:905. free-flowing in the pleural cavity. Thoracentesis at this stage yields fluid with a pH typically above 7.3, a glucose level greater than 60 mg/dL, and a low LDH level (<500 U/L). At this stage, the decision to use antibiotics alone or perform a repeat thoracentesis, chest tube drainage, thoracoscopy, or open thoracotomy depends on the amount of pleural fluid, its consistency, the clinical status of the patient, the degree of expansion of the lung after drainage, and the presence of loculated fluid in the pleural space (vs. free-flowing purulent fluid). Early in the parapneumonic process, when the purulent fluid is relatively Outpatient referral for management of MPE Decubitus films and/or CT scan Loculated fluid/trapped lung Placement of indwelling pleural catheter Free-flowing with full lung expansion Poor performance status/short life expectancy Excellent performance status/long life expectancy Placement of indwelling pleural catheter VATS pleurodesis Figure 19-51. Treatment decision algorithm for the management of malignant pleural effusion (MPE). CT = computed tomography; VATS = video-assisted thoracic surgery. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 19-37 Pathogenesis of empyema Source: Reproduced with permission from Paris F, et al. Empyema and bronchopleural fistula. In: Pearson FG, et al, eds. Thoracic Surgery. 2nd ed. New York: Churchill Livingstone; 2002:1177. Copyright Elsevier. thin, complete drainage with simple large-bore thoracentesis is possible. If complete lung expansion is obtained and the pneumonic process is responding to antibiotics, no further drainage may be necessary. Pleural fluid with a pH lower than 7.2 and with a glucose level of less than 40 mg/dL means that a more aggressive approach to drainage should be pursued. The pleural fluid may become thick and loculated over the course of hours to days and may be associated with fibrinous adhesions (the fibrinopurulent stage). At this stage, chest tube insertion with closed-system drainage or drainage with thoracoscopy may be necessary to remove the fluid and adhesions and facilitate complete lung expansion.201 Further progression of the inflammatory process leads to the formation of a pleural peel, which may be flimsy and easy to remove early on. However, as the process progresses, a thick pleural rind may develop, leaving a trapped lung; complete lung decortication by either thoracoscopy or thoracotomy would then be necessary. The use of intrapleural fibrinolytic therapy for management of empyema has been investigated in several large prospective trials. Intrapleural infusion of tissue plasminogen activator (t-PA) alone did not improve outcomes, whereas combined intrapleural t-PA and DNase was associated with a reduction in hospital stay of nearly 7 days, 77% fewer referrals for surgical intervention at 3 months, and more than double the reduction in the infected pleural fluid collection by CXR imaging.202 In this trial, the medications were given twice daily by intrapleural injection; the dose was 5 mg for the DNase and 10 mg for t-PA. The chest drain was clamped for 1 hour after injection and released. This study suggests that the combination of fibrinolysis (t-PA) and cleavage of uncoiled DNA by DNase reduces fluid viscosity and facilitates pleural clearance. Management. If there is a residual space, persistent pleural infection is likely to occur. A persistent pleural space may be secondary to contracted, but intact, underlying lung; or it may be secondary to surgical lung resection. If the space is small and well-drained by a chest tube, a conservative approach may be possible. This requires leaving the chest tubes in place and attached to closed-system drainage until symphysis of the visceral and parietal surfaces takes place. At this point, the chest tubes can be removed from suction; if the residual pleural space remains stable, the tubes can be cut and advanced out of the Chylothorax Chylothorax develops most commonly after surgical trauma to the thoracic duct or a major branch, but may be also associated with a number of other conditions (Table 19-38).204 It is generally unilateral; for example, it may occur after dissection of the distal esophagus where the duct lies in close proximity to the esophagus as it enters the right chest from its origin in the abdomen at the cisterna chyli (Fig. 19-52). If the mediastinal pleura are disrupted on both sides, bilateral chylothoraces may occur. Left-sided chylothoraces may develop after a left-sided neck dissection, especially in the region of the confluence of the subclavian and internal jugular veins. Chylothorax may also follow nonsurgical trauma, including penetrating or blunt injuries to the chest or neck area, central line placements, and other surgical misadventures. It may be seen in association with a variety of benign and malignant diseases that generally involve the lymphatic system of the mediastinum or neck. Given the significant variability of the course of the thoracic duct within the chest, some injuries are inevitable. Pathophysiology. Most commonly, the thoracic duct originates in the abdomen from the cisterna chyli, which is located in the midline, near the level of the second lumbar vertebra. From this origin, the thoracic duct ascends into the chest through the aortic hiatus at the level of T10 to T12, and courses just to the right of the aorta (see Fig. 19-52). As the thoracic duct courses cephalad above the diaphragm, it most commonly remains in the right chest, lying just behind the esophagus, between the aorta and azygos vein. The duct continues superiorly, lying just to the right of the vertebral column. Then, at the fifth or sixth thoracic vertebra, it crosses behind the aorta and the aortic arch into the left posterior mediastinum and travels superiorly, staying near the esophagus and mediastinal pleura as it exits the thoracic inlet. As it exits the thoracic inlet, it passes to the left, just behind the carotid sheath and anterior to the inferior thyroid and vertebral bodies. Just medial to the anterior scalene muscle, it courses inferiorly and drains into the union of the internal jugular and subclavian veins. Given the extreme variability in the main duct and its branches, accumulation of chyle in the chest or flow from penetrating wounds may be seen after a variety of traumatic and medical conditions.205 The main function of the duct is to transport fat absorbed from the digestive system along with variable amounts of protein and lymphatic material (Table 19-39). Given the high volume of chyle that flows through the thoracic duct, significant injuries can cause leaks in excess of 2 L per day; if left untreated, protein, lymphocyte, and volume depletion can lead to serious metabolic effects and death. Thoracentesis is usually grossly suggestive, revealing milky, nonpurulent pleural fluid. However, if the patient is taking nothing by mouth, the pleural VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 685 CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura  ontamination from a source contiguous to the pleural space C (50%–60%) Lung Mediastinum Deep cervical area Chest wall and spine Subphrenic area Direct inoculation of the pleural space (30%–40%) Minor thoracic interventions Postoperative infections Penetrating chest injuries Hematogenous infection of the pleural space from a distant site (<1%) chest over the course of several weeks. If the patient is stable, tube removal can frequently be done in the outpatient setting, guided by the degree of drainage and the size of the residual space visualized on serial CT scans. Larger spaces may require open thoracotomy and decortication in an attempt to re-expand the lung to fill this residual space. If re-expansion has failed or appears too high risk, then open drainage, rib resection, and prolonged packing may be required, with delayed closure with muscle flaps or thoracoplasty.203 Most chronic pleural space problems can be avoided by early specialized thoracic surgical consultation and complete drainage of empyema, allowing space obliteration by the reinflated lung. 686 Table 19-38 Etiology of chylothorax UNIT II PART SPECIFIC CONSIDERATIONS Congenital Atresia of thoracic duct Thoracic duct-pleural space fistula Birth trauma Traumatic and/or iatrogenic Blunt injury Penetrating injury Surgery   Cervical     Excision of lymph nodes    Radical neck dissection   Thoracic     Correction of patent ductus arteriosus     Correction of coarctation of the aorta    Vascular procedure involving the origin of the left subclavian artery    Esophagectomy    Sympathectomy     Resection of thoracic aneurysm     Resection of mediastinal tumors    Left pneumonectomy   Abdominal    Sympathectomy     Radical lymph node dissection   Diagnostic procedures    Translumbar arteriography    Subclavian vein catheterization    Left-sided heart catheterization Neoplasms Infections Tuberculous lymphadenitis Nonspecific mediastinitis Ascending lymphangitis Filariasis Miscellaneous Venous thrombosis    Left subclavian-jugular vein    Superior vena cava Pulmonary lymphangiomatosis Source: Reproduced with permission from Cohen RG, et al. The pleura. In: Sabiston DC, et al, eds. Surgery of the Chest. 6th ed. Philadelphia: Elsevier; 1995. Copyright Elsevier. fluid may not be grossly abnormal. Laboratory analysis of the pleural fluid shows a high lymphocyte count and high triglyceride levels. If the triglyceride level is greater than 110 mg/ 100 mL, a chylothorax is almost certainly present (a 99% accuracy rate). If the triglyceride level is less than 50 mg/mL, there is only a 5% chance of chylothorax. In many clinical situations, the accumulation of chyle may be slow, because of minimal digestive fat flowing through the gastrointestinal tract after major trauma or surgery, so the diagnosis may be more difficult to establish. Management. The treatment plan for any chylothorax depends on its cause, the amount of drainage, and the patient’s clinical status (Fig. 19-53). In general, most patients are treated with a short period of chest tube drainage, nothing by mouth (NPO) orders, total parenteral nutrition (TPN), and observation. Thoracic d. Cisterna chyli Figure 19-52. Normal thoracic duct anatomy. The esophagus comes into close proximity with the thoracic duct as it enters the chest from its origin in the abdomen at the cisterna chyli. Table 19-39 Composition of chyle Component Amount (per 100 mL) Total fat 0.4–5 g Total cholesterol 65–220 mg Total protein 2.21–5.9 g Albumin 1.1–4.1 g Globulin 1.1–3.1 g Fibrinogen 16–24 g Sugars 48–200 g Electrolytes Similar to levels in plasma Cellular elements Lymphocytes 400–6800/mm3 Erythrocytes 50–600/mm3 Antithrombin globulin >25% of plasma concentration Prothrombin >25% of plasma concentration Fibrinogen >25% of plasma concentration Source: Reproduced with permission from Miller.204 Copyright Elsevier. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 687 Thoracentesis Confirm diagnosis Chest tube CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura Conservative management NPO Chest tube to suction Central hyperalimentation Wait two weeks* (Nonmalignant) Drainage persists (>500 ml/d) Drainage decrease (<250 ml/d) Thoracotomy Duct ligation Mass ligation Decortication Pleurectomy Continue one week Radiation therapy Drainage stops Remove chest tube Malignant chylothorax Drainage persists Medically unstable Pleural peritoneal shunt Chest cavity drainage must be adequate to allow complete lung re-expansion. Somatostatin has been advocated by some authors, with variable results. If significant chyle drainage (>500 mL per day in an adult, >100 mL in an infant) continues despite TPN and good lung expansion, early surgical duct ligation or embolization is recommended. Ligation can be approached best by right thoracotomy, and in some experienced centers, by right VATS. Chylothoraces due to malignant conditions often respond to radiation and/or chemotherapy and less commonly require surgical ligation. Significant nutritional and immunologic depletion results from untreated chylothorax; associated mortality is in excess of 50%. With early recognition and aggressive medical management as well as early surgical ligation or embolization for persistent leaks, the mortality rate of chylothorax is now less than 10%. Tumors of the Pleura Malignant mesothelioma is the most common type of tumor of the pleura, with approximately 3000 cases per year in the Medically stable Thoracotomy Figure 19-53. Algorithm for the management of chylothorax. *If high output persists (>500 mL/d), early surgical ligation of the thoracic duct may be considered. NPO = nothing by mouth. United States. Other, less common tumors include benign and malignant fibrous tumors of the pleura, lipomas, and cysts. Malignant Mesothelioma. The only known risk factor for mesothelioma is exposure to asbestos, identified in over 50% of cases. Exposure is typically work-related in industries using asbestos in the manufacturing process, such as shipbuilding. The risk extends to family members who are exposed to the dust of the clothing or to the work environment. Asbestos exposure and smoking synergistically increase the risk for lung cancer, but smoking does not increase risk for malignant mesotheliomas. Male predominance is 2:1, and it occurs most commonly after the age of 40. Risk of developing mesothelioma after asbestos exposure differs depending on the physical characteristics of the asbestos and similar fibers (either serpentine or amphibole). The serpentine fibers are large and curly and are generally not able to travel beyond larger airways. However, the narrow, straight VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 688 UNIT II PART amphibole fibers, in particular the crocidolite fibers, may navigate distally into the pulmonary parenchyma and are most clearly associated with mesotheliomas. The latency period between asbestos exposure and the development of mesothelioma is at least 20 years. The tumor generally is multicentric, with multiple pleural-based nodules coalescing to form sheets of tumor. This process initially involves the parietal pleura, generally with early spread to the visceral surfaces and with a variable degree of invasion of surrounding structures. Autopsy studies have shown that most patients have distant metastases, but the natural history of the disease in untreated patients culminates in death due to local extension. Other risk factors include radiation exposure. SPECIFIC CONSIDERATIONS Clinical Presentation. Most patients present with dyspnea and chest pain. Over 90% have a pleural effusion, but thoracentesis is diagnostic in less than 10% of patients. Frequently, a thoracoscopy or open pleural biopsy with special stains is required to differentiate mesotheliomas from adenocarcinomas (Table 19-40). Epithelial subtypes are associated with a more favorable prognosis, and long-term survival may be seen in rare patients with no treatment. Sarcomatous and mixed tumors share a more aggressive course. Management. The treatment of malignant mesotheliomas remains controversial. Prognosis depends on the stage of the disease (Table 19-41),206 but most patients present with advanced local or distant disease beyond curative potential. Treatment options include supportive care only, surgical resection, and multimodality approaches (using a combination of surgery, chemotherapy, and radiation therapy).207 Palliative approaches, such as pleurectomy or talc pleurodesis, may lead to local control and a modest improvement in short-term survival. Several reports of trials of extrapleural pneumonectomy and adjuvant chemotherapy and radiation have shown reasonable improvements in survival for patients with early-stage tumors (as compared with historical controls). In one series of 183 patients, a subset of 31 patients had favorable prognostic features (i.e., epithelial cell type), negative resection margins, and negative extrapleural node status. This favorable subset had a 5-year survival rate of 46%, as compared with 15% for the entire group.208 In another series, 88 patients with mesotheliomas were studied prospectively. Adjuvant radiation therapy was given to 54 patients after extrapleural pneumonectomy; the median survival Table 19-40 Differentiation of mesothelioma from adenocarcinoma Mesothelioma Adenocarcinoma Immunohistochemical results  Carcinoembryonic antigen Negative Positive  Vimentin Positive Negative  Low molecular weight cytokeratins Positive Negative Electron microscopic features Long, sinuous villi Short, straight villi with fuzzy glycocalyx was 17 months. However, in patients with stage I and II disease, the median survival was significantly better at 33.0 months.209 Intrapleural therapy has been explored to improve the locoregional control of malignant mesotheliomas. In a phase II trial, 37 patients underwent pleurectomy with decortication, followed by intrapleural and systemic therapy with cisplatin and mitomycin C. Their median survival was 17 months, with a locoregional recurrence rate of 80%.210 According to another study, the addition of hyperthermic intrapleural perfusion seems to be pharmacokinetically advantageous; of seven patients, three underwent pleurectomy with decortication and received hyperthermic cisplatin. Systemic drug concentrations were greater after pleurectomy with decortication than after pleuropneumonectomy. The local tissue:perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than normothermic perfusion.211 Another promising alternative to enhance the local efficacy of chemotherapy against malignant mesotheliomas is L-NDDP (cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum). A phase II trial of L-NDDP enrolled 33 patients to receive a thoracoscopic biopsy and a thoracoscopic posttreatment pleural biopsy after each cycle. Of those 33 patients, 14 (42%) had a complete pathologic response, with three treatmentrelated deaths due to infection. Buried residual tumor was found at pleural decortications in another two patients who had pathologic response.212 These findings are encouraging, but the optimal regimen for intrapleural treatment for mesothelioma remains to be fully defined. The authors’ current approach to malignant mesothelioma is based on tumor stage and patient performance status. Extrapleural pneumonectomy is recommended, especially for epithelial mesotheliomas, early-stage mesotheliomas, and good pulmonary function. For more advanced disease, decortication with intrapleural chemotherapy is administered, using an institutional protocol, for patients who are fit for surgery. Whenever possible, patients are referred for clinical trials of multimodality therapy. For more advanced disease, or if patients have lessthan-optimal pulmonary function or performance status, talc pleurodesis or supportive therapy is recommended. Fibrous Tumors of the Pleura. Fibrous tumors of the pleura are unrelated to asbestos exposure or malignant mesotheliomas. They generally occur as a single pedunculated mass arising from the visceral pleura but can occasionally arise from the parietal pleura. They can grow to be quite large, with most ranging from 5 to 10 cm and 100 to 400 g in size by the time they are discovered. Architecturally, the most common microscopic feature is the “patternless pattern.” This is characterized by randomly situated areas of hypercellularity, containing spindle cells with bland, vesicular, ovoidal nuclei and scarce cytoplasm, and hypocellularity, with fibrous connective tissue, hemorrhage, myxoid, or necrosis. They can also have an hemangiopericytoma-like appearance. The neoplastic cells are immunoreactive for CD34 and CD99 but negative for cytokeratins and desmin. Immunoreactivity for Bcl-2 is variably positive.213 They are frequently discovered incidentally on routine CXRs, without an associated pleural effusion. They occur with equal frequency in males and females and are most common in the sixth to seventh decade of life. Fibrous tumors of the pleura may be benign or malignant.214 Symptoms such as cough, chest pain, and dyspnea occur in 30% to 40% of patients but are found in 75% of patients with malignant tumors. Malignant tumors VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 689 Table 19-41 International Mesothelioma Interest Group staging system for diffuse malignant pleural mesothelioma T Tumor T1a  Tumor limited to the ipsilateral parietal ± mediastinal ± diaphragmatic pleura No involvement of the visceral pleura T1b  Tumor involving the ipsilateral parietal ± mediastinal ± diaphragmatic pleura Tumor also involving the visceral pleura T2 Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleurae) with at least one of the following features: Involvement of diaphragmatic muscle Extension of tumor from visceral pleura into the underlying pulmonary parenchyma T3 Describes locally advanced but potentially resectable tumor Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleurae) with at least one of the following features: Involvement of the endothoracic fascia Extension into the mediastinal fat Solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall Nontransmural involvement of the pericardium T4 Describes locally advanced technically unresectable tumor Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleurae) with at least one of the following features: Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction Direct transdiaphragmatic extension of tumor to the peritoneum Direct extension of tumor to the contralateral pleura Direct extension of tumor to mediastinal organs Direct extension of tumor into the spine Tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or tumor involving the myocardium N Lymph Nodes NX N0 N1 N2 N3 Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes including the ipsilateral internal mammary nodes Metastases in the contralateral mediastinal, contralateral internal mammary, or ipsilateral or contralateral supraclavicular lymph nodes M Metastases MX Presence of distant metastases cannot be assessed M0 No distant metastases M1 Distant metastases present Staging Stage I IA T1a IB T1b Stage II T2 Stage III Any T3 Stage IV Any T4 N0 N0 N0 Any N1 Any N2 Any N3 M0 M0 M0 M0 Any M1 Source: Reproduced with permission from International Mesothelioma Interest Group. A proposed new international TNM staging system for malignant pleural mesothelioma. Chest. 1995;108:1122. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 19 Chest Wall, Lung, Mediastinum, and Pleura T1 690 UNIT II PART SPECIFIC CONSIDERATIONS are differentiated from benign tumors based on high cellularity, more than 4 mitotic figures per 10 high-power fields, nuclear pleomorphism, tumor necrosis, and hemorrhage. They are more likely to arise from the parietal pleura of the chest wall, diaphragm, or mediastinum, or in the fissures or invaginating into the lung parenchyma. Hypoglycemia, associated pleural effusion, and hypertrophic pulmonary osteoarthropathy (clubbed digits, long bone ossifying periostitis, and arthritis) are associated with these lesions in approximately 25% of patients. Less common are fever and hemoptysis. Symptoms resolve with surgical resection. Given the wellcircumscribed and often pedunculated nature of fibrous tumors of the pleura, all benign lesions and approximately 50% of malignant lesions are cured by complete surgical resection.214 Incompletely resected malignant tumors may recur locally or metastasize, and more than 50% of patients with malignant tumors will die from the disease; frequently, they are fatal within 2 to 5 years. ACKNOWLEDGEMENT The authors wish to thank Shannon Wyszomierski for her invaluable help in compiling and editing this chapter. The authors also express appreciation to their spouses, Chris, Lee, and Chris. REFERENCES Entries highlighted in bright blue are key references. 1. Cusimano RJ, Pearson FG. Anatomy, physiology, and embryology of the upper airway. In: Pearson FG, Cooper JD, Deslauriers J, et al, eds. Thoracic Surgery. 2nd ed. New York: Churchill Livingstone; 2002:215. 2. Grillo HC. Surgical treatment of postintubation tracheal injuries. J Thorac Cardiovasc Surg. 1979;78(6):860-875. 3. 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Chahinian AP. Chemotherapy of thymomas and thymic carcinomas. Chest Surg Clin N Am. 2001;11:447. 179. Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg. 1995;60:908; discussion 914. 180. Weksler B, Shende M. The role of adjuvant radiation therapy for resected stage III thymoma: a population-based study. Ann Thorac Surg. 2012;93:1822-1828; discussion 1828-1829. 181. Suster S, Rosai J. Thymic carcinoma. A clinicopathologic study of 60 cases. Cancer. 1991;67:1025. 182. Bousamra M. Neurogenic tumors of the mediastinum. In: Pearson FG, ed. Thoracic Surgery. 2nd ed. New York: Churchill Livingstone; 2002:1732. 183. Venissac N, Leo F, Hofman P, et al. Mediastinal neurogenic tumors and video-assisted thoracoscopy: always the right choice? Surg Laparosc Endosc Percutan Tech. 2004; 14:20. 184. Coleman BG, Arger PH, Dalinka MK, et al. CT of sarcomatous degeneration in neurofibromatosis. AJR Am J Roentgenol. 1983;140:383. 185. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986;57:2006. 186. Nichols CR, Saxman S, Williams SD, et al. Primary mediastinal nonseminomatous germ cell tumors. A modern single institution experience. Cancer. 1990;65:1641. 187. Kesler KA, Rieger KM, Hammoud Z, et al. A 25-year single institution experience with surgery for primary mediastinal nonseminomatous germ cell tumors. Ann Thorac Surg. 2008;85:371-378. 188. Rice TW. Benign neoplasms and cysts of the mediastinum. Semin Thorac Cardiovasc Surg. 1992;4:25. 189. Di Lorenzo M, Collin PP, Vaillancourt R, et al. Bronchogenic cysts. J Pediatr Surg. 1989;24:988. 190. Ribet ME, Copin MC, Gosselin B. Bronchogenic cysts of the mediastinum. J Thorac Cardiovasc Surg. 1995;109:1003. 191. St-Georges R, Deslauriers J, Duranceau A, et al. Clinical spectrum of bronchogenic cysts of the mediastinum and lung in the adult. Ann Thorac Surg. 1991;52:6. 192. Agostoni E. Mechanics of the pleural space. In: Fisherman AP, Macklem PT, Mead J, et al, eds. Mechanics of Breathing: Handbook of Physiology. vol 3. Bethesda: American Physiological Society; 1986. 193. Lawrence GH. Considerations of the anatomy and physiology of the pleural space. In: Lawrence GH, ed. Problems of the Pleural Space. Philadelphia: WB Saunders; 1983. 194. Rusch VW. Pleural effusion: benign and malignant. In: Pearson FG, ed. Thoracic Surgery. 2nd ed. New York: Churchill Livingstone; 2002:1157. 195. Gammie JS, Banks MC, Fuhrman CR, et al. The pigtail catheter for pleural drainage: a less invasive alternative to tube thoracostomy. JSLS. 1999;3:57. 196. Luketich JD, Kiss M, Hershey J, et al. Chest tube insertion: a prospective evaluation of pain management. Clin J Pain. 1998;14:152. 197. Johnston WW. The malignant pleural effusion. A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer. 1985;56:905. 198. Ocana I, Martinez-Vazquez JM, Segura RM, et al. Adenosine deaminase in pleural fluids. Test for diagnosis of tuberculous pleural effusion. Chest. 1983;84:51. 199. Lee YC, Rogers JT, Rodriguez RM, et al. Adenosine deaminase levels in nontuberculous lymphocytic pleural effusions. Chest. 2001;120:356. 200. Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest. 2006;129:362. 201. Light RW. Parapneumonic effusions and empyema. Clin Chest Med. 1985;6:55. 202. Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365:518-526. 203. Miller JI Jr. The history of surgery of empyema, thoracoplasty, Eloesser flap, and muscle flap transposition. Chest Surg Clin N Am. 2000;10:45. 204. Miller JI Jr. Diagnosis and management of chylothorax. Chest Surg Clin N Am. 1996;6:139. 205. Malthaner RA, Inculet RI. The thoracic duct and chylothorax. In: Pearson FG, ed. Thoracic Surgery. 2nd ed. New York: Churchill Livingstone; 2002:1228. 206. Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest. 1995;108:1122. 207. Khalil MY, Mapa M, Shin HJ, et al. Advances in the management of malignant mesothelioma. Curr Oncol Rep. 2003; 5:334. 208. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg. 1999;117:54; discussion 63. 209. Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2001;122:788. 210. Rusch V, Saltz L, Venkatraman E, et al. A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol. 1994;12:1156. 211. Ratto GB, Civalleri D, Esposito M, et al. Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study. J Thorac Cardiovasc Surg. 1999;117:759. 212. Lu C, Perez-Soler R, Piperdi B, et al. Phase II study of a liposome-entrapped cisplatin analog (L-NDDP) administered intrapleurally and pathologic response rates in patients with malignant pleural mesothelioma. J Clin Oncol. 2005;23:3495. 213. Fletcher CDM, Unni KK, Mertens F. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002. 214. England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumors of the pleura. A clinicopathologic review of 223 cases. Am J Surg Pathol. 1989;13:640. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 20 chapter Introduction Defects Where Repair Is the Only or Best Option Tara Karamlou, Yasuhiro Kotani, and Glen A. Van Arsdell 695 Tricuspid Atresia / 712 Hypoplastic Left Heart Syndrome / 716 695 Defects That May Be Palliated or Repaired Atrial Septal Defect / 695 Aortic Stenosis / 698 Patent Ductus Arteriosus / 702 Aortic Coarctation / 705 Truncus Arteriosus / 706 Total Anomalous Pulmonary Venous Connection / 707 Cor Triatriatum / 710 Aortopulmonary Window / 711 Defects Requiring Palliation Congenital Heart Disease 712 719 Ebstein’s Anomaly / 719 Transposition of the Great Arteries / 720 Double-Outlet Right Ventricle / 721 Double-Outlet Right Ventricle with Noncommitted Ventricular Septal Defect / 722 Double-Outlet Right Ventricle with Subaortic or Doubly Committed Ventricular Septal Defect Without Pulmonary Stenosis / 723 INTRODUCTION Congenital heart surgery is a dynamic and evolving field. The last 20 years have brought about rapid developments in technology, emphasis on a multidisciplinary approach to treatment, and a more thorough understanding of both the anatomy and pathophysiology of congenital heart disease, leading to the improved care of these challenging patients. These advancements have created and sustained a paradigm shift in the field of congenital heart surgery. The traditional strategy of initial palliation followed by definitive correction at a later age, which had pervaded the thinking of most surgeons, began to evolve to one emphasizing early repair, even in the tiniest patients. Furthermore, some of the defects that were virtually uniformly fatal (such as hypoplastic left heart syndrome) are now successfully treated with aggressive forms of palliation using cardiopulmonary bypass, resulting in outstanding survival for many of these children. Because the goal in most cases of congenital heart disease (CHD) is now early repair, as opposed to subdividing lesions into cyanotic or noncyanotic lesions, a more appropriate classification scheme divides particular defects into three categories based on the feasibility of achieving this goal: (a) defects that have no reasonable palliation and for which repair is the only option; (b) defects for which repair is not possible and for which palliation is the only option; and (c) defects that can either be repaired or palliated in infancy. It bears mentioning that all defects in the second category are those in which the appropriate anatomic components either are not present, as in hypoplastic left heart syndrome, or cannot be created from 1 existing structures. Double-Outlet Right Ventricle with Subaortic or Doubly Committed Ventricular Septal Defect with Pulmonary Stenosis / 723 Taussig-Bing Syndrome without Pulmonary Stenosis / 723 Taussig-Bing Syndrome with Pulmonary Stenosis / 723 Tetralogy of Fallot / 724 Ventricular Septal Defect / 726 Atrioventricular Canal Defects / 727 Interrupted Aortic Arch / 729 DEFECTS WHERE REPAIR IS THE ONLY OR BEST OPTION Atrial Septal Defect An atrial septal defect (ASD) is defined as an opening in the interatrial septum that enables the mixing of blood from the ­systemic venous and pulmonary venous circulations. Embryology. The atrial and ventricular septa form between the third and sixth weeks of fetal development. After the paired heart tubes fuse into a single tube folded onto itself, the distal portion of the tube causes an indentation to form in the roof of the common atrium. Near this portion of the roof, the septum primum arises and extends into a crescentic formation toward the atrioventricular (AV) junction. The gap remaining between the septum primum and the developing tissues of the AV junction is called the ostium primum. Before the septum primum fuses completely with the endocardial cushions, a series of fenestrations appear in the septum primum that coalesce into the ostium secundum. During this coalescence, the ­septum secundum grows downward from the roof of the atrium, ­parallel to and to the right of the septum primum. The septum primum does not fuse, but creates an oblique pathway, called the foramen ovale, within the interatrial septum. After birth, the increase in left atrial pressure normally closes this pathway, obliterating the interatrial connection. Anatomy. ASDs can be classified into three different types: (a) sinus venosus defects, comprising approximately 5% to 10% of all ASDs; (b) ostium primum defects, which are more correctly described as partial AV canal defects; and (c) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 UNIT II PART SPECIFIC CONSIDERATIONS 3 4 Congenital heart disease comprises a wide morphologic spectrum. In general, lesions can be conceptualized as those that can be completely repaired, those that should be palliated, and those that can be either repaired or palliated depending on particular patient and institutional characteristics. Percutaneous therapies for congenital heart disease are quickly becoming important adjuncts, and in some cases, alternatives, to standard surgical therapy. Important examples include percutaneous closure of atrial and ventricular septal defects, the hybrid approach to hypoplastic left heart syndrome, radiofrequency perforation of the pulmonary valve, and percutaneous pulmonary valve placement. Further studies are necessary to establish criteria and current benchmarks for the safe integration of these novel approaches into the care of patients with congenital heart surgery. Patients with critical left ventricular outflow tract obstruction, such as neonatal critical aortic stenosis, represent a challenging population. It is critical that the correct decision (whether to pursue a univentricular or biventricular) be made at the initial operation, as attrition when the incorrect decision is made is high. There are several published criteria (Congenital Heart Surgeons’ Society critical stenosis calculator) to help surgeons decide which strategy to pursue. Optimum strategy for repair of total anomalous pulmonary venous connection (TAPVC) remains a topic of some contention. Sutureless repair, formerly reserved for initial restenosis after conventional repair, has evolved in many centers to be 5 6 the primary treatment of choice for high-risk patients. Defining whether sutureless repair should be considered in all patients with TAPVC will require further study. A recent prospective, randomized, multi-institutional trial sponsored by the National Institutes of Health, the Systemic Ventricle Reconstruction (SVR) trial, compared the outcomes of neonates with hypoplastic left heart syndrome having either a modified Blalock-Taussig shunt versus a right ventricle-to-pulmonary artery (RV-PA) shunt. The SVR trial demonstrated that transplantation-free survival 12 months after randomization was higher with the RV-PA shunt than with the modified Blalock-Taussig shunt. However, data collected over a mean follow-up period of 32 ± 11 months showed a nonsignificant difference in ­transplantation-­free survival between the two groups. Outcomes have improved substantially over time in congenital heart surgery, and most complex lesions can be operated in early infancy. Neurologic protection, however, remains a key issue in the care of neonates undergoing surgery with cardiopulmonary bypass and deep hypothermic circulatory arrest. New monitoring devices and perioperative strategies are currently under investigation. Attention in the field has shifted currently from analyses of perioperative mortality, which for most lesions is under 10%, to longer-term outcomes, including quality of life and neurologic function. ostium secundum defects, which are the most prevalent subtype, comprising 80% of all ASDs (Fig. 20-1).1 696 Pathophysiology. ASDs result in an increase in pulmonary blood flow secondary to left-to-right shunting through the defect. The direction of the intracardiac shunt is predominantly determined by the compliance of the respective ventricles. In utero, the distensibility, or compliance, of the right and left ventricles is equal, but postnatally the left ventricle (LV) becomes less compliant than the right ventricle (RV). This shift occurs because the resistance of the downstream vascular beds changes after birth. The pulmonary v­ ascular resistance falls with the infant’s first breath, decreasing RV pressure, whereas the systemic vascular resistance rises ­dramatically, increasing LV pressure. The increased LV pressure creates a thicker muscle mass, which offers a greater resistance to diastolic filling than does the RV; thus, the majority of flow through the ASD occurs from left to right. The greater volume of blood returning to the right atrium causes volume overload in the RV, but because of its lower muscle mass and low-resistance output, it easily distends to accommodate this load. The long-term consequences of RV volume overload include hypertrophy with elevated RV end-diastolic pressure and a relative pulmonary stenosis across the pulmonary valve, because it cannot accommodate the increased RV flow. The resistance at the level of the pulmonary valve then contributes a further pressure load on the RV, which accelerates RV hypertrophy. Compliance gradually decreases as the right ventricular pressure approaches systemic pressure, and the Figure 20-1. The anatomy of atrial septal defects. In the sinus venosus type (A), the right upper and middle pulmonary veins frequently drain to the superior vena cava or right atrium. B. Secundum defects generally occur as isolated lesions. C. Primum defects are part of a more complex lesion and are best considered as incomplete atrioventricular septal defects. (Reproduced with permission from Greenfield LJ, Mulholland MW, Oldham KT, et al, eds. ­Surgery: Scientific Principles and Practice. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:1444.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Diagnosis. Patients with ASDs may present with few physical findings. Auscultation may reveal prominence of the first heart sound with fixed splitting of the second heart sound. This results from the relatively fixed left-to-right shunt throughout all phases of the cardiac cycle. A diastolic flow murmur indicating increased flow across the tricuspid valve may be discerned, and frequently, an ejection flow murmur can be heard across the pulmonary valve. A right ventricular heave and increased intensity of the pulmonary component of the second heart sound indicates pulmonary hypertension and possible unrepairability. Chest radiographs in the patient with an ASD may show evidence of increased pulmonary vascularity, with prominent hilar markings and cardiomegaly. The electrocardiogram shows right axis deviation with an incomplete bundle-branch block. When right bundle-branch block is associated with a leftward or superior axis, an AV canal defect should be strongly suspected. Diagnosis is clarified by two-dimensional echocardiography, and use of color-flow mapping facilitates an understanding of the physiologic derangements created by the defects. Older children and adults with unrepaired ASDs may present with stroke or systemic embolism from paradoxical embolism or atrial arrhythmias from dilation of the right atrium. Echocardiography also enables the clinician to estimate the amount of intracardiac shunting, can demonstrate the degree of mitral regurgitation in patients with ostium primum defects, and with the addition of microcavitation, can assist in the detection of sinus venosus defects. The advent of two-dimensional echocardiography with color-flow Doppler has largely obviated the need for cardiac catheterization because the exact nature of the ASD can be precisely defined by echocardiography alone. However, in cases where the patient is older than age 40 years, catheterization can quantify the degree of pulmonary hypertension present, because those with a fixed pulmonary vascular resistance greater than 12 U/mL are considered inoperable.4 Cardiac catheterization also can be useful in that it provides data that enable the calculation of Qp and Qs so that the magnitude of the intracardiac shunt can be determined. The ratio (Qp:Qs) can then be used to ­determine whether closure is indicated in equivocal cases, because a Qp:Qs greater than 1.5:1 is generally accepted as the threshold for surgical intervention. Finally, in patients older than age 40 years, cardiac catheterization can be important to disclose the presence of coronary artery disease. In general, ASDs are closed when patients are between 4 and 5 years of age. Children of this size can usually be operated on without the use of blood transfusion and generally have excellent outcomes. Patients who are symptomatic may require repair earlier, even in infancy. Some surgeons, however, advocate routine repair in infants and children, as even smaller defects are associated with the risk of paradoxical embolism. In a recent review by Reddy and colleagues, 116 neonates weighing less than 2500 g who underwent repair of simple and complex cardiac defects with the use of cardiopulmonary bypass were found to have no intracerebral hemorrhages, no long-term neurologic sequelae, and a low operative mortality rate (10%). These results correlated with the length of cardiopulmonary bypass and the complexity of repair.5 These investigators also found an 80% actuarial survival at 1 year and, more importantly, that growth following complete repair was equivalent to weightmatched neonates free from cardiac defects.5 Treatment. ASDs can be repaired in a facile manner using standard cardiopulmonary bypass (CPB) techniques through a midline sternotomy approach. The details of the repair itself are generally straightforward. An oblique atriotomy is made, the position of the coronary sinus and all systemic and pulmonary veins are determined, and the rim of the defect is completely visualized. Closure of ostium secundum defects is accomplished either by primary repair or by insertion of a patch that is sutured to the rim of the defect. The decision of whether patch closure is necessary can be determined by the size and shape of the defect as well as by the quality of the edges. The type of repair used for sinus venosus ASDs associated with partial anomalous pulmonary venous connection is dictated by the location of the anomalous pulmonary veins. If the anomalous veins connect to the atria or to the superior vena cava caudal to where the cava is crossed by the right pulmonary artery, the ASD can be repaired by inserting a patch, with redirection of the pulmonary veins behind the patch to the left atrium. Care must be taken with this approach to avoid obstruction of the pulmonary veins or the superior vena cava, although usually the superior vena cava is dilated and provides ample room for patch insertion. If the anomalous vein connects to the superior vena cava cranial to the right pulmonary artery, an alternative technique, the Warden procedure, may be necessary. In this operation, the superior vena cava is transected cranial to the connection of the anomalous vein (usually the right superior pulmonary vein). The caudal end of the transected cava is oversewn. The cranial end of the transected cava is anastomosed to the auricle of the right atrium. Inside the atrium, a patch is used to redirect pulmonary venous blood flow to the left atrium. In contrast to the repair for a defect where the pulmonary veins enter the right atrium or the superior vena cava below the right pulmonary artery, the patch covers the superior vena caval right atrial junction so that blood from the anomalous pulmonary vein that enters the cava is directed to the left atrium. Blood returning from the upper body enters the right atrium via the anastomosis between the superior vena cava and the right atrial appendage. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 697 CHAPTER 20 Congenital Heart Disease size of the ­left-to-right shunt decreases. Patients at this stage have a balanced circulation and may deceptively appear less ­symptomatic. A minority of patients with ASDs develop progressive ­pulmonary vascular changes as a result of chronic overcirculation. The increased pulmonary vascular resistance in these patients leads to an equalization of left and right ventricular pressures, and their ratio of pulmonary (Qp) to systemic flow (Qs), Qp:Qs, will approach 1.2 This does not mean, however, that there is no intracardiac shunting, only that the ratio between the left-to-right component and the right-to-left component is equal. The ability of the RV to recover normal function is related to the duration of chronic overload, because those undergoing ASD closure before age 10 years have a better likelihood of achieving normal RV function in the postoperative period.3 The physiology of sinus venosus ASDs is similar to that discussed earlier, except that these are frequently accompanied by anomalous pulmonary venous drainage. This often results in significant hemodynamic derangements that accelerate the clinical course of these infants. The same increase in symptoms is true for those with ostium primum defects because the associated mitral insufficiency from the “cleft” mitral valve can lead to more atrial volume load and increased atrial level shunting. 698 Results and Complications of Surgical ASD Closure. UNIT II PART SPECIFIC CONSIDERATIONS Traditional operative strategies, such as pericardial or synthetic patch closure, have been well established, with a low complication rate and a mortality rate of zero among patients without pulmonary hypertension.6 The most frequently reported immediate complications include postpericardiotomy syndrome and atrial arrhythmias. Beyond immediate postoperative outcomes, long-term outcomes following s­ urgical closure (up to 20 years) document the low attrition rate and durability of functional ­status benefit. Importantly, however, atrial arrhythmias are not completely mitigated by closure and can occur in 10% to 40% of patients, especially in older patients (>40 years) or those with pre-existing arrhythmias.7 Kutty and colleagues8 followed 300 patients from their institution, 152 of whom had surgical closure. Late mortality at 10 years was 3%, and functional health status had declined in only 15 patients during follow-up. Recently, there have been an increasing number of reports regarding the results following surgical closure among elderly patients (>60 years of age), which demonstrate equivalent survival to younger patients, albeit with slightly higher complication rates.8-10 Hanninen and ­colleagues11 studied 68 patients between 68 and 86 years at their institution undergoing either surgical (n = 13) or device (n = 54) closure. Although the 23% incidence of major complications (including pneumothorax, heart failure, and pneumonia) was higher than that recently reported by Mascio et al12 using the Society of Thoracic Surgeons’ Congenital Database (20%) or a single-institution review by Hopkins et al13 (12%), there were no operative deaths among the elderly cohort. Moreover, after ASD closure, echocardiographic indices of right ventricular size and function were significantly improved from preoperative values, and functional capacity as measured by standardized survey instruments was also significantly improved. New and Future Approaches to Traditional Surgical ASD Closure. Because of the uniformly excellent outcomes with traditional surgery, attention has shifted to improving the c­ osmetic result and minimizing hospital stay and convalescence. Multiple strategies have been described to achieve these aims, including the right submammary incision with anterior thoracotomy, limited bilateral submammary incision with partial sternal split, and limited midline incision with partial sternal split. Some surgeons use either video-assisted thoracic surgery (VATS) in conjunction with the submammary and transxiphoid approaches to facilitate closure within a constricted operative field or totally endoscopic repair in selected patients.14-16 Use of robotics has also been reported in a small series of 12 adult patients by Argenziano and colleagues.15 The morbidity and mortality of all of these approaches are comparable to those of the traditional median sternotomy; however, each has technical drawbacks. Operative precision must be maintained with limited exposure in any minimally invasive technique. Extended CPB and aortic cross-clamp times, coupled with increased cost, may limit the utility of totally endoscopic or robotic-assisted ASD closure except at limited centers. Certain approaches have a specific patient population in whom they are applicable. For example, the anterolateral thoracotomy should not be employed in prepubescent girls because it will interfere with breast ­development. Most totally endoscopic approaches are not feasible in very young patients due to the size of the thoracoscopic ports. Despite these potential drawbacks, however, in carefully selected patients, minimally invasive techniques have d­ emonstrated benefits. Luo and associates performed a ­prospective randomized study comparing ministernotomy (division of the upper sternum for aortic and pulmonary lesions and the lower sternum for septal lesions) to full sternotomy in 100 consecutive patients undergoing repair of septal lesions.16 The patients in the ministernotomy group had longer procedure times (by 15 to 20 minutes), but had less bleeding and shorter hospital stays. Consistent with these initiatives, conversion of “low-risk” patients undergoing minimally invasive ASD closure to an ambulatory population (discharge from hospital within 24 hours) has recently been described.17 First performed in 1976, transcatheter closure of ASDs with the use of various occlusion devices is gaining widespread acceptance.18 Certain types of ASDs, including 2 patent foramen ovale, secundum defects, and some fenestrated secundum defects, are amenable to device closure, as long as particular anatomic criteria (e.g., an adequate superior and inferior rim for device seating and distance from the AV valve) are met. Since the introduction of percutaneous closure, there has been a dramatic rise in device closure prevalence to the point where device closure has supplanted surgical therapy as the dominant treatment modality for secundum ASD.19 A study from Karamlou et al19 recently found that ASD and patent foramen ovale closures per capita increased dramatically from 1.08 per 100,000 population in 1988 to 2.59 per 100,000 population in 2005, an increase of 139%. When analyzed by closure type, surgical closure increased by only 24% (from 0.86 per 100,000 population in 1988 to 1.07 per 100,000 in 2005), whereas transcatheter closure increased by 3475% (from 0.04 per 100,000 population in 1988 to 1.43 per 100,000 in 2005). Importantly, this study determined that the paradigm shift favoring transcatheter closure has occurred mainly due to increased prevalence of closure in adults over age 40 years rather than an increase in closure in infants or children. Despite the simplicity of ASD repair, there are a myriad of options for patients and physicians who care for patients with CHD. The patient population that might benefit from closure (whether device or surgical) is likely to increase, challenging current ideas and treatment algorithms that optimize outcomes. Aortic Stenosis Anatomy and Classification. The spectrum of aortic valve abnormality represents the most common form of CHD, with the great majority of patients being asymptomatic until midlife. Obstruction of the left ventricular outflow tract (LVOT) occurs at multiple levels: subvalvular, valvular, and supravalvular (Fig. 20-2). The critically stenotic aortic valve in the neonate or infant is commonly unicommissural or bicommissural, with thickened, dysmorphic, and myxomatous leaflet tissue and a reduced cross-sectional area at the valve level. Associated leftsided lesions are often present. In a review of 32 cases from the Children’s Hospital in Boston, 59% had unicommissural valves and 40% had bicommissural valves.20 Associated lesions were frequent, occurring in 88% of patients, most commonly patent ductus arteriosus, mitral regurgitation, and hypoplastic LV. Endocardial fibroelastosis also is common among infants with critical aortic ­stenosis (AS). In this condition, the LV is largely nonfunctional, and these patients are not candidates for balloon valvotomy, simple valve replacement, or repair, because the LV VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ once the ductus closes, with dyspnea, tachypnea, irritability, narrowed pulse pressure, oliguria, and profound metabolic acidosis.7,21 If ductal patency is maintained, systemic perfusion will be provided by the RV via ductal flow, and cyanosis may be the only finding. is incapable of supporting the systemic circulation. Often, the LV is markedly hypertrophic with a reduced cavity size, but on rare occasion, a dilated LV, reminiscent of overt heart failure, is encountered.20 Pathophysiology. The unique intracardiac and extracardiac shunts present in fetal life allow even neonates with critical AS to survive. In utero, left ventricular hypertrophy and ischemia cause left atrial hypertension, which reduces the right-to-left flow across the foramen ovale. In severe cases, a reversal of flow may occur, causing right ventricular volume loading. The RV then provides the entire systemic output via the patent ductus arteriosus (ductal-dependent systemic blood flow). Although cardiac output is maintained, the LV suffers continued damage as the intracavitary pressure precludes adequate coronary perfusion, resulting in LV infarction and subendocardial fibroelastosis. The presentation of the neonate with critical AS is then determined by the morphology of the LV and other left-sided heart structures, the degree of left ventricular dysfunction, and the completeness of the transition from a parallel circulation to an in-series circulation (i.e., on closure of the foramen ovale and the ­ductus arteriosus). Those infants with mild-to-moderate AS in whom LV function is preserved are asymptomatic at birth. The only abnormalities may be a systolic ejection murmur and electrocardiogram (ECG) evidence of left ventricular hypertrophy. However, those neonates with severe AS and compromised LV function are unable to provide adequate cardiac output at birth and will present in circulatory collapse Treatment. The first decision that must be made in the neonate with critical LVOT obstruction is whether the patient is a candidate for biventricular or univentricular repair. Central to this decision is assessment of the degree of hypoplasia of the LV and other left-sided structures. Alsoufi and ­colleagues23 recently described a rational approach to the neonate 3 with critical LVOT obstruction (Fig. 20-3). The infant with severe AS requires urgent intervention. Preoperative stabilization, however, has dramatically altered the clinical algorithm and outcomes for this patient population.19,21 The preoperative strategy begins with endotracheal intubation and inotropic support. Prostaglandin infusion is initiated to maintain ductal patency, and confirmatory studies are performed prior to operative intervention. Therapy is generally indicated in the presence of a transvalvular gradient of 50 mmHg with associated symptoms including syncope, CHF, or angina, or if a gradient of 50 to 75 mmHg exists with concomitant ECG evidence of LV strain or ischemia. In the critically ill neonate, there may be little gradient across the aortic valve because of poor LV function. These patients depend on patency of the ductus arteriosus to provide systemic perfusion from the RV, and all ductal-dependent patients with critical AS require treatment. However, the decision regarding treatment options must be based on a complete understanding of associated defects. For example, in the presence of a hypoplastic LV (left ventricular end-diastolic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease Figure 20-2. The anatomy of the types of congenital aortic stenosis. A. Valvar aortic stenosis. B. Supravalvar aortic stenosis and its repair (insert). C. Tunnel-type subvalvar aortic stenosis. D. Membranous subvalvar aortic stenosis. (Reproduced with ­permission from Greenfield LJ, Mulholland MW, Oldham KT, et al, eds. Surgery: Scientific Principles and Practice. 3rd ed. ­Philadelphia: Lippincott Williams & Wilkins; 2001:1448.) Diagnosis. Neonates and infants with severe valvular AS may have a relatively nonspecific history of irritability and failure to thrive. Angina, if present, is usually manifested by episodic, inconsolable crying that coincides with feeding. As discussed previously, evidence of poor peripheral perfusion, such as extreme pallor, indicates severe LVOT obstruction. Differential cyanosis is an uncommon finding, but is present when enough antegrade flow occurs only to maintain normal upper body perfusion, while a large patent ductus arteriosus produces blue discoloration of the abdomen and legs. Physical findings include a systolic ejection murmur, although a quiet murmur may paradoxically indicate a more severe condition with reduced cardiac output. A systolic click correlates with a valvular etiology of obstruction. As LV dysfunction progresses, evidence of congestive heart failure occurs. The chest radiograph is variable but may show dilatation of the aortic root, and the ECG often demonstrates LV hypertrophy. Echocardiography with Doppler flow is extremely useful in establishing the diagnosis, as well as quantifying the transvalvular gradient.22 Furthermore, echocardiography can facilitate evaluation for the several associated defects that can be present in critical neonatal AS, including mitral stenosis, LV hypoplasia, LV endocardial fibroelastosis, subaortic stenosis, VSD, or coarctation. The presence of any or several of these defects has important implications related to treatment options for these patients. Although cardiac catheterization is not routinely performed for diagnostic purposes, it can be invaluable as part of the treatment algorithm if the lesion is amenable to balloon valvotomy. 699 700 Critical left ventricular outflow tract obstruction in neonate or infant Biventricle Single ventricle Staged correction Standard Norwood UNIT II PART Modified Norwood Hybrid strategy Heart transplantation Arch hypoplasia/coarctation No arch hypoplasia/coarctation Ventricular septal defect Intrinsic aortic valve stenosis Single level obstruction Percutaneous balloon valvuloplasty No intrinsic aortic valve stenosis Yasui operation SPECIFIC CONSIDERATIONS Ross Konno and arch repair Surgical valvotomy Arch repair and VSD closure Multi level obstruction No ventricular septal defect No intrinsic aortic valve stenosis Arch repair only Ross Konno operation Intrinsic aortic valve stenosis Arch reconstruction ± valvotomy/Ross Konno Figure 20-3. Treatment algorithm for neonates and infants with critical left ventricular outflow tract obstruction. Patients can be initially triaged to either a single or a biventricular approach depending on presenting morphologic, demographic, and institutional factors. VSD = ventricular septal defect. (From Alsoufi B, et al. Management options in neonates and infants with critical left ventricular outflow tract obstruction. Eur J Cardiothorac Surg. 2007;31:1013. Fig 1. By permission of Oxford University Press.) volume <20 mL/m2) or a markedly abnormal mitral valve, isolated aortic valvotomy should not be performed because studies have demonstrated high mortality in this population following isolated valvotomy.24 Patients who have an LV capable of providing systemic output are candidates for intervention to relieve AS, generally through balloon valvotomy. Very rarely, if catheter-based therapy is not an option, relief of valvular AS in infants and children can be accomplished with surgical valvotomy using standard techniques of CPB and direct exposure to the aortic valve. A transverse incision is made in the ascending aorta above the sinus of Valsalva, extending close to, but not into, the noncoronary sinus. Exposure is attained with placement of a retractor into the right coronary sinus. After inspection of the valve, the chosen commissure is incised to within 1 to 2 mm of the aortic wall (Fig. 20-4). Balloon valvotomy performed in the catheterization lab is the procedure of choice for reduction of transvalvular gradients in symptomatic infants and children. This procedure is an ideal palliative option because mortality from surgical valvotomy can be high due to the critical nature of these patients’ condition. Furthermore, balloon valvotomy provides relief of the valvular gradient and allows future surgical intervention (which is ­generally required in most patients when a larger prosthesis can be implanted) to be performed on an unscarred chest. An important issue when planning aortic valvotomy, whether percutaneously or via open surgical technique, is the risk of inducing hemodynamically significant aortic regurgitation. Induction of more than moderate aortic regurgitation is poorly tolerated in Ascending aorta incised Right coronary artery Left coronary artery Commissures Incised Figure 20-4. Aortic valvotomy with cardiopulmonary bypass. A transverse incision is made in the ascending aorta above the sinuses of Valsalva, extending close to, but not into, the noncoronary sinus. Exposure is accomplished with placement of a retractor into the right coronary sinus. After inspection of the valve, the chosen commissure is incised to within 1 to 2 mm of the aortic wall. (Reproduced with permission from Doty DB. Cardiac Surgery: A Looseleaf Workbook and Update Service. Chicago: Year Book; 1986. Copyright Elsevier) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ the hypoplastic left heart syndrome (HLHS), which is discussed later (see later section, Hypoplastic Left Heart Syndrome). Many surgeons previously avoided aortic valve replacement for AS in early childhood because the more commonly used mechanical valves would be outgrown and require replacement later and the obligatory anticoagulation for mechanical valves resulted in a substantial risk for complications. In addition, mechanical valves had an important incidence of bacterial endocarditis or perivalvular leak requiring re-intervention. The use of allografts and the advent of the Ross procedure have largely obviated these issues and made early definitive ­correction of critical AS a viable option.19,27,28 Donald Ross first described transposition of the pulmonary valve into the aortic position with allograft reconstruction of the pulmonary outflow tract in 1967.27 The result of this operation is a normal trileaflet semilunar valve made of a patient’s native tissue with the potential for growth to adult size in the aortic position in place of the damaged aortic valve (Fig. 20-5). The Ross procedure has become a useful option for aortic valve replacement in children, because it has improved durability and can be performed with acceptable morbidity and mortality rates. The placement of a pulmonary conduit, which does not grow and becomes calcified Diseased aortic valve Pulmonary autograft A B Pulmonary allograft C VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 20-5. A through C. The pulmonary autograft for aortic valve replacement. The aortic valve and adjacent aorta are excised, preserving buttons of aortic tissue around the coronary ostia. The pulmonary valve and main pulmonary artery are excised and transferred to the aortic position. The coronary buttons are then attached to the neoaortic root. A pulmonary allograft is inserted to re-establish the right ventricular outflow tract. (From Kouchokos NT, Davila-Roman VG, Spray TL, et al. Replacement of the aortic root with a pulmonary autograft in children and young adults with aortic-valve disease. N Engl J Med. 1994;330:1.) 701 CHAPTER 20 Congenital Heart Disease the infant with critical AS and may require an urgent procedure to replace or repair the aortic valve. In general, catheter-based balloon valvotomy has supplanted open surgical valvotomy. The decision regarding the most appropriate method to use depends on several factors, including the available medical expertise, the patient’s overall status and hemodynamics, and the presence of associated ­cardiac defects requiring repair.25 Although evidence is emerging to the contrary, simple valvotomy, whether performed using percutaneous or open technique, is generally considered a palliative procedure. The goal is to relieve LVOT obstruction without producing clinically significant regurgitation, in order to allow sufficient annular growth for eventual aortic valve replacement. The majority of infants who undergo aortic valvotomy will require further intervention on the aortic valve within 10 years following initial intervention.26 Valvotomy may result in aortic insufficiency that, while not important enough to require intervention in infancy, may alone or in combination with AS result in the need for an aortic valve replacement. Neonates with severely hypoplastic LVs or significant LV endocardial fibroelastosis may not be candidates for two-ventricle repair and are treated the same as infants with 702 Non-autograft Peak instantaneous AoV gradient (mm Hg) 80 60 40 Autograft 20 0 0 2 UNIT II PART 4 6 8 Years from initial AVR 10 SPECIFIC CONSIDERATIONS Figure 20-6. Predicted progression of the peak instantaneous prosthetic valve gradient after initial aortic valve replacement (AVR) stratified by prosthesis type (autograft vs. nonautograft) for a hypothetical patient of 3 years undergoing AVR in 1990. Solid lines represent point estimates from a mixed linear regression model (surrounded by their 90% confidence intervals in dashed lines). AoV = aortic valve. (Reproduced with permission from Karamlou T, et al. Outcomes and associated risk factors for aortic valve replacement in 160 children: A competing risks analysis. Circulation. 2005;112:3462.) and stenotic over time, does obligate the patient to reoperation to replace the RV-to-pulmonary artery conduit. Karamlou and colleagues29 recently reviewed the outcomes and associated risk factors for aortic valve replacement in 160 children from the Hospital for Sick Children in Toronto. They found that younger age, lower operative weight, concomitant performance of aortic root replacement or reconstruction, and use of prosthesis type other than a pulmonary autograft were significant predictors of death, whereas the use of a bioprosthetic or allograft valve type and earlier year of operation were identified as significant risk factors for repeated aortic valve replacement. Autograft use was associated with a blunted progression of the peak prosthetic valve gradient and a rapid decrease in the left ventricular end-diastolic dimension (Fig. 20-6). In agreement with these findings, Lupinetti and Jones28 compared allograft aortic valve replacement with the Ross procedure and found a more significant transvalvular gradient reduction and regression of left ventricular hypertrophy in those patients who underwent the Ross procedure. In some cases, the pulmonary valve may not be usable because of associated defects or congenital absence. These children are not candidates for the Ross procedure and are now most frequently treated with cryopreserved allografts (cadaveric human aortic valves). At times, there may be a size discrepancy between the right ventricular outflow tract (RVOT) and the LVOT, especially in cases of severe critical AS in infancy. For these cases, the pulmonary autograft is placed in a manner that also provides enlargement of the aortic annulus (Ross/Konno) (Fig. 20-7). Subvalvular AS occurs beneath the aortic valve and may be classified as discrete or tunnel-like (diffuse). A thin, fibromuscular diaphragm immediately proximal to the aortic valve characterizes discrete subaortic stenosis. This diaphragm typically extends for 180° or more in a crescentic or circular fashion, often attaching to the mitral valve as well as the interventricular septum.21 The aortic valve itself is usually normal in this condition, although the turbulence imparted by the subvalvular stenosis may affect leaflet morphology and valve competence. Diffuse subvalvular AS results in a long, tunnel-like obstruction that may extend to the left ventricular apex. In some individuals, there may be difficulty in distinguishing between hypertrophic cardiomyopathy and diffuse subaortic stenosis. Operation for subvalvular AS is indicated with a gradient exceeding 30 mmHg, in the presence of aortic valve insufficiency, or when symptoms indicating LVOT obstruction are present.30 Given that repair of isolated discrete subaortic ­stenosis can be done with low rates of morbidity and mortality, some surgeons advocate repair in all cases of discrete AS to avoid progression of the stenosis and the development of aortic insufficiency, although more recent data demonstrates that subaortic resection should be delayed until the LV gradient exceeds 30 mmHg because most children with an initial LV gradient less than 30 mmHg have quiescent disease.31 Diffuse AS is a more complex lesion and often requires aortoventriculoplasty as previously described. Results are generally excellent, with operative mortality less than 5%.32 Supravalvular AS occurs more rarely and also can be classified into a discrete type, which produces an hourglass deformity of the aorta, and a diffuse form that can involve the entire arch and brachiocephalic arteries. The aortic valve leaflets are usually normal, but in some cases, the leaflets may adhere to the supravalvular stenosis, thereby narrowing the sinuses of Valsalva in diastole and restricting coronary artery perfusion. In addition, accelerated intimal hyperplastic changes in the coronary arteries can be demonstrated in these patients because the proximal position of the coronary arteries subjects them to abnormally high perfusion pressures. The signs and symptoms of supravalvular AS are similar to other forms of LVOT obstruction. An asymptomatic murmur is the presenting manifestation in approximately half of these patients. Syncope, poor exercise tolerance, and angina may all occur with nearly equal frequency. Supravalvar AS is associated with Williams’ syndrome, a constellation of elfin facies, mental retardation, and hypercalcemia.33 Following routine evaluation, cardiac catheterization should be performed in order to delineate coronary anatomy, as well as to delineate the degree of obstruction. A gradient of 50 mmHg or greater is an indication for operation. However, the clinician must be cognizant of any coexistent lesions, most commonly pulmonic stenosis, which may add complexity to the repair. The localized form of supravalvular AS is treated by ­creating an inverted Y-shaped aortotomy across the area of ­stenosis, straddling the right coronary artery. The obstructing shelf is then excised and a pantaloon-shaped patch is used to close the ­incision.21 The diffuse form of supravalvular stenosis is more variable, and the particular operative approach must be tailored to each specific patient’s anatomy. In general, either an aortic ­endarterectomy with patch augmentation can be performed, or if the narrowing extends past the aorta arch, a prosthetic graft can be placed between the ascending and descending aorta. Operative results for discrete supravalvular AS are generally good, with a hospital mortality of less than 1% and an actuarial ­survival rate exceeding 90% at 20 years.34 In contrast, however, the diffuse form is more hazardous to repair and carried a mortality of 15% in a recent series.34,35 Patent Ductus Arteriosus Anatomy. The ductus arteriosus is derived from the sixth aortic arch and normally extends from the main or left pulmonary artery to the upper descending thoracic aorta, distal to the left subclavian artery. In the normal fetal cardiovascular VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 703 Dacron patch Vertical aortotomy Prosthetic valve Interventricular septum incised B A Pericardial patch C system, ductal flow is considerable (approximately 60% of the combined ventricular output) and is directed exclusively from the pulmonary artery to the aorta.36 In infancy, the length of the ductus may vary from 2 to 8 mm, with a diameter of 4 to 12 mm. Locally produced and circulating prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) induce active relaxation of the ductal musculature, maintaining maximal patency during the fetal period.37 At birth, increased pulmonary blood flow metabolizes these prostaglandin products, and absence of the placenta removes an important source of them, resulting in a marked decrease in these ductal-relaxing substances. In addition, release of histamines, catecholamines, bradykinin, and acetylcholine all promote ductal contraction. Despite all of these complex interactions, the rising oxygen tension in the fetal blood is the main stimulus causing smooth muscle contraction and ductal closure within 10 to 15 hours postnatally.38 Anatomic closure by fibrosis produces the ligamentum arteriosum connecting the pulmonary artery to the aorta. Delayed closure of the ductus is termed prolonged patency, whereas failure of closure causes persistent patency, which may occur as an isolated lesion or in association with more complex congenital heart defects. In many of these infants with more complex congenital heart defects, either pulmonary or systemic perfusion may depend on ductal flow, and these infants may decompensate if exogenous PGE is not administered to maintain ductal patency. Natural History. The incidence of patent ductus arteriosus (PDA) is approximately 1 in every 2000 births; however, it increases dramatically with increasing prematurity.39 In some series, PDAs have been noted in 75% of infants of 28 to 30 weeks gestation. Persistent patency occurs more commonly in females, with a 2:1 ratio.39 PDA is not a benign entity, although prolonged survival has been reported. The estimated death rate for infants with isolated, untreated PDA is approximately 30%.40 The leading cause of death is congestive heart failure, with respiratory infection as a secondary cause. Endocarditis is more likely to occur with a small ductus and is rarely fatal if aggressive antibiotic therapy is initiated early. Clinical Manifestations and Diagnosis. After birth, in an otherwise normal cardiovascular system, a PDA results in a left-to-right shunt that depends on both the size of the ­ductal lumen and its total length. As the pulmonary vascular resistance falls 16 to 18 weeks postnatally, the shunt will increase, and its flow will ultimately be determined by the relative resistances of the pulmonary and systemic ­circulations. The hemodynamic consequences of an unrestrictive ductal shunt are left ventricular volume overload with increased left atrial and pulmonary artery pressures, and right ventricular strain from the augmented afterload. These changes result in increased sympathetic discharge, tachycardia, tachypnea, and ventricular hypertrophy. The diastolic shunt results in lower aortic diastolic pressure and increases the potential for myocardial ischemia and underperfusion of other systemic organs, while the increased pulmonary flow leads to increased work of breathing and decreased gas exchange. Unrestrictive ductal flow may lead to pulmonary hypertension within the first year of life. These changes will be significantly attenuated if the size of the ductus is only moderate, and completely absent if the ductus is small. Physical examination of the afflicted infant will reveal evidence of a hyperdynamic circulation with a widened pulse pressure and a hyperactive precordium. Auscultation demonstrates a systolic or continuous murmur, often termed a machinery ­ murmur. Cyanosis is not present in uncomplicated isolated PDA. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease Figure 20-7. The Konno-Rastan aortoventriculoplasty permits significant enlargement of the aortic annulus and subaortic region. A. A vertical aortotomy is made to the left of the right coronary artery and extended into the right ventricular outflow tract. After excising the aortic valve, the interventricular septum is incised and an aortic valve prosthesis is secured within the enlarged annulus. B. A Dacron patch that is attached to the sewing ring of the prosthesis closes the interventricular septum and the aortotomy. C. A separate pericardial patch closes the right ventriculotomy. (Reproduced with permission from Misbach GA, Turley K, Ullyot DJ, et al. Left ventricular outflow enlargement by the Konno procedure. J Thorac Cardiovasc Surg. 1982;84:696. Copyright Elsevier.) 704 The chest radiograph may reveal increased pulmonary vascularity or cardiomegaly, and the ECG may show LV strain, left atrial enlargement, and possibly RV hypertrophy. Echocardiogram with color mapping reliably demonstrates the patency of the ductus as well as estimates the shunt size. Cardiac catheterization is necessary only when pulmonary hypertension is suspected. Therapy. The presence of a persistent PDA is sufficient indica- UNIT II PART SPECIFIC CONSIDERATIONS tion for closure because of the increased mortality and risk of endocarditis.2,4 In older patients with pulmonary hypertension, closure may not improve symptoms and is associated with much higher mortality. In premature infants, aggressive intervention with indomethacin or ibuprofen to achieve early closure of the PDA is beneficial unless contraindications such as necrotizing enterocolitis or renal insufficiency are present.41 Term infants, however, are generally unresponsive to pharmacologic therapy with indomethacin, so mechanical closure must be undertaken once the diagnosis is established. This can be accomplished either surgically or with catheter-based therapy.12,42,43 Currently, transluminal placement of various occlusive devices, such as the Rashkind double-umbrella device or embolization with G ­ ianturco coils, is in widespread use.42 However, there are a number of complications inherent with the use of percutaneous devices, such as thromboembolism, endocarditis, incomplete occlusion, vascular injury, and hemorrhage secondary to perforation.43 In addition, these techniques may not be applicable in very young infants, because the peripheral vessels do not provide adequate access for the delivery devices. Surgical closure can be achieved via either open or video-assisted approaches. The open approach employs a posterior ­lateral thoracotomy in the fourth or fifth i­ntercostal space on the side of the aorta (generally the left). The lung is then retracted anteriorly. In the neonate, the PDA is singly ligated with a surgical clip or permanent suture. In older patients, the PDA is triply ligated. Care must be taken to avoid the recurrent laryngeal nerve, which courses around the PDA. The PDA can also be ligated via a median sternotomy; however, this approach is generally reserved for patients who have additional cardiac or great vessel lesions requiring repair. Occasionally, a short, broad ductus, in which the dimension of its width approaches that of its length, will be encountered. In this case, division between vascular clamps with oversewing of both ends is advisable (Fig. 20-8). In extreme cases, the use of CPB to decompress the large ductus during ligation is an option. Video-assisted thoracoscopic occlusion, using metal clips, also has been described, although it offers few advantages over the standard surgical approach.12 Preterm newborns and children may do well with the thoracoscopic technique, while older patients (older than age 5 years) and those with smaller ducts (<3 mm) do well with coil occlusion. In fact, Moore and colleagues recently concluded from their series that coil occlusion is the procedure of choice for ducts smaller than 4 mm.44 Complete closure rates using catheter-based techniques have steadily improved. Comparative studies of cost and outcome between open surgery and transcatheter duct closure, however, have shown no overwhelming choice between the two modalities. Burke prospectively reviewed coil occlusion and VATS at Miami Children’s Hospital and found both options to be effective and less morbid than traditional thoracotomy.12 Outcomes. In premature infants, the surgical mortality is very low, although the overall hospital death rate is significant as a Pulmonary a. Aorta Left phrenic Recurrent laryngeal n. B Vagus n. C A Isthmus Descending aorta Patent ductus Triple ligature on ductus D Figure 20-8. A. Surgeon’s perspective of infant patent ductus arteriosus exposed via a left thoracotomy. B. The pleura over the aortic isthmus is incised and mobilized. C and D. Technique of triple ligation. a. = artery; n. = nerve. (From Castaneda AR, Jonas RA, Mayer JE, et al. Cardiac Surgery of the Neonate and Infant. Philadelphia: W.B. Saunders; 1994:208, with permission. Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ c­ onsequence of other complications of prematurity. In older infants and children, mortality is less than 1%. Bleeding, chylothorax, vocal cord paralysis, and the need for reoperation occur infrequently. With the advent of muscle-sparing thoracotomy, the risk of subsequent arm dysfunction or breast abnormalities is virtually eliminated.45 Aortic Coarctation Pathophysiology. Infants with COA develop symptoms consistent with left ventricular outflow obstruction, including pulmonary overcirculation and, later, biventricular failure. In addition, proximal systemic hypertension develops as a result of mechanical obstruction to ventricular ejection, as well as hypoperfusion-induced activation of the renin-angiotensinaldosterone system. Interestingly, hypertension is often persistent after surgical correction despite complete amelioration of the mechanical obstruction and pressure gradient.48 It has been shown that early surgical correction may prevent the development of long-term hypertension, which undoubtedly contributes to many of the adverse sequelae of COA, including the development of circle of Willis aneurysms, aortic dissection and rupture, and an increased incidence of coronary arteriopathy with resulting myocardial infarction.49 Diagnosis. COA is likely to become symptomatic either in the newborn period if other anomalies are present or in the late adolescent period with the onset of left ventricular ­failure. Physical examination will demonstrate a hyperdynamic precordium with a harsh murmur localized to the left chest and back. Femoral pulses will be dramatically decreased when compared to upper extremity pulses, and differential cyanosis may be apparent until ductal closure. Echocardiography will reliably demonstrate the narrowed aortic segment, as well as define the pressure gradient across the stenotic segment. In addition, detailed information regarding other associated anomalies can be gleaned. Aortography is reserved for those cases in which the echocardiographic findings are equivocal. Therapy. The routine management of hemodynamically s­ignificant COA in all age groups has traditionally been s­ u rgical. Transcatheter repairs are used with increasing ­frequency in older patients and those with re-coarctation VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 705 CHAPTER 20 Congenital Heart Disease Anatomy. Coarctation of the aorta (COA) is defined as a luminal narrowing in the aorta that causes an obstruction to blood flow. This narrowing is most commonly located distal to the left subclavian artery. The embryologic origin of COA is a subject of some controversy. One theory holds that the obstructing shelf, which is largely composed of tissue found within the ductus, forms as the ductus involutes.46 The other theory holds that a diminished aortic isthmus develops secondary to decreased aortic flow in infants with enhanced ductal circulation. Extensive collateral circulation develops, predominantly involving the intercostals and mammary arteries as a direct result of aortic flow obstruction. This translates into the wellknown finding of “rib-notching” on chest radiograph, as well as a prominent pulsation underneath the ribs. Other associated anomalies, such as ventricular septal defect, PDA, and ASD, may be seen with COA, but the most common is that of a bicuspid aortic valve, which can be demonstrated in 25% to 42% of cases.47 f­ ollowing surgical repair. Balloon dilatation of native coarctation in neonates has been recently utilized with poor results. The most common surgical techniques in current use are resection with end-to-end anastomosis or extended end-to-end anastomosis, taking care to remove all residual ductal tissue. 50,51 Extended end-to-end anastomosis may also allow the surgeon to treat transverse arch hypoplasia, which is commonly encountered in infants with aortic coarctation.52,53 The ­subclavian flap aortoplasty is another repair, although it is used less frequently in the modern era because of the risk of late aneurysm formation and possible underdevlopment of the left upper extremity or ischemia.51 In this method, the left subclavian artery is transected and brought down over the coarcted segment as a vascularized patch. The main benefit of these techniques is that they do not involve the use of prosthetic materials, and evidence suggests that extended end-to-end anastomosis may promote arch growth, especially in infants with the smallest initial aortic arch diameters.52 Despite the benefits, however, extended end-to-end anastomosis may not be feasible when there is a long segment of coarctation or in the presence of previous surgery, because ­sufficient mobilization of the aorta above and below the lesion may not be possible. In this instance, prosthetic materials, such as a patch aortoplasty, in which a prosthetic patch is used to enlarge the coarcted segment, or an interposition tube graft must be employed. The most common complications after COA repair are late restenosis and aneurysm formation at the repair site.54-56 Aneurysm formation is particularly common after patch aortoplasty when using Dacron material. In a large series of 891 patients, aneurysms occurred in 5.4% of the total, with 89% occurring in the group who received Dacron-patch aortoplasty and only 8% occurring in those who received resection with primary end-to-end anastomosis.54 A further complication, although uncommon, is lower-body paralysis resulting from ischemic spinal cord injury during the repair. This dreaded outcome complicates 0.5% of all surgical repairs, but its incidence can be lessened with the use of some form of distal perfusion, preferably left heart bypass with the use of femoral arterial or distal thoracic aorta for arterial inflow and the femoral vein or left atrium for venous return. 50 These techniques are generally reserved for older patients with complex coarctations that may need ­prolonged aortic cross clamp times for repair, often in the setting of large collateral vessels and/ or previous surgery. Hypertension is also well recognized following repair of COA. Bouchart and colleagues reported that in a cohort of 35 hypertensive adults (mean age, 28 years) undergoing repair, despite a satisfactory anatomic outcome, only 23 patients were normotensive at a mean follow-up period of 165 months.55 Likewise, Bhat and associates reported that in a series of 84 patients (mean age at repair, 29 years), 31% remained hypertensive at a mean follow-up of 5 years following surgery.56 Although operative repair is still the gold standard, treatment of COA by catheter-based intervention has become more widespread. Both balloon dilatation and primary stent implantation have been used successfully. The most extensive study of the results of balloon angioplasty reported on 970 procedures: 422 native and 548 recurrent COAs. Mean gradient reduction was 74% ± 24% for native and 70% ± 31% for recurrent COA.57 This demonstrated that catheterbased therapy could produce equally effective results both in 706 UNIT II PART SPECIFIC CONSIDERATIONS recurrent and in primary COA, a finding with far-reaching implications in the new paradigm of multidisciplinary treatment algorithms for CHD. In the ­Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) report, higher preangioplasty gradient, earlier procedure date, older patient age, and the presence of recurrent COA were independent risk factors for suboptimal procedural outcome.57 The gradient after balloon dilatation in most series is generally acceptable. However, there is a significant minority of patients (0%–26%) for whom the procedural outcome is suboptimal, with a postprocedure gradient of 20 mmHg or greater. These patients may be ideal candidates for primary stent placement. Restenosis is much less common in children, presumably reflecting the influence of vessel wall scarring and growth in the pediatric age group. Deaths from the procedure also are infrequent (<1% of cases), and the main major complication is aneurysm formation, which occurs in 7% of patients.50 With stent implantation, many authors have demonstrated improved resolution of stenosis compared with balloon dilatation alone, yet the long-term complications on vessel wall compliance remain largely unknown because only mid-term data are widely available. In summary, children younger than age 6 months with native COA should be treated with surgical repair, while those requiring intervention at later ages may be ideal candidates for balloon dilatation or primary stent implantation.50 Additionally, catheter-based therapy should be employed for those cases of restenosis following either surgical or primary endovascular management. Truncus Arteriosus Anatomy. Truncus arteriosus is a rare anomaly, comprising between 1% and 4% of all cases of CHD.58 It is characterized by a single great artery that arises from the heart, overrides the ventricular septum, and supplies the pulmonary, systemic, and coronary circulations. The two major classification systems are those of C ­ ollett and Edwards, described in 1949, and Van Praagh and Van Praagh, described in 1965 (Fig. 20-9).59,60 The Collett and Edwards classification focuses mainly on the origin of the pulmonary arteries from the common arterial trunk, whereas the Van Praagh system is based on the presence or absence of a VSD, the degree of formation of the aorticopulmonary septum, and the status of the aortic arch. During embryonic life, the truncus arteriosus normally begins to separate and spiral into a distinguishable anterior pulmonary artery and posterior aorta. Persistent truncus, therefore, represents an arrest in embryologic development at this stage.61 Other implicated events include twisting of the dividing truncus because of ventricular looping, subinfundibular atresia, and abnormal location of the semilunar valve anlages.62 The neural crest may also play a crucial role in the normal formation of the great vessels, as experimental studies in chick embryos have shown that ablation of the neural crest results in persistent truncus arteriosus.63 The neural crest also develops into the pharyngeal pouches that give rise to the thymus and parathyroids, which likely explains the prevalent association of truncus arteriosus and DiGeorge’s syndrome.64 The annulus of the truncal valve usually straddles the ventricular septum in a “balanced” fashion; however, it is not unusual for it to be positioned predominantly over the RV, which increases the potential for LVOT obstruction following surgical repair. In the great majority of cases, the leaflets are thickened and deformed, which leads to valvular insufficiency. There are usually three leaflets (60%), but occasionally a bicuspid (50%) or even a quadricuspid valve (25%) is present.65 In truncus arteriosus, the pulmonary trunk bifurcates, with the left and right pulmonary arteries forming posteriorly and to the left in most cases. The caliber of the pulmonary arterial branches is usually normal, with stenosis or diffuse hypoplasia occurring in rare instances. Collett & Edwards I A1 II III IV A3 A2 A4 Van Praagh Figure 20-9. There are similarities between the Collett and Edwards and the Van Praagh classifications of truncus arteriosus. Type I is the same as A1. Types II and III are grouped as a single type A2 because they are not significantly distinct embryologically or therapeutically. Type A3 denotes unilateral pulmonary artery with collateral supply to the contralateral lung (hemitruncus). Type A4 is truncus associated with interrupted aortic arch (13% of all cases of truncus arteriosus). (Reproduced with permission from Fyler DC. Truncus arteriosus. In: Fyler DC, ed. Nadas’ Pediatric Cardiology. Philadelphia: Hanley & Belfus; 1992:676. Copyright Elsevier. As adapted with permission from Hernanz-Schulman M, Fellows KE. Persistent truncus arteriosus: pathologic, diagnostic and therapeutic considerations. Semin Roentgenol. 1985;20:121. Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Physiology and Diagnosis. The main pathophysiologic consequences of truncus arteriosus are (a) the obligatory mixing of systemic and pulmonary venous blood at the level of the ventricular septal defect (VSD) and truncal valve, which leads to arterial saturations near 85%, and (b) the presence of a nonrestrictive left-to-right shunt, which occurs during both systole and diastole, the volume of which is determined by the relative resistances of the pulmonary and systemic circulations.65 Additionally, truncal valve stenosis or regurgitation, the presence of important LVOT obstruction, and stenosis of pulmonary artery branches can further contribute to both pressure- and volumeloading of the ventricles. The presence of these lesions often results in severe heart failure and cardiovascular instability early in life. Pulmonary vascular resistance may develop as early as 6 months of age, leading to poor results with late surgical correction. Patients with truncus arteriosus usually present in the neonatal period, with signs and symptoms of congestive heart failure and mild to moderate cyanosis. A pansystolic murmur may be noted at the left sternal border, and occasionally a ­diastolic murmur may be heard in the presence of truncal regurgitation. Chest radiography will be consistent with pulmonary overcirculation, and a right aortic arch can be appreciated 35% of the time. The ECG is usually nonspecific, demonstrating normal sinus rhythm with biventricular hypertrophy. Echocardiography with Doppler color-flow or pulsed Doppler is diagnostic and usually provides sufficient information to determine the type of truncus arteriosus, the origin of the coronary arteries and their proximity to the pulmonary trunk, the character of the truncal valves, and the extent of truncal insufficiency.65 Cardiac catheterization can be helpful in cases where pulmonary hypertension is suspected or to further delineate coronary artery anomalies prior to repair. The presence of truncus is an indication for surgery. Repair should be undertaken in the neonatal period or as soon as the diagnosis is established. Eisenmenger’s physiology, which is found primarily in older children, is the only absolute contraindication to correction. Repair. Truncus arteriosus was first managed with pulmonary artery banding as described by Armer and colleagues in 1961.67 However, this technique led to only marginal improvements in 1-year survival rates because ventricular failure inevitably occurred. In 1967, however, complete repair was accomplished by McGoon and his associates based on the experimental work of Rastelli, who introduced the idea that an extracardiac valved conduit could be used to restore ventricular-to-pulmonary artery continuity.68 Over the next 20 years, improved survival rates led to ­uniform adoption of complete repair even in the youngest and ­smallest infants.58,65,69 Surgical correction entails the use of CPB. Repair is completed by separation of the pulmonary arteries from the aorta, closure of the aortic defect (occasionally with a patch) to minimize coronary flow complications, placement of a valved cryopreserved allograft or jugular venous valved conduit (Contegra) to reconstruct the RVOT, and VSD c­ losure. Important branch pulmonary arterial stenosis should be repaired at the time of complete repair and can usually be accomplished with longitudinal allograft patch arterioplasty. Severe truncal valve insufficiency occasionally requires truncal valve replacement, which can be accomplished with a cryopreserved allograft.70 Results. The results of complete repair of truncus have steadily improved. Ebert reported a 91% survival rate in his series of 77 patients who were younger than 6 months of age; later reports by others confirmed these findings and demonstrated that excellent results could be achieved in even smaller infants with complex-associated defects.11,69 Newer extracardiac conduits also have been developed and used with success, which has widened the repertoire of the modern congenital heart surgeon and improved outcomes.71 Severe truncal regurgitation, interrupted aortic arch, coexistent coronary anomalies, chromosomal or genetic anomalies, and age younger than 100 days are risk factors associated with perioperative death and poor outcome. Total Anomalous Pulmonary Venous Connection Total anomalous pulmonary venous connection (TAPVC) occurs in 1% to 2% of all cardiac malformations and is characterized by abnormal drainage of the pulmonary veins into the right heart, whether through connections into the right atrium or into its tributaries.72 Accordingly, the only mechanism by which oxygenated blood can return to the left heart is through an ASD, which is almost uniformly present with TAPVC. Unique to this lesion is the absence of a definitive form of palliation. Thus, TAPVC with concomitant obstruction represents one of the only true surgical emergencies across the entire spectrum of congenital heart surgery. Anatomy and Embryology. The lungs develop from an outpouching of the foregut, and their venous plexus arises as part of the splanchnic venous system. TAPVC arises when the pulmonary vein evagination from the posterior surface of the left atrium fails to fuse with the pulmonary venous plexus surrounding the lung buds. In place of the usual connection to the left atrium, at least one connection of the pulmonary plexus to the splanchnic plexus persists. Accordingly, the pulmonary veins drain to the heart through a systemic vein (Fig. 20-10). Darling and colleagues classified TAPVC according to the site or level of connection of the pulmonary veins to the systemic venous system73: type I (45%), anomalous connection at the supracardiac level; type II (25%), anomalous connection at the cardiac level; type III (25%), anomalous connection at the infracardiac level; and type IV (5%), anomalous connection at multiple levels.74 Within each category, further subdivisions can be implemented, depending on whether pulmonary venous obstruction exists. Obstruction to pulmonary venous drainage VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 707 CHAPTER 20 Congenital Heart Disease The coronary arteries may be normal; however, anomalies are not unusual and occur in 50% of cases.65,66 Many of these are relatively minor, although two variations are of particular importance, because they have implications in the conduct of operative repair. The first is that the left coronary ostium may arise high in the sinus of Valsalva or even from the truncal tissue at the margin of the pulmonary artery tissue. This coronary artery can be injured during repair when the pulmonary arteries are removed from the trunk or when the resulting truncal defect is closed. The second is that the right coronary artery can give rise to an important accessory anterior descending artery, which often passes across the RV in the exact location where the right ventriculotomy is commonly performed during repair.65,66 708 Foregut covered by splanchnic plexus Right anterior cardinal vein Right lung bud Right common cardinal vein Left anterior cardinal vein Primordial pulmonary vein Left lung bud Sinus venosus n dso r Do Af t e UNIT II PART Left common cardinal vein SPECIFIC CONSIDERATIONS is a powerful predictor of adverse natural outcome and occurs most frequently with the infracardiac type, especially when the pattern of infracardiac connection prevents the ductus venosus from bypassing the liver.75 Pathophysiology and Diagnosis. Because both pulmonary and systemic venous blood returns to the right atrium in all forms of TAPVC, a right-to-left intracardiac shunt must be present in order for the afflicted infant to survive. This invariably occurs via a nonrestrictive patent foramen ovale. Because of this obligatory mixing, cyanosis is usually present, and its degree depends on the ratio of pulmonary to systemic blood flow. Decreased pulmonary blood flow is a consequence of pulmonary venous obstruction, the presence of which is unlikely if the right ventricular pressure is less than 85% of systemic pressure.76 The child with TAPVC may present with severe cyanosis and respiratory distress, necessitating urgent surgical intervention if a severe degree of pulmonary venous obstruction is present. However, in cases where there is no obstructive component, the clinical picture is usually one of pulmonary overcirculation, hepatomegaly, tachycardia, and tachypnea with feeding. In a child with serious obstruction, arterial blood gas analysis reveals severe hypoxemia (partial pressure of oxygen [Po2] <20 mmHg), with metabolic acidosis.77 Chest radiography will show normal heart size with generalized pulmonary edema. Two-dimensional echocardiography is very useful in establishing the diagnosis and also can assess ventricular septal position, which may be leftward secondary to small left ventricular volumes, as well as estimate the right ventricular pressure based on the height of the tricuspid regurgitant jet. Echocardiography can usually identify the pulmonary venous connections (types I to IV), and it is rarely necessary to perform other diagnostic tests. Cardiac catheterization is not recommended in these patients because the osmotic load from the intravenous contrast can exacerbate the degree of pulmonary edema.78 When cardiac catheterization is performed, equalization of oxygen saturations in all four heart chambers is a hallmark finding in this disease since the mixed blood returned to the right atrium gets distributed throughout the heart. Figure 20-10. Total anomalous pulmonary venous connection results when the primordial pulmonary vein fails to unite with the plexus of veins that surround the lung buds and is derived from the splanchnic venous plexus, including the cardinal veins and umbilicovitelline veins. (From Castaneda AR, Jonas RA, Mayer JE, et al. Cardiac Surgery of the Neonate and Infant. Philadelphia: W.B. Saunders; 1994:158, with permission. Copyright Elsevier.) Therapy. Operative correction of TAPVC requires anastomosis of the common pulmonary venous channel to the left atrium, obliteration of the anomalous venous connection, and closure of the ASD.77,79 All types of TAPVC are approached through a median sternotomy, and many surgeons use deep hypothermic circulatory arrest in order to achieve an accurate and widely patent anastomosis. The technique for supracardiac TAPVC includes early division of the vertical vein, retraction of the aorta and the superior vena cava laterally to expose the posterior aspect of the left atrium and the pulmonary venous confluence, and a side-to-side anastomosis between a long, horizontal biatrial incision and a longitudinal incision within the pulmonary venous confluence. The ASD can then be closed with an autologous pericardial or synthetic patch. In patients with TAPVC to the coronary sinus without obstruction, a simple unroofing of the coronary sinus can be performed through a single right atriotomy with concomitant closure of the ASD. If pulmonary venous obstruction is present, the repair should include generous resection of roof of the coronary sinus.77 Repair of infracardiac TAPVC entails ligation of the vertical vein at the diaphragm, followed by construction of a proximal, patulous longitudinal venotomy. This repair is usually performed by “rolling” the heart toward the left, thus exposing the left atrium where it usually overlies the descending vertical vein (Fig. 20-11). As originally described by Lacour-Gayet and colleagues at the Marie-Lannelongue Hospital, Paris, and Coles and colleagues at The Hospital for Sick Children, Toronto, the sutureless technique was developed for patients with anastomotic stenosis occurring after TAPVC repair.78,79 After determining that favorable outcomes were possible using this technique, it is currently used in selected patients upon initial presentation of TAPVC.79 Incisions are made in the venous confluence. Based on the surgeon’s discretion, the incisions are extended into both upper and lower pulmonary veins separately if judged to be important for an unobstructed pathway. An atriopericardial anastomosis is created using the pericardium adjacent to where the pulmonary veins enter the pericardium (Fig. 20-12). This anastomosis avoids direct contact with the incision site in the wall of the pulmonary veins and allows the free egress of 4 blood from the lungs to the left atrium. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 709 Superior vena cava Descending aorta Right pulmonary artery Interior edge of foramen ovale Left pulmonary artery Right atrium Left atrium Extent of cut Atrial septum Right pulmonary veins Anomalous vertical vein Inferior vena cava The perioperative care of these infants is crucial because episodes of pulmonary hypertension can occur within the first 48 hours, which contribute significantly to mortality following repair.6 Muscle relaxants and narcotics should be administered during this period to maintain a constant state of anesthesia. Arterial partial pressure of carbon dioxide (Pco2) should be maintained at 30 mmHg with use of a volume ventilator, and the fraction of inspired oxygen (Fio2) should be increased to keep the pulmonary arterial pressure at less than two thirds of the systemic pressure. Results. Results of TAPVC in infancy have markedly improved in recent years, with an operative mortality of 5% or Infracardiac TAPVC Conventional Repair Sutureless Repair Figure 20-12. Differences between conventional repair of total anomalous pulmonary venous connection (TAPVC) and sutureless repair of TAPVC. In the sutureless techniques, there are no sutures placed in the fragile veins themselves. Rather, the pericardial flaps are used to create a “well” for the pulmonary venous return (bottom inset). Early and late extrinsic stenosis are thought to be reduced using this latter technique. Figure 20-11. Operative exposure obtained with infradiaphragmatic total anomalous pulmonary venous connection, using an approach from the right. (From Castaneda AR, Jonas RA, Mayer JE, et al. Cardiac Surgery of the Neonate and Infant. Philadelphia: W.B. Saunders; 1994:161, with permission. Copyright Elsevier.) less in some series.77-80 This improvement is probably multifactorial, mainly as a consequence of early noninvasive diagnosis and aggressive perioperative management. The routine use of echocardiography; improvements in myocardial protection with specific attention to the RV; creation of a large, tension-free anastomosis with maximal use of the venous confluence and atrial tissue; use of a sutureless technique in selected cases; and prevention of pulmonary hypertensive events have likely played a major role in reducing operative mortality. The importance of risk factors for early mortality, such as venous obstruction at presentation, urgency of ­operative repair, and infradiaphragmatic anatomic type, have been debated.79,81 Bando and colleagues82 made the controversial statement that both preoperative pulmonary venous obstruction and anatomic type had been neutralized as potential risk factors beyond calendar year 1991. Hyde et al80 similarly reported that connection type was not related to outcome. However, a recent large single-institution report of 377 children with TAPVC by the author from the Hospital for Sick Children in Toronto83 found that, although outcomes had improved over time, patient anatomic factors were still important determinants of both survival and the need for subsequent reoperation. Risk factors for postrepair death were earlier operation year, younger age at repair, cardiac connection type, and postoperative pulmonary venous obstruction. Risk-adjusted estimated 1-year survival for a patient repaired at birth with unfavorable morphology in 2006 was 37% (95% confidence interval [CI], 8%–80%) compared with 96% (95% CI, 91%–99%) for a patient with favorable morphology repaired at age 1 year. Freedom from reoperation was 82% ± 6% at 11 years after repair, with increased risk associated with mixed connection and postoperative pulmonary venous obstruction (Fig. 20-13). A recent study from the Hospital for Sick Children, Toronto, showed a lower incidence of reoperation in the sutureless technique compared to conventional ­pulmonary VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease Left pulmonary veins 710 a 2006 1996 % Survival 100 80 1985 60 40 20 0 0 2 4 6 8 10 Years from complete repair b SPECIFIC CONSIDERATIONS Predicted survival at 1 year after operation (%) UNIT II PART 100 A) Favorable patient (97%) 80 B) Unfavorable patient 60 40 (37%) 20 0 1952 1963 1974 1985 1996 2006 Year of operation Figure 20-13. a. Risk-adjusted survival from repair improved significantly with increasing year of operation, indicating a strong era effect. Solid lines are continuous point estimates enclosed by dashed 95% confidence limits showing three different solutions to the multivariable equation for death after repair. All other predictors have been set to mean values to illustrate the favorable influence of later operation year on survival after repair. b. Risk-adjusted nomograms show 1-year survival after repair expressed as a function of increasing year of operation for two different patients. The top line (A) shows the multivariable solution for a patient with favorable anatomic characteristics (noncardiac connection without pulmonary venous obstruction) undergoing repair at 1 year of age; the bottom line (B) shows the solution for a patient with unfavorable characteristics (cardiac connection with pulmonary venous obstruction) undergoing operation at birth. The nomograms show that the more recent era has improved survival in all patients, especially within the last few decades. However, unfavorable anatomic characteristics have not been neutralized as important determinants of postrepair survival despite improvements in perioperative care. Numbers in parentheses represent parametric estimates of median survival at 1 year after repair in 2005. (Reproduced with permission from Karamlou T, et al. Factors associated with mortality and reoperation in 377 children with total anomalous pulmonary venous connection. Circulation. 2007;115:1591.) venous confluence–left atrial anastomosis.84 However, there was no statistically significant difference suggesting similar results between the strategies.9 Although the sutureless technique appears to have favorable outcomes at primary repair for TAPVC, long-term follow-up is necessary to evaluate the occurrence of arrhythmias, such as complete heart block and atrial tachycardia, since an incision on the atrial septum and atrial wall is more invasive compared to the conventional technique. The most significant postoperative complication of TAPVC repair is pulmonary venous obstruction, which occurs 9% to 11% of the time, regardless of the surgical t­ echnique employed. Mortality varies between 30% and 45%, and alternative catheter interventions do not offer definitive solutions.78 Recurrent pulmonary venous obstruction can be localized at the site of the pulmonary venous anastomosis (extrinsic), which can usually be cured with patch enlargement or balloon dilatation, or it may be secondary to endocardial thickening of the pulmonary venous ostia frequently resulting in diffuse pulmonary venous sclerosis (intrinsic), which carries a 66% mortality rate because few good solutions exist. 75 More commonly, postrepair left ventricular dysfunction can occur as the noncompliant LV suddenly is required to handle an increased volume load from redirected pulmonary venous return. This can manifest as an increase in pulmonary artery pressure but is distinguishable from ­primary pulmonary hypertension (another possible postoperative complication following repair of TAPVC) from the elevated left atrial pressure and LV dysfunction along with echocardiographic evidence of poor LV contractility. In pulmonary hypertension, the left atrial pressure may be low, the LV may appear “underfilled” (by echocardiography), and the RV may appear dilated. In either case, postoperative support for a few days with extracorporeal membrane oxygenation may be lifesaving, and TAPVC should be repaired in centers that have this capacity. Some investigators have speculated that preoperative pulmonary venous obstruction is associated with increased medial thickness within the pulmonary vasculature, which may predispose these infants to intrinsic pulmonary venous stenosis despite adequate pulmonary venous decompression.80 The majority of studies demonstrating that preoperative pulmonary venous obstruction is a predictor of subsequent need for reoperation to correct recurrent pulmonary venous obstruction lend credence to this notion. Cor Triatriatum Anatomy. Cor triatriatum is a rare CHD characterized by the presence of a fibromuscular diaphragm that partitions the left atrium into two chambers: a superior chamber that receives drainage from the pulmonary veins, and an inferior chamber that communicates with the mitral valve and the LV (Fig. 20-14). An ASD frequently exists between the superior chamber and the right atrium, or, more rarely, between the right atrium and the inferior chamber. Pathophysiology and Diagnosis. Cor triatriatum results in obstruction of pulmonary venous return to the left atrium. The degree of obstruction is variable and depends on the size of fenestrations present in the left atrial membrane, the size of the ASD, and the existence of other associated anomalies. If the communication between the superior and inferior chambers is less than 3 mm, patients usually are symptomatic during the first year of life. The afflicted infant will present with the stigmata of low cardiac output and pulmonary venous hypertension, as well as congestive heart failure and poor feeding. Physical examination may demonstrate a loud pulmonary S2 sound and a right ventricular heave, as well as ­jugular venous distention and hepatomegaly. Chest radiography will show ­cardiomegaly and pulmonary vascular prominence, and the ECG will suggest right ventricular hypertrophy. T ­ wo-dimensional echocardiography provides a definitive diagnosis in most cases, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 711 CPCV RA LA B with catheterization necessary only when echocardiographic evaluation is equivocal. Therapy. Operative treatment for cor triatriatum is fairly s­ imple. CPB and cardioplegic arrest are used. A right ­atriotomy usually allows access to the left atrial membrane through the existing ASD, because it is dilated secondary to communication with the pulmonary venous chamber. The membrane is then excised, taking care not to injure the mitral valve or the interatrial septum, and the ASD is closed with a patch. ­Alternatively, if the right atrium is small, the membrane can be exposed through an incision directly into the superior left atrial chamber, just anterior to the right pulmonary veins.7,82 Surgical results are uniformly excellent for this defect, with survival approaching 100%. The utility of catheter-based intervention for this diagnosis remains controversial, although there have been two recent reports of successful balloon dilatation.83,85 Aortopulmonary Window Embryology and Anatomy. Aortopulmonary window (APW) is a rare congenital lesion, occurring in about 0.2% of patients, characterized by incomplete development of the septum that normally divides the truncus into the aorta and the pulmonary artery.86 In the vast majority of cases, APW occurs as a single defect of minimal length, which begins a few millimeters above the semilunar valves on the left lateral wall of the aorta (Fig. 20-15). Coronary artery anomalies, such as aberrant origin of the right or left coronary artery from the main pulmonary artery, are occasionally present. Pathophysiology and Diagnosis. The dominant pathophysiology of APW is that of a large left-to-right shunt with increased pulmonary flow and the early development of congestive heart failure. Like other lesions with left-to-right flow, the magnitude of the shunt is determined by both the size of the defect and the pulmonary vascular resistance. Infants with APW present with frequent respiratory tract infections, tachypnea with feeding, and failure to thrive. A B C Figure 20-15. A through C. Classification of aortopulmonary window. (Reproduced with permission from Mori K, Ando M, Takao A. Distal type of aortopulmonary window: report of 4 cases. Br Heart J. 1978;40:681. With permission from the BMJ Publishing Group.) ­ yanosis is usually absent because these infants deteriorate C prior to the onset of significant pulmonary hypertension. The rapid decline with this defect occurs because shunt flow continues during both phases of the cardiac cycle, which limits ­systemic perfusion and increases ventricular work.86 The diagnosis of APW begins with the physical examination, which may demonstrate a systolic flow murmur, a hyperdynamic precordium, and bounding peripheral pulses. The chest radiograph will show pulmonary overcirculation and cardiomegaly, and the ECG will usually demonstrate either left ventricular hypertrophy or biventricular hypertrophy. Echocardiography can detect the defect and also provide information about associated anomalies. Retrograde aortography will confirm the diagnosis but is rarely necessary. Therapy. All infants with APW require surgical correction once the diagnosis is made. Repair is undertaken through a median sternotomy and the use of CPB. The pulmonary arteries are occluded once the distal aorta is cannulated, and a transaortic repair using a prosthetic patch for pulmonary artery closure is then carried out. The coronary ostia must be carefully visualized and included on the aortic side of the patch. Alternatively, a two-patch technique can be used, which may eliminate recurrent fistulas from suture line VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease A Figure 20-14. Variants of cor triatriatum with imperforate membrane between common pulmonary venous chamber (CPVC) and left atrium (LA). A. Common chamber draining to right atrium directly. B. Common chamber draining into systemic venous circulation via anomalous vein. RA = right atrium. (Adapted with permission from Krabill KA, Lucas RV Jr. Abnormal pulmonary venous connections. In: Emmanouilides GC, ed. Moss and Adams’ Heart Disease in Infants, Children, and Adolescents. 5th ed. Baltimore: Lippincott Williams & Wilkins, 1995.) 712 UNIT II PART Figure 20-16. Two-patch repair of aortopulmonary window. A. The aorta and right atrium are cannulated through a median sternotomy, and once the patient is on cardiopulmonary bypass, the right and left pulmonary arteries are occluded with snares. The ductus arteriosus (when present) can be ligated. The aorta is cross-clamped and the heart arrested with cardioplegia. The aortopulmonary window is then divided, with the left coronary ostia being carefully protected. B. A piece of previously prepared pulmonary homograft material is used to patch the aortic defect. In older children, polytetrafluoroethylene material can be safely used. C. Once the aortic portion of the defect has been safely repaired, the aortic cross-clamp may be removed to restore perfusion to the heart. During rewarming, the pulmonary portion of the defect is repaired using a similar piece of homograft or polytetrafluoroethylene. D. At the completion of repair, the patient is easily weaned from cardiopulmonary bypass, and the cannulas are removed. This type of repair restores normal anatomy, with a reduced likelihood of longterm fistula formation. (From Gaynor et al,88 with permission.) SPECIFIC CONSIDERATIONS leaks that occasionally occur with the single-patch method (Fig. 20-16).86 Results. Results are generally excellent, with an operative mortality in most large series of less than 5%.86-88 DEFECTS REQUIRING PALLIATION Tricuspid Atresia Tricuspid atresia occurs in 2% to 3% of patients with CHD and is characterized by atresia of the tricuspid valve. This results in discontinuity between the right atrium and RV. The RV is generally hypoplastic, and left-heart filling is dependent on an ASD. Tricuspid atresia is the most common form of the singleventricle complex, indicating that there is functionally only one ventricular chamber. Anatomy. As mentioned, tricuspid atresia results in a lack of communication between the right atrium and the RV, and in the majority of patients, there is no identifiable valve tissue or remnant.89 The right atrium is generally enlarged and muscular, with a fibrofatty floor. An unrestrictive ASD is usually present. The LV is often enlarged as it receives both systemic and pulmonary blood flow, but the left AV valve is usually normal. The RV, however, is usually severely hypoplastic, and there is sometimes a VSD in its trabeculated or infundibular portion. In many cases, the interventricular communication is a site of obstruction to pulmonary blood flow, but obstruction may also occur at the level of the outlet valve or in the subvalvular infundibulum.90 In most cases, pulmonary blood flow is dependent on the presence of a PDA, and there may be no flow into the pulmonary circulation except for this PDA. Tricuspid atresia is classified according to the relationship of the great vessels and by the degree of obstruction to pulmonary blood flow (Fig. 20-17). Because of the rarity of tricuspid atresia with transposed great arteries, we will restrict our discussion to tricuspid atresia with normally related great vessels. Pathophysiology. The main pathophysiology in tricuspid atresia is that of a univentricular heart of left ventricular morphology. That is, the LV must receive systemic blood via the interatrial communication and then distribute it to both the pulmonary circulation and the systemic circulation. Unless there is a VSD (as is found in some cases), pulmonary flow is dependent on the presence of a PDA. As the ductus begins to close shortly after birth, infants become intensely c yanotic. ­ ­ R e-establishing ductal patency (with PGE 1) restores pulmonary blood flow and stabilizes patients for surgical ­intervention. Pulmonary hypertension is unusual in tricuspid atresia. However, occasional patients have a large VSD between the LV and the infundibular portion of the RV (just below the pulmonary valve). If there is no obstruction at the level of this VSD or at the valve, these infants may actually present with heart failure from excessive pulmonary blood flow. Regardless of whether these infants are “ductal-­ dependent” for pulmonary blood flow or have pulmonary blood flow provided across a VSD, they will be cyanotic since the obligatory right-to-left shunt at the atrial level will provide complete mixing of systemic and p­ ulmonary venous VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 713 return so that the LV ejects a hypoxemic mixture into the aorta. Diagnosis. The signs and symptoms of tricuspid atresia are dependent on the underlying anatomic variant, but most infants are cyanotic and hypoxic as a result of decreased pulmonary blood flow and the complete mixing at the atrial level. When pulmonary blood flow is provided through a VSD, there may be a prominent systolic murmur. Tricuspid atresia with pulmonary blood flow from a PDA may present with the soft, continuous murmur of a PDA in conjunction with cyanosis. In the minority of patients with tricuspid atresia, symptoms of congestive heart failure will predominate. This is often related to excessive flow across a VSD. The natural history of the muscular VSDs in these infants is that they will close and the congestive heart failure will dissipate and transform into cyanosis with reduced pulmonary blood flow. Chest radiography will show decreased pulmonary vascularity. The ECG is strongly suggestive, because uncharacteristic left axis deviation will be present, due to underdevelopment of the RV. Two-dimensional echocardiography readily confirms the diagnosis and the anatomic subtype. Treatment. The treatment for tricuspid atresia in the e­ arlier era of palliation was aimed at correcting the defect in the pulmonary circulation. That is, patients with too much pulmonary flow received a pulmonary band, and those with insufficient flow received a systemic-to-pulmonary artery shunt. ­Systemic-to-pulmonary artery shunts, or Blalock-Taussig (B-T) shunts, were first applied to patients with tricuspid atresia in the 1940s and 1950s.91 Likewise pulmonary artery banding was applied to patients with tricuspid atresia and congestive failure in 1957. However, despite the initial relief of either cyanosis or congestive heart failure, long-term mortality was high, as the single ventricle was left unprotected from either volume or p­ ressure overload.92 Recognizing the inadequacies of the initial repairs, Glenn described the first successful cavopulmonary anastomosis, an end-to-side right pulmonary artery-to-superior vena cava shunt in 1958, and later modified this to allow flow to both pulmonary arteries.93 This end-to-side right pulmonary artery-to-superior vena cava anastomosis was known as the bidirectional Glenn, and is the first stage to final Fontan repair in widespread use today (Fig. 20-18). The Fontan repair was a major advancement in the treatment of CHD, as it essentially bypassed the right heart and allowed separation of the pulmonary and systemic circulations. It was first performed by Fontan in 1971, and consisted of a classic Glenn anastomosis, ASD closure, and direct connection of the right atrium to the proximal end of the left pulmonary artery using an aortic homograft.94 The main pulmonary artery was ligated, and a homograft valve was inserted into the orifice of the inferior vena cava. Multiple modifications of this initial repair were performed over the next 20 years. One of the most important was the description by deLeval and colleagues of the creation of an interatrial lateral tunnel that allowed the inferior vena caval blood to be channeled exclusively to the superior vena cava.95 A total cavopulmonary connection could then be accomplished by dividing the superior vena cava and suturing the superior portion to the upper side of the right pulmonary artery and the inferior end to the augmented undersurface of the right pulmonary artery. Pulmonary flow then occurs passively, in a laminar fashion, driven by the central venous pressure. This repair became known as the modified Fontan operation. Another important modification, the fenestrated Fontan repair, was introduced in 1988.96 In this procedure, a residual 20% to 30% right-to-left shunt is either created or left unrepaired at the time of cavopulmonary connection to help sustain systemic output in the face of transient elevations in the pulmonary vascular resistance postoperatively (Fig. 20-19).96 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease Figure 20-17. Classification of t­ ricuspid atresia. Type I, normally related great arteries with: IA, pulmonary atresia with virtual absence of right ventricle; IB, pulmonary stenosis with small ventricular septal defect; IC, normal pulmonary valve, large ventricular septal defect. Type II, transposed great arteries with: IIA, pulmonary atresia; IIB, pulmonary or subpulmonary stenosis; IIC, normal or enlarged pulmonary valve and artery without subpulmonary stenosis. (Reproduced with permission from Tricuspid atresia. In: Mavroudis C, Backer CL, eds. Pediatric Cardiac Surgery. 2nd ed. St. Louis: Mosby; 1994:381.) 714 UNIT II PART SPECIFIC CONSIDERATIONS Figure 20-18. Superior vena cava–pulmonary artery shunts. A. Classic Glenn shunt. End-to-side right pulmonary artery (RPA)-to-superior vena cava (SVC) anastomosis with ligation of SVC–right atrial junction. B. Method of takedown of classic Glenn shunt and creation of total cavopulmonary anastomosis during Fontan operation. C. Bidirectional Glenn shunt (bidirectional SVC–­ pulmonary artery shunt), end-to-side SVC-to-RPA anastomosis. D. Method of construction of bidirectional Glenn shunt, one cannula in the high SVC or innominate vein and another cannula in the right atrium connected to a Y-connector. (Reproduced with permission from Tricuspid atresia. In: Mavroudis C, Backer CL, eds. Pediatric Cardiac Surgery. 2nd ed. St. Louis: Mosby; 1994:383.) SVC Aorta PA PA Lateral tunnel Figure 20-19. The fenestrated Fontan procedure. Using a polytetrafluoroethylene patch, a tunnel is created in the lateral wall of the right atrium to direct inferior vena cava (IVC) flow to the superior vena cava (SVC) that is anastomosed to the pulmonary artery (PA). A 4- to 5-mm fenestration in the baffle diminishes systemic venous pressure and improves cardiac output at the expense of a small decrease in systemic arterial oxygen saturation. (Reproduced with permission from Kopf GS, Kleinman CS, Hijazi ZM, et al. Fenestrated Fontan operation with delayed transcatheter closure of atrial septal defect: improved results in high-risk patients. J Thorac Cardiovasc Surg. 1992;103:1039. Copyright Elsevier.) Fenestration IVC VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Results. Recent reports of the Fontan procedure for tricuspid atresia have been encouraging, with an overall survival of 86% and an operative mortality of 2%.8 The main complications following repair are atrial arrhythmias, particularly atrial flutter; conduit obstruction requiring reoperation; protein-losing enteropathy; and decreased exercise tolerance. A recent prospective multi-institutional study from the Congenital Heart Surgeons Society reported the outcomes of 150 neonates with tricuspid atresia and normally related great vessels.99 Five-year survival was 86%, and by the age of 2 years, 89% had undergone cavopulmonary anastomosis, and 75% of those surviving cavopulmonary anastomosis underwent Fontan operation within 3 years. Competing risks methodology was used in this study to determine the rates of transition to BDCPA (2 year prevalence = 90%) 100 Proportion (%) of patients in each state Occasionally, if a previous B-T shunt was performed, arterioplasty of the right pulmonary artery may be required to ensure adequate size and unobstructed bilateral flow.2 The bidirectional Glenn shunt or hemi-Fontan operation effectively avoids recirculation of both systemic and pulmonary venous return, thus preventing volume overload of the single ventricle and its attendant sequelae.95 Pulmonary artery banding is ­necessary in 10% to 15% of patients with markedly increased pulmonary blood flow and florid congestive heart failure. The Fontan is usually performed when the child is between 2 and 4 years of age, and it is generally successful if the infant was staged properly, with a protected single ventricle, and there is adequate pulmonary artery growth. The pulmonary vascular resistance should be below 4 Wood units, and the ejection fraction should be more than 45% to ensure success.98 In patients with high pulmonary artery pressure, fenestration of the atrial baffle may be helpful because their pulmonary vascular resistance may preclude adequate cardiac output postoperatively.92,96 80 Alive without BDCPA (2 year prevalence = 4%) 60 Dead without BDCPA (2 year prevalence = 5%) 40 Single-stage Fontan (2 year prevalence = 1%) 20 0 0.0 0.4 0.8 1.2 Years from diagnosis 1.6 2.0 Figure 20-20. Competing risks depiction of events after diagnosis in 150 patients with tricuspid atresia. All patients began alive and thereafter migrated to one of four mutually exclusive end states (death, bidirectional cavopulmonary anastomosis [BDCPA], single-stage Fontan completion, or remaining alive without BDCPA) at time-dependent rates defined by the underlying hazard functions. At any point in time, the sum of proportions of children in each state is 100%. For example, estimated prevalences after 2 years from diagnosis are as follows: 89% BDCPA, 6% dead without BDCPA, 4% alive without BDCPA, and 1% single-stage Fontan completion. Solid lines represent parametric point estimates; dashed lines enclose 70% confidence intervals; circles with error bars represent nonparametric estimates; numbers in parentheses indicate the estimated proportion of patients in each state at 2 years from diagnosis. (From Karamlou et al,99 Fig. 1, with permission. Copyright Elsevier.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 715 CHAPTER 20 Congenital Heart Disease The last notable variation on the original Fontan repair uses an extracardiac prosthetic tube graft, usually 20 mm in diameter, as the conduit directing inferior vena cava blood to the pulmonary arteries.95 This technique has the advantages of decreasing atrial geometric alterations by avoiding intra-atrial suture lines and improving flow dynamics in the systemic venous ­pathway by maximizing laminar flow. Several ­investigators have shown a decrease in supraventricular arrhythmias, as well as an improvement in ventricular function, which may be secondary to decreased atrial tension and alleviation of chronic elevations in coronary sinus pressure.95,96 The extracardiac Fontan operation can be completed without the use of CPB in selected cases, which may further improve outcomes.97 One potential disadvantage of the extracardiac Fontan is that it delays performance of the Fontan in order to allow placement of a conduit of sufficient size. Despite these innovative approaches, the current strategy for operative management still relies on the idea of palliation. Patients are approached in a staged manner, to maximize their physiologic state so that they will survive to undergo a Fontan operation. The therapeutic strategy must begin in the neonatal period and should be directed toward reducing the patient’s subsequent risk factors for a Fontan procedure. Accordingly, small systemic pulmonary shunts, which are usually performed through a median sternotomy, should be constructed for palliation of ductus-dependent univentricular physiology. This can easily be replaced with a bidirectional Glenn shunt or hemi-Fontan operation at 6 months of life. In non–ductus-dependent univentricular physiology, the infant can be managed medically until primary construction of a bidirectional cavopulmonary anastomosis becomes feasible. This is possible in the majority of cases because the physiologically elevated pulmonary vascular resistance prevents pulmonary overcirculation during the neonatal period. 716 e­ nd-states and their associated determinants (Fig. 20-20). Risk factors for death without cavopulmonary anastomosis in this study included the presence of mitral regurgitation and palliation with systemic-to-pulmonary artery shunts not originating from the innominate artery. Factors associated with decreased transition rate to cavopulmonary anastomosis included patient variables (younger age at admission to a participating institution and noncardiac anomalies) and procedural variables (larger systemicto-pulmonary arterial shunt diameter and previous palliation).99 UNIT II PART Hypoplastic Left Heart Syndrome SPECIFIC CONSIDERATIONS HLHS comprises a wide spectrum of cardiac malformations, including hypoplasia or atresia of the aortic and mitral valves and hypoplasia of the LV and ascending aorta.100 HLHS has a reported prevalence of 0.2 per 1000 live births and occurs twice as often in boys as in girls. Left untreated, HLHS is invariably fatal and is responsible for 25% of early cardiac deaths in neonates.101 However, the recent evolution of palliative surgical procedures has dramatically improved the outlook for patients with HLHS, and an improved understanding of anatomic and physiologic alterations has spurred advances in parallel arenas such as intrauterine diagnosis and fetal intervention, echocardiographic imaging, and neonatal critical care. Anatomy. As implied by its name, HLHS involves varying degrees of underdevelopment of left-sided structures, including the LV and the aortic and mitral valves. Thus, HLHS can be classified into four anatomic subtypes based on the valvular morphology: (a) aortic and mitral stenosis; (b) aortic and mitral atresia; (c) aortic atresia and mitral stenosis; and (d) AS and mitral atresia. Aortic atresia tends to be associated with more severe degrees of hypoplasia of the ascending aorta than does AS. Even in cases without frank aortic atresia, however, the aortic arch is generally hypoplastic and, in severe cases, may even be interrupted. There is an associated coarctation shelf in 80% of patients with HLHS, and the ductus itself is usually quite large, as is the main pulmonary artery.7 The segmental pulmonary arteries, however, are small, secondary to reduced intrauterine pulmonary blood flow, which is itself a consequence of the left-sided outflow obstruction. The left atrial cavity is generally smaller than normal and is accentuated because of the leftward displacement of the septum primum. There is almost always an interatrial communication via the foramen ovale, which can be large, but more commonly restricts right-to-left flow. In rare cases, there is no atrial-level communication, which can be lethal for these infants because there is no way for pulmonary venous return to cross over to the RV. Associated defects can occur with HLHS, and many of them have importance with respect to operative repair. For example, if a VSD is present, the LV can retain its normal size during development even in the presence of mitral atresia. This is because a right-to-left shunt through the defect impels growth of the LV.102 This introduces the feasibility of biventricular repair for this subset of patients. Although HLHS undoubtedly results from a complex interplay of developmental errors in the early stages of cardiogenesis, many investigators have hypothesized that the altered blood flow is responsible for the structural underdevelopment that characterizes HLHS. In other words, if the stimulus for normal development of the ascending aorta from the primordial aortic sac is high-pressure systemic blood flow from the LV through the aortic valve, then an atretic or stenotic aortic valve, which impedes flow and leads to only low-pressure diastolic retrograde flow via the ductus, will change the developmental signals and result in hypoplasia of the downstream structures. Normal growth and development of the LV and mitral valve can be secondarily affected, resulting in hypoplasia or atresia of these structures.100 Pathophysiology and Diagnosis. In HLHS, pulmonary venous blood enters the left atrium, but atrial systole cannot propel blood across the stenotic or atretic mitral valve into the LV. Thus, the blood is shunted across the foramen ovale into the right atrium, where it contributes to volume loading of the RV. The end result is pulmonary venous hypertension from outflow obstruction at the level of the left atrium, as well as pulmonary overcirculation and right ventricular failure. As the pulmonary vascular resistance falls postnatally, the condition is exacerbated because right ventricular output is preferentially directed away from the systemic circulation, resulting in profound underperfusion of the coronary arteries and the vital organs. Closure of the ductus is incompatible with life in these neonates. Neonates with severe HLHS receive all pulmonary, systemic, and coronary blood flow from the RV. Generally, a child with HLHS will present with respiratory distress within the first day of life, and mild cyanosis may be noted. These infants must be rapidly triaged to a tertiary center, and echocardiography should be performed to confirm the diagnosis. Prostaglandin E1 must be administered to maintain ductal patency, and the ventilatory settings must be adjusted to avoid excessive oxygenation and increase carbon dioxide tension. These maneuvers will maintain pulmonary vascular resistance and promote improved systemic perfusion.2,7,100 Cardiac catheterization should generally be avoided because it is not usually helpful and might result in injury to the ductus and compromised renal function secondary to the osmotic dye load. Treatment. In 1983, Norwood and colleagues described a twostage palliative surgical procedure for relief of HLHS103 that was later modified to the currently used three-stage method of palliation.104 Stage 1 palliation, also known as the modified Norwood procedure, bypasses the LV by creating a single outflow vessel, the neoaorta, which arises from the RV. The current technique of arch reconstruction involves completion of a connection between the pulmonary root, the native ascending aorta, and a piece of pulmonary homograft used to augment the diminutive native aorta. There are several modifications of this anastomosis, most notably the DamusKaye-Stansel (DKS) anastomosis, which involves dividing both the aorta and the pulmonary artery at the sinotubular junction. The proximal aorta is anastomosed to the proximal pulmonary artery, creating a “double-barreled” outlet from the heart. This outlet is anastomosed to the distal aorta, which can be augmented with homograft material if there is an associated coarctation. At the completion of arch reconstruction, a 3.5- or 4-mm shunt is placed from the innominate artery to the right pulmonary artery. The interatrial septum is then widely excised, thereby creating a large interatrial communication and preventing pulmonary venous hypertension (Fig. 20-21). The DKS connection, as described earlier, might avoid postoperative distortion of the tripartite connection in the neoaorta, and thus decrease the risk of coronary insufficiency.105 It can be used when the aorta is 4 mm or larger. Unfortunately, in VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 717 Aorta B Homograft C Main pulmonary a. D E F Figure 20-21. Current techniques for first-stage palliation of the hypoplastic left-heart syndrome. A. Incisions used for the procedure, incorporating a cuff of arterial wall allograft. The distal divided main pulmonary artery may be closed by direct suture or with a patch. B. Dimensions of the cuff of the arterial wall allograft. C. The arterial wall allograft is used to supplement the anastomosis between the proximal divided main pulmonary artery and the ascending aorta, aortic arch, and proximal descending aorta. D and E. The procedure is completed by atrial septectomy and a 3- to 5-mm modified right Blalock shunt. F. When the ascending aorta is particularly small, an alternative procedure involves placement of a complete tube of arterial allograft. The tiny ascending aorta may be left in situ, as indicated, or implanted into the side of the neoaorta. a. = artery. (From Castaneda AR, Jonas RA, Mayer JE, et al. Cardiac Surgery of the Neonate and Infant. Philadelphia: W.B. Saunders; 1994:371, with permission. Copyright Elsevier.) many infants with HLHS, especially if there is aortic atresia, the aorta is diminutive and often less than 2 mm in diameter. The postoperative management of infants following stage 1 palliation is complex because favorable outcomes depend on establishing a delicate balance between pulmonary and systemic perfusion. Recent literature suggests that these infants require adequate postoperative cardiac output in order to supply both the pulmonary and the systemic circulations and that the use of oximetric catheters to monitor mixed venous oxygen saturation (Svo2) aids clinicians in both the selection of inotropic agents and in ventilatory management.106 Recent introduction of a modification that includes arch reconstruction and placement of the shunt between the RV and the pulmonary artery (Sano shunt) diminishes the diastolic flow created by the classical B-T shunt and may augment coronary perfusion, resulting in improved postoperative cardiac function. A recent prospective, r­andomized, multi-institutional trial sponsored by the National Institutes of Health, the Systemic Ventricle Reconstruction (SVR) trial, compared the outcomes of neonates having either a modified B-T shunt vs. a Sano shunt.107 The SVR trial demonstrated that transplantation-free survival 12 months after randomization was higher with the Sano shunt than with the modified B-T shunt (74% vs. 64%, P = .01). However, the Sano shunt group had more unintended interventions (P = .003) and complications (P = .002). Right ventricular size and function at the age of 14 months and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups. Data collected over a mean (± standard deviation) follow-up period of 32 ± 11 months showed a nonsignificant difference in transplan5 tation-free survival between the two groups (P = .06).107 Although surgical palliation with the Norwood procedure is still the mainstay of therapy for infants with HLHS, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease A 718 UNIT II PART SPECIFIC CONSIDERATIONS a combined surgical and percutaneous option (hybrid procedure), which consists of bilateral pulmonary artery banding and placement of a ductal stent, has emerged as a promising ­alternative that obviates the need for CPB in the fragile neonatal period.108,109 The hybrid procedure is performed in a “hybrid suite,” incorporating both advanced fluoroscopic imaging facilities combined with complete operating room capabilities. A 3or 3.5-mm PTFE tube graft is cut to a width of 3 to 4 mm and used as the bands on the branch pulmonary arteries, placed just distal to the main pulmonary artery. The ductal stent is then positioned in order to cover all ductal tissue and is deployed through a purse-string suture in the main pulmonary artery. A reverse systemic-to-pulmonary shunt is considered in patients with aortic atresia and preductal coarctation to improve coronary perfusion; however, a recent study demonstrated no difference in survival between those with and without the shunt.110 The hybrid procedure can also be used as a bridge to heart transplantation in those infants with severe AV valve regurgitation or otherwise unsuitable single-ventricle anatomy. Following stage 1 palliation, the second surgical procedure is the creation of a bidirectional cavopulmonary shunt or hemi-Fontan, generally at 3 to 6 months of life when the pulmonary vascular resistance has decreased to normal levels. This is the first step in separating the pulmonary and systemic circulations, and it decreases the volume load on the single ventricle. The existing innominate artery-to-pulmonary shunt (or RV-to-pulmonary shunt) is eliminated during the same operation (Fig. 20-22). The third stage of surgical palliation, known as the modified Fontan procedure, completes the separation of the s­ ystemic and pulmonary circulations and is performed between 18 months and 3 years of age, or when the patient experiences increased cyanosis (i.e., has outgrown the capacity to perfuse the systemic circulation with adequately oxygenated blood). This has traditionally required a lateral tunnel within the right atrium to direct blood from the inferior vena cava to the pulmonary artery, allowing further relief of the volume load on the RV and providing increased pulmonary blood flow to alleviate cyanosis. More recently, many favor using an extracardiac conduit (e.g., 20-mm tube graft) to connect the inferior vena cava to the pulmonary artery. Not all patients with HLHS require this three-stage palliative repair. Some infants afflicted with a milder form of HLHS, recently described as hypoplastic left heart complex (HLHC), have aortic or mitral hypoplasia without intrinsic valve stenosis and antegrade flow in the ascending aorta. In this group, a two-ventricle repair can be achieved with reasonable outcome. Tchervenkov recently published the results with 12 patients with HLHC who underwent biventricular repair at a mean age of 7 days.106 The operative technique consisted of a ­pulmonary homograft patch aortoplasty of the aortic arch and ascending aorta and closure of the interatrial and interventricular communications. The left heart was capable of sustaining systemic perfusion in 92% of patients, and early mortality was 15.4%. Four patients required reoperations to relieve LVOT obstruction, most commonly between 12 and 39 months ­following repair. Although the Norwood procedure is the most widely performed initial operation for HLHS, transplantation can be used as a first-line therapy and may be preferred when anatomic or physiologic considerations exist that preclude a Shunt divided Homograft patch Pulmonary artery Aorta VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 20-22. Technique of a bidirectional Glenn shunt. The divided right superior vena cava has been anastomosed at the previous site of the distal anastomosis of the modified right Blalock shunt. The cardiac end of the divided superior vena cava may also be anastomosed to the right pulmonary artery, with the internal orifice being closed with a Gore-Tex patch. (From Castaneda AR, Jonas RA, Mayer JE, et al. Cardiac Surgery of the Neonate and Infant. Philadelphia: W.B. Saunders; 1994:376, with permission. Copyright Elsevier.) Results. Outcomes for HLHS are still significantly worse than those for other complex cardiac defects. However, with improvements in perioperative care and modifications in surgical technique, the survival following the Norwood procedure now exceeds 80% in experienced centers.100,105,107,109 The outcome for low-birth-weight infants has improved, but low weight still remains a major predictor of adverse survival, especially when accompanied by additional cardiac defects, such as systemic outflow obstruction or extracardiac ­anomalies. DEFECTS THAT MAY BE PALLIATED OR REPAIRED Ebstein’s Anomaly Anatomy. This is a rare defect, occurring in less than 1% of CHD patients. The predominant maldevelopment in this lesion is the inferior displacement of the tricuspid valve into the RV, although Bove113 and others have emphasized the fact that Ebstein’s anomaly is primarily a defect in right ventriclar morphology rather than an isolated defect in the tricuspid valve. The anterior leaflet is usually attached in its normal position to the annulus, but the septal and posterior leaflets are displaced toward the ventricle. This effectively divides the RV into two parts: the inlet portion (atrialized RV) and the outlet portion (true or trabeculated RV). The atrialized RV is usually thin and dilated. Similarly, the tricuspid annulus and the right atrium are extremely dilated, and the tricuspid valve is usually regurgitant with a “sail-like” leaflet. There is commonly an ASD present, which results in a right-to-left shunt at the atrial level. Occasionally, there is true anatomic pulmonary atresia or milder forms of RVOT obstruction. A Wolff-Parkinson-White syndrome type of accessory pathway with associated pre-excitation is present in 15% of patients.113 Pathophysiology. Right ventricular dysfunction occurs in patients with Ebstein’s anomaly because of two basic mechanisms: the inflow obstruction at the level of the atrialized ventricle, which produces ineffective RV filling and contractile dysfunction. Inflow obstruction and tricuspid regurgitation, which is exacerbated by progressive annular dilatation, both produce ineffective RV filling. Contractile dysfunction of the RV is a result of a decrease in the number of myocardial fibers, as well as the discordant contraction of the large atrialized ­portion. The lack of forward flow at the right ventricular level may lead to physiologic or functional pulmonary atresia, and the infant is dependent on ductal patency for survival. All ­systemic venous return must be directed through an ASD to the left atrium, where it can be shunted through the ductus for gas exchange. However, the left ventricular function is usually compromised in infants with severe Ebstein’s anomaly as well, because the enormous RV and the to-and-fro flow within the atrialized RV prevent adequate intracardiac mixing. Left ventricular function may also be severely compromised in Ebstein’s anomaly because the large RV causes left ventricular compression. Diagnosis. There is a spectrum of clinical presentation in infants with Ebstein’s anomaly that mirrors the anatomic spectrum of this anomaly. Some infants with less severe forms may present with a mild degree of cyanosis, whereas the onset of clinical symptoms in patients surviving childhood is gradual, with the average age of diagnosis in the mid-teens. However, the infant with severe atrialization and pulmonary stenosis will be both cyanotic and acidotic at birth. The chest radiograph may demonstrate the classic appearance, which consists of a globular “wall-to-wall” heart, similar to that seen with pericardial effusion. The ECG may show right bundlebranch block and right axis deviation. Wolff-Parkinson-White (WPW) syndrome, as mentioned earlier, is a common finding in these patients. Echocardiography will confirm the diagnosis and provide critical information including tricuspid valvular function, size of the atrialized portion of the RV, degree of pulmonary stenosis, and the atrial size.6,113 The Great Ormond Street Score (GOSE),114 which consists of the area of the right atrium plus the area of the atrialized ­portion of the RV divided by the diastolic area of the remaining cardiac chambers, has been proposed as a useful prognostic tool to stratify neonates with Ebstein’s anomaly. A score of greater than 1 translates into uniformly fatal outcome. Electrophysiology study with radiofrequency ablation is indicated in patients with evidence of WPW syndrome or in children with a ­history of supraventricular tachycardia, undefined wide-complex ­tachycardia, or syncope. Treatment. Surgery is indicated for symptomatic infants and for older children and adults with arrhythmias, progressive cyanosis, or New York Heart Association class III or IV. However, the operative repair may be different, depending on the patient’s age, because older children usually are candidates for a biventricular or one-and-a-half ventricle repair, whereas moderate survival has been reported for neonates, using a procedure that converts the anatomy to a single-ventricle physiology, as described by Starnes and coworkers.115 The surgical approach in widespread use today for patients surviving infancy was described by Danielson and colleagues in 1992.6,113,116 This procedure entails excision of redundant right atrial tissue and patch closure of any associated ASD, plication of the atrialized portion of the ventricle with obliteration of the aneurysmal cavity, posterior tricuspid annuloplasty to narrow the tricuspid annulus, reconstruction of the tricuspid valve if the anterior leaflet is satisfactory, or replacement of the tricuspid valve if necessary.116 If the tricuspid valve is not amenable to reconstruction, valve replacement should be considered. Care must be taken when performing the posterior annuloplasty, or during the conduct of tricuspid valve replacement, to avoid the conduction system, because complete heart block can complicate this procedure. In addition, patients who demonstrated preoperative evidence of ­pre-excitation should undergo electrophysiologic mapping and ablation. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 719 CHAPTER 20 Congenital Heart Disease favorable outcome with palliative repair. Significant tricuspid regurgitation, intractable pulmonary artery hypertension, or progressive right ventricular failure are cases where cardiac replacement may be advantageous. Widespread adaptation of transplantation as first-line treatment for HLHS has been limited by improved Norwood survival rates as the operation and pre- and postoperative management of the patient have evolved and by limited organ availability. Organ availability should be considered prior to electing transplantation, as 24% of infants died awaiting transplantation in the largest series to date.111,112 720 UNIT II PART SPECIFIC CONSIDERATIONS Neonatal Ebstein’s anomaly is a separate entity. Results with surgical correction have been poor, and many neonates are not candidates for operative repair as previously described. Surgical options for the symptomatic neonate include palliative procedures, the one-and-a-half ventricle repair, or conversion to single-ventricle physiology.1,7,117 Arguably, the most favorable outcomes in symptomatic neonatal Ebstein’s anomaly or repair in slightly older infants have been achieved using the right ventricular exclusion premise. This technique, known as the “Starnes” procedure,115 uses a fenestrated patch to close the tricuspid valve orifice coupled with systemic-to-pulmonary artery shunt. The patch must be fenestrated to allow decompression of the RV in instances of anatomic pulmonary atresia. Although Knott-Craig and colleagues117 have described tricuspid valve repair for the full spectrum of neonates and infants with excellent short- and midterm results, these results have not been reproduced in other institutions.118 The one-and-a-half ventricle repair was first described by Billingsly and coworkers as an attempt to achieve a more physiologic “pulsatile” pulmonary circulation in patients with a hypoplastic or dysplastic RV.119 This is accomplished by diverting the superior vena caval blood directly into the pulmonary arterial system by a bidirectional cavopulmonary shunt while recruiting the RV to propel the inferior vena caval blood directly to the pulmonary arteries via the RVOT. Thus the hemodynamics of the one-and-a-half ventricle repair are characterized by separate systemic and pulmonary circulations in series. The systemic circulation is fully supported by a systemic ventricle, and the pulmonary circulation is supported by both the bidirectional Glenn shunt and the hypoplastic (pulmonary) ventricle. Proponents of this approach report a decreased right atrial pressure and a decrease in inferior vena cava hypertension, which is theorized to be responsible for many of the dreaded complications of the Fontan circulation, including protein-losing encephalopathy, hepatic congestion, atrial arrhythmias, and systemic ventricular failure. In addition, the maintenance of pulsatile pulmonary blood flow, as opposed to continuous laminar flow as in the Fontan circulation, may be advantageous to the pulmonary microcirculation, although it has not been proven in any studies thus far.119,120 Certain criteria, most notably an adequate tricuspid valve Z score, as well as the absence of severe pulmonary hypertension or concomitant defects requiring intricate intracardiac repair, should be satisfied prior to electing the one-and-a-half ventricle approach.121 Patients who do not fulfill these criteria may be approached with a two-ventricle repair and atrial fenestration or a Fontan repair. In the infant with severe Ebstein’s anomaly, initial ­stabilization with prostaglandin to maintain ductal patency, mechanical ventilation, and correction of cyanosis is mandatory. Metabolic acidosis, if present from compromised systemic perfusion, must be aggressively treated with afterload reduction. Many of these infants will improve over 1 to 2 weeks as pulmonary vascular resistance falls and they are able to improve antegrade flow into the pulmonary circulation through their abnormal RV and tricuspid valve. When stabilization and medical palliation fail, surgical management remains an option, although its success depends on numerous anatomic factors (e.g., adequacy of the tricuspid valve, RV and pulmonary outflow tract), and surgery for symptomatic neonates with Ebstein’s anomaly carries a high risk. Recently, Knott-Craig and associates reported three cases where twoventricle repair was undertaken by subtotal closure of the ASD, extensive resection of the right atrium, and vertical plication of the atrialized chamber.117 Five-year follow-up revealed all patients to be asymptomatic and in sinus rhythm without medications. Results. In the neonatal period, the most common postoperative problem, whether after a simple palliative procedure such as a B-T shunt or following a more extensive procedure such as attempted exclusion of the RV, has been low cardiac output. Supraventricular tachycardia also has been problematic postoperatively. Complete heart blockage necessitating pacemaker implantation should be uncommon if the techniques described to avoid suturing between the coronary sinus and the tricuspid annulus are used. There are few published reports of outcomes, due to the rarity of this defect. However, based on the natural history of this condition, which is remarkably benign for the majority of older patients, the outlook should be excellent for patients who have survived ASD closure, plication, and tricuspid annuloplasty.7,112,116,117 Transposition of the Great Arteries Anatomy. Complete transposition is characterized by connection of the atria to their appropriate ventricles with inappropriate ventriculoarterial connections. Thus, the aorta arises anteriorly from the RV, while the pulmonary artery arises posteriorly from the LV. Van Praagh and coworkers introduced the term D-transposition of the great arteries (D-TGA) to describe this defect, whereas L-TGA describes a form of corrected transposition where there is concomitant AV discordance.122,123 D-TGA requires an obligatory intracardiac mixing of blood, which usually occurs at both the atrial and the ventricular levels or via a patent ductus. Significant coronary anomalies occur frequently in patients with D-TGA.7 The most common pattern, occurring in 68% of cases, is characterized by the left main coronary artery arising from the leftward coronary sinus, giving rise to the left anterior descending and circumflex arteries. The most common variant is for the circumflex coronary artery to arise as a branch from the right coronary artery instead of from the left coronary artery. Pathophysiology. D-TGA results in parallel pulmonary and systemic circulations, with patient survival dependent on intracardiac mixing of blood. After birth, both ventricles are relatively noncompliant, and thus, infants initially have higher pulmonary flow due to the decreased downstream resistance. This causes left atrial enlargement and a left-to-right shunt via the patent foramen ovale. Postnatally, the LV does not hypertrophy because it is not subjected to systemic afterload. The lack of normal extrauterine left ventricular maturation has important implications for the timing of surgical repair because the LV must be converted to the systemic ventricle and be able to function against systemic vascular resistance. If complete repair is done within the first few weeks of life, the LV usually adapts easily to systemic resistance since it is conditioned to high intrauterine pulmonary vascular resistance. After a few weeks of life, the LV that is conditioned to the decrease in pulmonary resistance that occurs when the lungs inflate after birth may have difficulty adapting to systemic vascular resistance without preoperative preparation or postoperative support. Novel techniques of LV “preparation” using a pulmonary arterial band have been used in cases where complete repair has been delayed. Clinical Manifestations and Diagnosis. Infants with D-TGA and an intact ventricular septum are usually ­cyanotic VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ at birth, with an arterial Po2 between 25 and 40 mmHg. If ductal patency is not maintained, deterioration will be rapid with ensuing metabolic acidosis and death. Conversely, those infants with a coexisting VSD may be only mildly hypoxemic and may come to medical attention after 2 to 3 weeks, when the falling pulmonary vascular resistance leads to symptoms of congestive heart failure. The ECG will reveal right ventricular hypertrophy, and the chest radiograph will reveal the classic egg-shaped ­configuration. Definitive diagnosis is made by echocardiography, which reliably demonstrates ventriculoarterial discordance and any associated lesions. Cardiac catheterization is rarely necessary, except in infants requiring surgery after the neonatal period to assess the suitability of the LV to support the systemic circulation. Limited catheterization, however, is useful for performance of atrial septostomy in neonates with inadequate intracardiac mixing. Figure 20-23. The Senning operation. A. The atrial septum is cut near the tricuspid valve, creating a flap attached posteriorly between the caval veins. B. The flap of atrial septum is sutured to the anterior lip of the orifices of the left pulmonary veins, effectively separating the pulmonary and systemic venous channels. C. The posterior edge of the right atrial incision is sutured to the remnant of the atrial septum, diverting the systemic venous channel to the mitral valve. D. The anterior edge of the right atrial incision (lengthened by short incisions at each corner) is sutured around the cava above and below to the lateral edge of the LA incision, completing the pulmonary channel and diversion of pulmonary venous blood to the tricuspid valve area. (Reproduced with permission from D-Transposition of the great arteries. In: Mavroudis C, Backer CL, eds. Pediatric Cardiac Surgery. 2nd ed. St. Louis: Mosby; 1994:345.) The subset of patients who present with D-TGA complicated by LVOT obstruction and VSD may not be suitable for an arterial switch operation. The Rastelli operation, first performed in 1968, uses placement of an intracardiac baffle to direct left ventricular blood to the aorta and an extracardiac valved conduit to establish continuity between the RV and the pulmonary artery, which has led to successful outcomes in these complex patients.128 Results. For patients with D-TGA, intact ventricular ­septum, and VSD, the arterial switch operation provides excellent longterm results with a mortality rate of less than 5%. Operative risk is increased when unfavorable coronary anatomic configurations are present or when augmentation of the aortic arch is required. The most common complication is supravalvular pulmonary stenosis, occurring 10% of the time, which may require reoperation.4,7,129 Results of the Rastelli operation have improved substantially, with an early mortality rate of 5% in a 2001 review.130 Late mortality rate results were less favorable because conduit failure requiring reoperation, pacemaker insertion, or relief of LVOT obstruction was frequent. Double-Outlet Right Ventricle Anatomy. Double-outlet RV (DORV) accounts for 5% of CHD and exists when both the aorta and pulmonary artery arise wholly, or in large part, from the RV. DORV encompasses a spectrum of malformations, because the incomplete shift of the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease Surgical Repair. Blalock and Hanlon introduced the first operative intervention for D-TGA with the creation of an atrial septectomy to enhance intracardiac mixing.124 This initial procedure was feasible in the pre-CPB era, but carried a high mortality rate. Later, Rashkind and Causo developed a catheter-based balloon septostomy, which largely obviated the need for open septectomy.42 These early palliative maneuvers, however, met with limited success, and it was not until the late 1950s, when Senning and Mustard developed the first “atrial repair,” that outcomes improved. The Senning operation consisted of rerouting venous flow at the atrial level by incising and realigning the atrial septum over the pulmonary veins and using the right atrial free wall to create a pulmonary venous baffle (Fig. 20-23).125 Although the Mustard repair was similar, it made use of either autologous pericardium or synthetic material to create the interatrial baffle.126 These atrial switch procedures resulted in a physiologic correction, but not an anatomic one, as the systemic circulation is still based on the RV. Still, survival rose to 95% in most centers by using an early balloon septostomy followed by an atrial switch procedure at 3 to 8 months of age.125,126 Despite the improved early survival rates, long-term problems, such as superior vena cava or pulmonary venous obstruction, baffle leak, arrhythmias, tricuspid valve regurgitation, and right ventricular failure, prompted the development of the arterial switch procedure by Jatene in 1975.127 The arterial switch procedure involves the division of the aorta and the pulmonary artery, posterior translocation of the aorta (LeCompte maneuver), mobilization of the coronary arteries, placement of a pantaloon-shaped pericardial patch, and proper alignment of the coronary arteries on the neoaorta (Fig. 20-24). The most important consideration is the timing of surgical repair, because arterial switch should be performed within 2 weeks after birth, before the LV loses its ability to pump against systemic afterload.2,4,7 In patients presenting later than 2 weeks, the LV can be retrained with preliminary pulmonary artery banding and aortopulmonary shunt followed by definitive repair. Alternatively, the unprepared LV can be supported following arterial switch with a mechanical assist device for a few days while it recovers ability to manage systemic pressures. Echocardiography can be used to assess left ventricular performance and guide operative planning in these circumstances. 721 722 UNIT II PART Figure 20-24. A. The maneuver of Lecompte (positioning the pulmonary artery anterior to the aorta) is shown with aortic cross-clamp repositioning to retract the pulmonary artery during the neoaortic reconstruction. A and B. After the coronary patches are rotated for an optimal lie, they are sutured to the linearly incised sinuses of Valsalva at the old pulmonary artery (neoaorta) (C). (Reproduced with permission from Backer CL, Idriss FS, Mavroudis C. Surgical techniques and intraoperative judgments to facilitate the arterial switch operation in transposition with intact ventricular septum. In: Mavroudis C, Backer CL, eds. Arterial Switch. Cardiac Surgery: State of the Art Review. Vol. 5, no. 1. Philadelphia: Hanley & Belfus; 1991:108. Copyright Elsevier.) SPECIFIC CONSIDERATIONS aorta toward the LV is often associated with other abnormalities of cardiac development, such as ventricular looping and infundibular-truncal spiraling.131 The vast majority of hearts exhibiting DORV have a concomitant VSD, which varies in its size and spatial association with the great vessels. The VSD is usually nonrestrictive and represents the only outflow for the LV; its location relative to the great vessels dictates the dominant physiology of DORV, which can be analogous to that of a large isolated VSD, tetralogy of Fallot, or D-TGA. Lev et al, in 1972,132 suggested considering DORV as a spectrum of hearts that “pass imperceptibly from tetralogy with VSD with overriding aorta into double-outlet right ventricle with subaortic VSD.” Thus, Lev and colleagues described a classification scheme for DORV based on the “commitment” of the VSD to either or both great arteries.7,132 The VSD can be subaortic, doubly committed, noncommitted, or subpulmonic. The subaortic type is the most common (50%) and occurs when the VSD is located directly beneath the aortic annulus. Doubly committed VSD (10%) is present when the VSD lies beneath both the aorta and the pulmonary artery, which are usually side-by-side in this lesion. The noncommitted VSD (10%–20%) exists when the VSD is remote from the great vessels. The subset of DORV hearts with the VSD located beneath the pulmonary valve also are classified as the Taussig-Bing syndrome.133 This occurs in 30% of cases of DORV with VSD, and it occurs when the aorta rotates more anteriorly, with the pulmonary artery rotated more posteriorly (Fig. 20-25). Clinical Manifestations and Diagnosis. Patients with DORV typically present with one of the following three scenarios: (a) those with doubly committed or subaortic VSD present with congestive heart failure and a high propensity for pulmonary hypertension, much like infants with a large single VSD; (b) those with a subaortic VSD and pulmonary stenosis present with cyanosis and hypoxia, much like infants with tetralogy of Fallot; and (c) those with subpulmonic VSD present with cyanosis, much like those with D-TGA, because streaming directs desaturated systemic venous blood to the aorta and oxygenated blood to the pulmonary artery.131 Thus, the three critical factors influencing the clinical presentation and subsequent ­management of infants with DORV are the size and loactaion of the VSD, the presence or absence of important RVOT obstruction, and the presence of other anomalies (especially associated hypoplasia of left-sided structures sometimes seen with subpulmonary VSD). Echocardiography is the mainstay of diagnosis and can also provide valuable information regarding the feasibility of biventricular repair. Specific anatomic questions that should be resolved to assist in surgical planning in addition to those mentioned earlier include the coronary anatomy (presence of a conal branch or left anterior descending from the right coronary coursing across the conus), the presence of additional muscular VSDs remote from either great vessel, and the distance between the tricuspid and pulmonary valve. Cardiac catheterization is rarely necessary in neonates or infants, except to determine the degree of pulmonary hypertension and to determine the effects of previous palliative procedures on the pulmonary arterial anatomy. Therapy. The goals of corrective surgery are to relieve p­ ulmonary stenosis, to provide separate and unobstructed outflow pathways from each ventricle to the correct great vessel, and to achieve separation of the systemic and ­pulmonary ­circulations. Double-Outlet Right Ventricle with Noncommitted Ventricular Septal Defect The repair of hearts with DORV and noncommitted VSD can be accomplished by constructing an intraventricular tunnel connecting the VSD to the aorta, closing the pulmonary artery, and placing a valved extracardiac conduit from the RV to the ­pulmonary artery. In patients without pulmonary stenosis who VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ SVC FO A Double-Outlet Right Ventricle with Subaortic or Doubly Committed Ventricular Septal Defect Without Pulmonary Stenosis PA CS A IVC B Double-Outlet Right Ventricle with Subaortic or Doubly Committed Ventricular Septal Defect with Pulmonary Stenosis C Repair of this defect is similar to the above except that concomitant RVOT reconstruction must be performed in addition to the intracardiac tunnel. The RVOT augmentation can be accomplished with the placement of a transannular patch or with placement of an extracardiac valved conduit when an anomalous left anterior descending artery precludes use of a patch. D Taussig-Bing Syndrome without Pulmonary Stenosis E F Figure 20-25. The relationship of the ventricular septal defect (VSD) to the great arteries in double-outlet right ventricle (DORV). A. Subaortic VSD without pulmonary stenosis. B. Subaortic VSD with pulmonary stenosis. C. Subpulmonary VSD (Taussig-Bing malformation). D. Doubly committed VSD. E. Noncommitted (remote) VSD. F. Intact interventricular septum. A = aorta; CS = coronary sinus; D = ventricular septal defect; FO = foramen ovale; IVC = inferior vena cava; PA = pulmonary artery; RV = right ventricle; SVC = superior vena cava. (Adapted with permission from Zamora R, Moller JH, Edwards JE. Double-outlet right ventricle. Chest. 1975;68:672.) have ­intractable congestive failure, a pulmonary artery band can be placed in the first 6 months to control pulmonary artery overcirculation and prevent the development of pulmonary hypertension. Infants with pulmonary stenosis can be managed with a systemic-to-pulmonary shunt followed by biventricular repair as described by Belli and colleagues in 1999, or with a modified Fontan.134 There is no consensus on the timing of repair, but recent literature suggests that repair within the first 6 months is associated with better outcome. However, in cases where an extracardiac valved conduit is necessary, it is better to delay definitive repair until the child is 2 to 3 years of age, because this allows placement of a larger ­conduit and possibly reduces the number of future obligatory conduit replacements.7,131 These infants are best treated with a balloon septostomy during the neonatal period to improve mixing, followed by VSD closure baffling LV egress to the pulmonary artery and an arterial switch operation. The Kawashima procedure,135 in which an intraventricular tunnel is used to baffle LV egress directly to the aorta, may alternatively be used when the aorta is more posterior or when there is associated pulmonary stenosis. Taussig-Bing Syndrome with Pulmonary Stenosis This defect may be treated with a variety of techniques, depending on the specific anatomic details and the expertise of the treatment team. A Rastelli-type repair, which involves construction of an intraventricular tunnel through the existing VSD that connects the LV to both great vessels, followed by division of the pulmonary artery at its origin and insertion of a valved conduit from the RV to the distal pulmonary artery, can be performed.136 Alternatively, a Yasui procedure, which involves baffling the VSD to the pulmonary artery and creation of a DKS anastomosis between the pulmonary artery and the aorta with patch augmentation, can be accomplished concomitant with placement of a RV-pulmonary artery conduit.137 Results. The results of DORV repairs are generally favorable, especially for the tetralogy-type DORV with subaortic VSD.138,139 However, more complex types of DORV, including noncommitted VSD and Taussig-Bing type, still carry important morbidity and mortality.134,138,139 Furthermore, repeated interventions for RVOT reconstruction or staged operations for patients triaged to single-ventricle pathways pose late hazards for patients surviving initial repair. A recent single-institution series evaluated 393 patients with DORV.138 The authors found that the need for reintervention approached 37% at 15 years following repair. Arterial switch operation, as opposed VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease This group of patients can be treated by creating an intracardiac baffle that directs blood from the LV into the aorta. Enlargement of the VSD may be necessary to allow ample room for the baffle; this should be done anterosuperiorly to avoid injury to the conduction system that normally lies inferoposteriorly along the border of the VSD. In addition, other important considerations in constructing the LV outflow tunnel include the prominence of the conal septum, the attachments of the tricuspid valve to the conal septum, and the distance between the tricuspid and pulmonary valves. In some instances, unfavorable anatomy may preclude placement of an adequate intracardiac baffle, necessitating single ventricle repair. D RV 723 724 to ­Rastelli-type repair, was associated with an increased risk of early postrepair mortality, but mitigated against the risk of late death. Patients with hypoplastic left-sided structures and a nonsubaortic VSD may fare better with a single-ventricle repair. Tetralogy of Fallot Anatomy. The original description of tetralogy of Fallot (TOF) UNIT II PART SPECIFIC CONSIDERATIONS by Ettienne Louis Fallot,140 as the name implies, included four abnormalities: a large perimembranous VSD adjacent to the tricuspid valve; an overriding aorta; a variable degree of RVOT obstruction, which might include hypoplasia and dysplasia of the pulmonary valve as well as obstruction at the subvalvar and pulmonary artery level; and right ventricular hypertrophy. More recently, the Van Praagh et al141 pointed out that TOF could be more correctly termed monology of Fallot, since the four components are explained by the malposition of the infundibular septum. When the infundibular septum is displaced anteriorly and leftward, the RVOT is narrowed and its anterior displacement results in failure of fusion of the ventricular septum between the arms of the trabeculo-septo-marginalis (Fig. 20-26). The morphology of TOF is markedly heterogeneous and includes an absent pulmonary valve, concomitant AV septal defects, and pulmonary atresia with major aortopulmonary collaterals. The present discussion will focus only on the so-called classic presentation of TOF without coexisting intracardiac defects. Anomalous coronary artery patterns, related to either origin or distribution, have been described in TOF.142 However, the most surgically important coronary anomaly occurs when the left anterior descending artery arises as a branch of the right coronary artery. This occurs in approximately 3% of cases of TOF and may preclude placement of a transannular patch, as the left anterior descending coronary artery crosses the RVOT at varying distances from the pulmonary valve annulus.143 Figure 20-26. Pathologic specimen of the heart in a patient with tetralogy of Fallot. The four anatomic components comprising tetralogy of Fallot can be conceptualized as a monology of Fallot, because they can be explained by malposition of the interventricular septum. AO = aorta; RV = right ventricle; RVOT = right ventricular outflow tract; TV = tricuspid valve; VSD = ventricular septal defect. (From Van Praagh et al,141 with permission. © Elsevier Ltd.) Pathophysiology and Clinical Presentation. The initial presentation of a child afflicted with TOF depends on the degree of RVOT obstruction. Children with cyanosis at birth usually have severe pulmonary annular hypoplasia with concomitant hypoplasia of the peripheral pulmonary arteries. Most children, however, present with mild cyanosis at birth, which then progresses as the right ventricular hypertrophy further compromises the RVOT. Cyanosis usually becomes significant within the first 6 to 12 months of life, and the child may develop characteristic “tet” spells, which are periods of extreme hypoxemia. These spells are characterized by decreased pulmonary blood flow and an increase in systemic blood flow. They can be triggered by any stimulus that decreases systemic vascular resistance, such as fever, agitation, or vigorous physical activity. Cyanotic spells increase in severity and frequency as the child grows, and older patients with uncorrected TOF may often squat, which increases peripheral vascular resistance and relieves the cyanosis. Evaluation in the older patient with TOF may demonstrate clubbing, polycythemia, hemoptysis, or brain abscesses. Chest radiography will demonstrate a boot-shaped heart, and ECG will show the normal pattern of right ventricular hypertrophy. Echocardiography confirms the diagnosis because it demonstrates the position and nature of the VSD, defines the character of the RVOT obstruction, and often visualizes the branch pulmonary arteries and the proximal coronary arteries. Cardiac catheterization is rarely necessary and is actually risky in TOF since it can create spasm of the RVOT muscle and result in a hypercyanotic episode (tet spell). Occasionally, aortography is necessary to delineate the coronary artery anatomy. Treatment. John Deanfield144 stated “…long follow-up inevitably means surgery in an earlier era: More recent surgery, at a younger age, with better preoperative, operative, and postoperative care, will improve long-term results. Data from the former (earlier) era will be overly pessimistic.” This statement is particularly pertinent as surgical correction of TOF has evolved from a staged approach of antecedent palliation in infancy followed by intracardiac repair to primary repair during the first few months of life without prior palliative surgery. However, systemic-to-pulmonary shunts, generally a B-T shunt, may still be preferred with an unstable neonate younger than 3 months of age, when an extracardiac conduit is required because of an anomalous left anterior descending coronary artery, or when pulmonary atresia, significant branch pulmonary artery hypoplasia, or severe noncardiac anomalies coexist with TOF. Traditionally, TOF was repaired through a right ventriculotomy, providing excellent exposure for closure of the VSD and relief of the RVOT obstruction, but concerns that the resultant scar would significantly impair right ventricular function or lead to lethal arrhythmias led to the development of a transatrial approach. Transatrial repair, except in cases when the presence of diffuse RVOT hypoplasia requires insertion of a transannular patch, is now being increasingly advocated by many, although its superiority has not been ­conclusively demonstrated.145 The operative technique involves the use of CPB. All existing systemic-to-pulmonary arterial shunts, as well as the ductus arteriosus, are ligated. A right atriotomy is then made, and the anatomy of the VSD and the RVOT are assessed by VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Parietal extension Beginning of parietal extension A Amputation Dotted outline of TV leaflets Transection Aortic valve Anterior ML B TV post. leaflet C TV septal leaflet Infundibular septum D E retracting the tricuspid valve (Fig. 20-27). The outflow tract obstruction is relieved by resecting the offending portion of the infundibular septum as well as any muscle trabeculations. If necessary, a pulmonary valvotomy or, alternatively, a longitudinal incision in the main pulmonary artery can be performed to improve exposure. The diameter of the pulmonary valve annulus is assessed by inserting Hegar dilators across the outflow tract; if the pulmonary artery/aorta diameter is less than 0.5, or the estimated RV/LV pressure is greater than 0.7, a transannular patch is inserted. 21 Patch closure of the VSD is then accomplished, taking care when placing sutures along the posteroinferior portion to avoid the conduction ­system. Results. Operative mortality for primary repair of TOF in infancy is less than 5% in most series.4,7,145 Previously reported risk factors such as transannular patch insertion or younger age at time of repair have been eliminated secondary to improved intraoperative and postoperative care. According to the Society of Thoracic Surgeons Congenital Heart Surgery Database, discharge mortality from 3059 operations from 2002 to 2007 was 7.5% for initial palliation, 1.3% for primary repair, and 0.9% for staged repair, indicating receiving outcomes for patients getting primary repair compared to staged repair.146 Nevertheless, for neonatal repair, discharge mortality increased to 6.2% with palliation and 7.8% with primary repair. This may be partly explained by a higher chance of postoperative complications in neonates. A major complication of repaired TOF is the development of pulmonary insufficiency, which subjects the RV to the adverse effects of acute and chronic volume overload. This is especially problematic if residual lesions such as a VSD or peripheral pulmonary stenosis exist. Pulmonary valve regurgitation after repair of TOF is relatively well tolerated in the short term, partly because the hypertrophied RV usually adapts to the altered hemodynamic load.147,148 The detrimental effects of chronic pulmonary valve regurgitation are, however, numerous, and include progressive right ventricular dilatation and failure, tricuspid valve regurgitation, exercise intolerance, arrhythmia, and sudden death. Mechanoelectrical interaction, by which a dilatated RV provides the substrate for electrical instability, might underlie the propensity toward ventricular arrhythmia.149 In support of this contention, Gatzoulis and colleagues147,149 found that the risk of symptomatic arrhythmia was high in patients with marked right ventricular enlargement and QRS prolongation on resting ECG of more than 180 ms. Karamlou et al have shown that similar structural and hemodynamic abnormalities, including a larger right atrial volume and right ventricular chamber size, are also related to atrial arrhythmias in patients following TOF repair.150 We found that prolongation of the QRS duration beyond a threshold of 160 ms increased the risk of atrial arrhythmias.150 Together, these data show that a similar mechanism could be responsible for both atrial and ventricular arrhythmias after repair in TOF patients. When significant deterioration of ventricular function occurs, insertion of a pulmonary valve may be required, although this is rarely necessary in infants. Unfortunately, there are no universal criteria establishing the timing of pulmonary valve replacement, although dilation of the RV, prolongation of the QRS duration beyond 180 ms, important atrial arrhythmias, and impaired ventricular function are widely used. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 725 CHAPTER 20 Congenital Heart Disease TV ant. leaflet Figure 20-27. The anatomy from the perspective of the right atrial (RA) approach, shown as if the right atrial free wall and tricuspid valve were translucent. The free edge of the tricuspid leaflets is shown by dashed lines. A. The difference from the right ventricular (RV) perspective is in the apparent position of the parietal extension. From the RA perspective, the surgeon looks beneath this, as the parietal extension arches over the right ventricular outflow tract. B. The same perspective without the outline of the tricuspid valve leaflets. The parietal extension is transected at its origin from the infundibular septum, dissected up toward the free wall, and amputated at the free wall. C. A pledgetted mattress suture is placed from the RA side through the base of the commissural tissue between septal and tricuspid leaflets and through the patch. D. The suturing is continued onto the parietal extension and infundibular septum, visualizing and staying close to the aortic valve leaflets to avoid leaving a hole between muscular bands. When working from the RA, it is particularly important to stay close to the aortic valve leaflets in the direction of the septum to avoid narrowing the RV outflow tract. E. The repair of the ventricular septal defect is completed. Note that the suture line is away from the bundle of His and its branches, except where it crosses the right bundle branch anteroinferiorly. ant. = anterior; ML = mitral leaflet; post. = posterior; TV = tricuspid valve. (Reproduced with permission from Kouchoukos NT, Blackstone EH, et al: Kirklin/Barratt-Boyes Cardiac Surgery. 4th ed. Philadelphia: Elsevier, 2013, p 1384. Copyright Elsevier.) 726 UNIT II PART SPECIFIC CONSIDERATIONS Arrhythmias are potentially the most serious late complication following TOF repair. In a multicenter cohort of 793 patients studied by Gatzoulis et al,149 a steady increase was documented in the prevalence of ventricular and atrial tachyarrhythmia and sudden cardiac death in the first 5 to 10 years after intracardiac repair. Clinical events were reported in 12% of patients at 35 years after repair. Prevalence of atrial arrhythmias from other studies, however, ranges from 1% to 11%,147,149 which is a reflection of the strong time dependence of arrhythmia onset. Underlying causes of arrhythmia following repair are complex and multifactorial, resulting in poorly defined optimum screening and treatment algorithms. Older repair age has been associated with an increased frequency of both atrial and ventricular arrhythmias. Impaired ventricular function secondary to a protracted period of cyanosis before repair might contribute to the propensity for arrhythmia in older patients. Ventricular Septal Defect Anatomy. VSD refers to a hole between the LV and RV. These defects are common, comprising 20% to 30% of all cases of CHD, and may occur as an isolated lesion or as part of a more complex malformation.151 VSDs vary in size from 3 to 4 mm to more than 3 cm and are classified into four types based on their location in the ventricular septum: perimembranous, AV canal, outlet or supracristal, and muscular (Fig. 20-28). Perimembranous VSDs are the most common type requiring surgical intervention, comprising approximately 80% of cases.151 These defects involve the membranous septum and include the malalignment defects seen in tetralogy of Fallot. In rare instances, the anterior and septal leaflets of the tricuspid valve adhere to the edges of the perimembranous defect, forming a channel between the LV and the right atrium. These defects result in a large left-to-right shunt due to the large pressure differential between the two chambers. AV canal defects, also known as inlet defects, occur when part or all of the septum of the AV canal is absent. The VSD lies beneath the tricuspid valve and is limited upstream by the tricuspid annulus, without intervening muscle. The supracristal or outlet VSD results from a defect within the conal septum. Characteristically, these defects are limited upstream by the pulmonary valve and are otherwise surrounded by the muscle of the infundibular septum. Muscular VSDs are the most common type and may lie in four locations: anterior, midventricular, posterior, or apical. These are surrounded by muscle and can occur anywhere Figure 20-28. Classic anatomic types of ventricular septal defect (VSD). A. Type I (conal, infundibular, supracristal, subarterial) VSD. B. Type II or perimembranous VSD. C. Type III VSD (atrioventricular canal type or inlet septum type). D. Type IV VSD (single or multiple). (Reproduced with permission from Ventricular septal defect. In: Mavroudis C, Backer CL, eds. Pediatric Cardiac Surgery. 2nd ed. St. Louis: Mosby; 1994:70.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ along the trabecular portion of the septum. The rare “Swisscheese” type of muscular VSD consists of multiple communications between the RV and LV, complicating operative repair. Pathophysiology and Clinical Presentation. The size of Diagnosis. The child with a large VSD will present with severe congestive heart failure and frequent respiratory tract infections. Children with Eisenmenger’s syndrome may be deceptively asymptomatic until frank cyanosis develops. The chest radiograph will show cardiomegaly and pulmonary overcirculation, and the ECG will show signs of left ventricular or biventricular hypertrophy. Echocardiography provides definitive diagnosis and can estimate the degree of shunting as well as pulmonary arterial pressures. Cardiac catheterization has largely been supplanted by echocardiography, except in older children where measurement of pulmonary resistance is necessary prior to recommending closure of the defect. Treatment. VSDs may close or narrow spontaneously, and the probability of closure is inversely related to the age at which the defect is observed. Thus, infants at 1 month of age have an 80% incidence of spontaneous closure, whereas a child at 12 months of age has only a 25% chance of closure.152 This has an important impact on operative decision making, because a small or moderate-size VSD may be observed for a period of time in the absence of symptoms. Large defects and those in severely symptomatic neonates should be repaired during infancy to relieve symptoms and because irreversible changes in pulmonary vascular resistance may develop during the first year of life. Repair of isolated VSDs requires the use of CPB with moderate hypothermia and cardioplegic arrest. The right atrial approach is preferable for most defects, except apical muscular defects, which often require a right ventriculotomy for adequate exposure. Supracristal defects may alternatively be exposed via a transverse or longitudinal incision in the RV immediately beneath the pulmonary valve. ­Regardless of the type Results. Even in very small infants, closure of VSDs can be safely performed with hospital mortality near 0%.4,7,155 The main risk factor remains the presence of other associated lesions, especially when present in symptomatic neonates with large VSDs. Atrioventricular Canal Defects Anatomy. AV canal defects result from failure of fusion of the endocardial cushions in the central portion of the heart, causing a lesion that involves the atrial and the ventricular septum, as well as the anterior mitral and septal tricuspid valve leaflets. Defects involving primarily the atrial septum are known as partial AV canal defects and frequently occur in conjunction with a cleft anterior mitral leaflet. Complete AV canal defects have a combined deficiency of the atrial and ventricular septum associated with a common AV orifice rather than separate tricuspid and mitral valves. The common AV valve generally has five leaflets, three lateral (free wall) and two bridging (septal) leaflets. The defect in the ventricular septum can lie either between the two bridging leaflets or beneath them. The relationship between the septal defect and the anterior bridging leaflet forms the basis of the Rastelli classification for complete AV canal defects (Fig. 20-30).156 Pathophysiology and Diagnosis. Partial AV canal defects, in the absence of AV valvular regurgitation, frequently resemble isolated ASDs. Left-to-right shunting predominates as long as pulmonary vascular resistance remains low. However, 40% of patients with partial AV canal defects have moderateto-severe valve incompetence, and progressive heart f­ ailure VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 727 CHAPTER 20 Congenital Heart Disease the VSD determines the initial pathophysiology of the disease. Large VSDs are classified as nonrestrictive and are at least equal in diameter to the aortic annulus. These defects allow free flow of blood from the LV to the RV, elevating right ventricular pressures to the same level as systemic pressure. Consequently, the pulmonary-to-systemic flow ratio (Qp:Qs) is inversely dependent on the ratio of pulmonary vascular resistance to systemic vascular resistance. Nonrestrictive VSDs produce a large increase in pulmonary blood flow, and the afflicted infant will present with symptoms of congestive heart failure. However, if untreated, these defects will cause pulmonary hypertension with a corresponding increase in pulmonary vascular resistance. This will lead to a reversal of flow (a right-to-left shunt), which is known as Eisenmenger’s syndrome. Small restrictive VSDs offer significant resistance to the passage of blood across the defect, and therefore right ventricular pressure is either normal or only minimally elevated and Qp:Qs rarely exceeds 1.5.4,7 These defects are generally asymptomatic because there are few physiologic consequences. However, there is a long-term risk of endocarditis, because endocardial damage from the jet of blood through the defect may serve as a possible nidus for colonization. of defect present, a right atrial approach can be used ­initially to inspect the anatomy, as this may be abandoned should it offer inadequate exposure for repair. After careful inspection of the heart for any associated malformations, a patch repair is employed, taking care to avoid the conduction system (Fig. 20-29). Routine use of intraoperative transesophageal echocardiography should be used to assess for any residual defects. Successful percutaneous device closure of VSDs using the Amplatzer muscular VSD was recently described.153 The device has demonstrated a 100% closure rate in a small series of patients with isolated or residual VSDs, or as a collaborative treatment strategy for the VSD component in more complex congenital lesions. Proponents of device closure argue that its use can decrease the complexity of surgical repair, avoid reoperation for a small residual lesion, or avoid the need for a ventriculotomy. Multiple or “Swiss-cheese” VSDs represent a special case, and many cannot be repaired during infancy. In patients in whom definitive VSD closure cannot be accomplished, temporary placement of a pulmonary artery band can be employed to control pulmonary flow. This allows time for spontaneous closure of many of the smaller defects, thus simplifying ­surgical repair. Some centers, however, have advocated early definitive repair of the Swiss-cheese septum, by using oversize patches, fibrin glue, and combined intraoperative device closure, as well as techniques to complete the repair transatrially. 154 At the ­University of California, San Francisco, 69% of patients with multiple VSDs underwent single-stage correction, and the repaired group had improved outcome compared with the ­palliated group.154 728 UNIT II PART SPECIFIC CONSIDERATIONS Figure 20-29. A. Right atrial incision and exposure of perimembranous ventricular septal defect (VSD) in the region of the tricuspid anteroseptal commissure. Stay sutures have been placed to slightly evert the atrial wall. Note that initially, the superior edge of this typical perimembranous defect is not visible. The atrioventricular node is in the muscular portion of the atrioventricular septum, just on the atrial side of the commissure between the tricuspid septal and anterior leaflets. The bundle of His thus penetrates at the posterior angle of the VSD, where it is vulnerable to injury. B and C. The repair of the perimembranous VSD is completed with use of a slightly oversized Dacron patch, taking care to place stitches 3 to 5 mm away from the edge of the defect itself to avoid injury to the conduction system. (Reproduced with permission from Walters HL, Pacifico AD, Kirklin JK: Ventricular septal defects. In: Sabiston DC, Lyerly HK, eds. Textbook of Surgery: The Biologic Basis of Modern Surgical Practice. Philadelphia: W.B. Saunders; 1997:2014. Copyright Elsevier.) S P A A A A P Normal mitral and tricuspid valves S P P P Partial atrioventricular canal Intermediate atrioventricular canal AB PB Type A Embryologic atrioventricular canal AB A P P A LEC IEC P PB SEC LEC A AB P P P A AB P P PB PB Type B Type C A P Complete atrioventricular canal VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 20-30. Formation of mitral and tricuspid leaflets and probable embryogenesis of partial, intermediate, and complete forms of atrioventricular canal defects. A = anterior; AB = anterior bridging leaflet; IEC = inferior endocardial cushion; LEC = lateral endocardial cushion; P = posterior; PB = posterior bridging leaflet; S = septal; SEC = superior endocardial cushion. (Reproduced from Feldt RH, Porter CJ, Edwards WD, et al. Defects of the atrial septum and the atrioventricular canal. In: Adams FH, Emmanouilides GC, eds. Moss’ Heart Disease in Infants, Children, and Adolescents. 4th ed. Baltimore: Lippincott Williams & Wilkins; 1989. © Mayo Clinic ID #: CP1214116B-2. Used with permission of Mayo Foundation for Medical Education and Research.) IA LC RPA Ao IA LS LC IA PDA LS PDA LC LS LPA MPA A B C Figure 20-31. Anatomic types of interrupted aortic arch. A. Interruption distal to the left subclavian artery. B. Interruption between the left subclavian and left carotid arteries. C. Interruption between the left carotid and innominate arteries. Ao = aorta; IA = innominate artery; LPA, MPA, RPA = left, main, and right pulmonary arteries; LC = left carotid artery; LS = left subclavian artery; PDA = patent ductus arteriosus. (Reproduced with permission from Jonas RA. Interrupted aortic arch. In: Mavroudis C, Backer CL, eds. Pediatric Cardiac Surgery. 2nd ed. St. Louis: Mosby; 1994:184.) Treatment. The management of patients with AV canal defects can be especially challenging. Timing of operation is individualized. Patients with partial defects can be electively repaired between 2 and 5 years of age, whereas complete AV canal defects should be repaired within the first year of life to prevent irreversible changes in the pulmonary circulation. Complete repair in infancy should be accomplished, with palliative procedures such as pulmonary artery banding reserved for only those infants with other complex lesions or who are too ill to tolerate CPB. The operative technique requires the use of either continuous hypothermic CPB or, for small infants, deep hypothermic circulatory arrest. The heart is initially approached through an oblique right atriotomy, and the anatomy is carefully observed. In the case of a partial AV canal, the cleft in the mitral valve is repaired with interrupted sutures and the ASD is closed with a pericardial patch.148 Complete AV canal defects are repaired by patch closure of the VSD, separating the common AV valve into tricuspid and mitral components and suspending the neovalves from the top of the VSD patch and closing the ASD. Results. Partial AV canal defects have an excellent outcome, with a mortality rate of 0% to 2% in most series.156 Complete AV canal defects are associated with a poorer prognosis, with an operative mortality of 3% to 13%. The most frequently encountered postoperative problems are complete heart block (1%–2%), right bundle-branch block (22%), arrhythmias (11%), RVOT obstruction (11%), and severe mitral regurgitation (13%–24%). 156 The increasing use of intraoperative transesophageal echocardiography may positively influence outcomes, as the adequacy of repair can be assessed and treated without need for subsequent reoperation.156-158 Interrupted Aortic Arch Anatomy. Interrupted aortic arch (IAA) is a rare defect, comprising approximately 1% of all cases of CHD.7,148 It is defined as an absence of luminal continuity between the ascending and descending aorta and does not occur as an isolated defect in most cases, because a VSD or PDA is usually present. IAA is classified based on the location of the interruption (Fig. 20-31). 729 Clinical Manifestations and Diagnosis. Infants with IAA have ductal-dependent systemic blood flow and will develop profound metabolic acidosis and hemodynamic collapse upon ductal closure. In the rare instance of failed ductal closure, the diagnosis may be missed during infancy, and the child will present with symptoms of congestive heart failure from a persistent left-to-right shunt. Once definitive diagnosis is made in infants, usually with echocardiography, preparations are made for operative intervention, and prostaglandin E1 is infused to maintain ductal patency and correct acidosis. The infant’s hemodynamic status should be optimized with mechanical ventilation and inotropic support. An effort should be made to increase pulmonary vascular resistance by decreasing the fractional inspired oxygen and avoiding hyperventilation, because this will preferentially direct blood into the systemic circulation. Treatment. Initial strategies for the management of IAA involved palliation though a left thoracotomy by using one of the arch vessels as a conduit to restore aortic continuity. Pulmonary artery banding can be simultaneously performed to limit left-to-right shunting, because it is not feasible to repair the VSD or other intracardiac communications with this approach. However, complete surgical repair in infants with IAA is now preferable. The operative technique involves use of a median sternotomy and CPB with short periods of circulatory arrest. Aortic arch reconstruction can be accomplished with either direct anastomosis or patch aortoplasty followed by ­closure of the VSD.148 In certain cases, the defect will involve hypoplasia of the left heart, precluding attempts at definitive repair. These infants should be managed with a Norwood procedure followed by a Fontan repair. Results. Outcomes in infants with IAA have improved substantially over the last decades as a result of improved perioperative care. Operative mortality is now less than 10% in most series.157 Some authors advocate the use of patch augmentation of the aorta to ensure adequate relief of LVOT obstruction and to diminish anastomotic tension, thus reducing the subsequent risk of restenosis and tracheobronchial compression.7,157,159 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 20 Congenital Heart Disease occurs early in this patient population.157 Complete AV canal defects produce more severe pathophysiologic changes, because the large intracardiac communication and significant AV valve regurgitation contribute to ventricular volume loading and pulmonary hypertension. Children with complete AV canal defects develop signs of congestive heart failure within the first few months of life. Physical examination may reveal a right ventricular heave and a systolic murmur. Children may also present with endocarditis or paradoxical emboli as a result of the intracardiac communication. Chest radiography will be consistent with congestive heart failure, and the ECG demonstrates right ventricular hypertrophy with a prolonged PR interval. Two-dimensional echocardiography with color-flow mapping is confirmatory, but cardiac catheterization can be employed to define the status of the pulmonary vasculature, with a pulmonary vascular resistance greater than 12 Wood units indicating inoperability.157 730 REFERENCES Entries highlighted in bright blue are key references. UNIT II PART SPECIFIC CONSIDERATIONS 1. Kouchoukos NT, Blackstone EH, Doty DB, et al. Atrial septal defect and partial anomalous pulmonary venous connection. In: Kouchoukos NT, Blackstone EH, Doty DB, et al, eds. Kirklin/Barrat-Boyes Cardiac Surgery. 3rd ed. Philadelphia: Churchill Livingstone; 2003:716. 2. Kirklin JW, Pacifico AD, Kirklin JK. 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Baba K, Honjo O, Chaturvedi R, et al. “Reverse BlalockTaussig shunt”: application in single ventricle hybrid palliation. J Thorac Cardiovasc Surg. 2013;146(2):352-357. 111. Bailey LL, Gundry SR, Razzouk AJ, et al. Bless the babies: 115 late survivors of heart transplantation during the first year of life. The Loma Linda University Pediatric Heart Transplant Group. J Thorac Cardiovas Surg. 1993;105:805. 112. Gaynor JW, Mahle WT, Cohen MI, et al. Risk factors for mortality after the Norwood procedure. Eur J Cardiothorac Surg. 2002;22:88. 113. Bove EL. Ebstein’s anomaly in the neonate. Am Assoc Thorac Surg. 2008 (abstr). 114. Celermajer DS, Cullen S, Sullivan ID, et al. Outcome in neonates with Ebstein’s anomaly. J Am Coll Cardiol. 1992;19: 1041-1046. 115. Starnes VA, Pitlick PT, Bernstein D, et al. Ebstein’s anomaly appearing in the neonate. J Thorac Cardiovasc Surg. 1991; 101:1082. 116. Danielson GK, Driscoll DJ, Mair DD, et al. Operative treatment of Ebstein’s anomaly. J Thorac Cardiovasc Surg. 1992; 104:1195. 117. Knott-Craig CJ, Overholt ED, Ward KE, et al. Neonatal repair of Ebstein’s anomaly: indications, surgical technique, and medium-term follow-up. Ann Thorac Surg. 2000; 69:1505. 118. Yetman AT, Freedom RM, McCrindle BW. Outcome in cyanotic neonates with Ebstein’s anomaly. Am J Cardiol. 1998; 81:749. 119. Billingsly AM, Laks H, Boyce SW, et al. Definitive repair in patients with pulmonary atresia and intact ventricular septum. J Thorac Cardiovasc Surg. 1989;97:746. 120. Stellin G, Vida VL, Milanesi O, et al. Surgical treatment of complex cardiac anomalies: the “one and one half ventricle repair.” Eur J Cardiothorac Surg. 2002;22:435. 121. Chowdhury UK, Airan B, Sharma R, et al. One and a half ventricle repair with pulsatile Glenn: results and guidelines for patient selection. Ann Thorac Surg. 2001;71:2000. 122. Van Praagh R, Van Praagh S, Vlad P. Anatomic subtypes of congenital dextrocardia: diagnostic and embryologic implications. Am J Cardiol. 1964;13:510. 123. Van Praagh R, Van Praagh S. Isolated ventricular inversion: a consideration of the morphogenesis, definition, and diagnosis of nontransposed and transposed great arteries. Am J Cardiol. 1966;17:395. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 144. Deanfield JE. Adult congenital heart disease with special refernce to the data on long-term follow-up of patients ­surviving to adulthood with or without surgical correction. Eur Heart J. 1992;13(Suppl H):111-116. 145. Alexiou C, Chen Q, Galogavrou M, et al. Repair of tetralogy of Fallot in infancy with a transventricular or a transatrial approach. Eur J Cardiothorac Surg. 2002;22:174. 146. Al Habib HF, Jacobs JP, Mavroudis C, et al. Contemporary patterns of management of tetralogy of Fallot: data from the Society of Thoracic Surgeons database. Ann Thorac Surg. 2010;90(3):813-819; discussion 819-820. 147. Karamlou T, McCrindle BW, Williams WG. Surgery insight: late complications following repair of tetralogy of Fallot and related surgical strategies for management. Nature Cardiovasc Med. 2006;3:611-622. 148. Kouchoukos NT, Blackstone EH, Doty DB, et al: Ventricular septal defect. In: Kouchoukos NT, Blackstone EH, Doty DB, et al, eds. Kirklin/Barrat-Boyes Cardiac Surgery. 3rd ed. Philadelphia: Churchill Livingstone; 2003:851. 149. Gatzoulis MA, Till JA, Somerville J, et al. Mechanoelectrical interaction in tetralogy of Fallot. QRS prolongation relates to right ventricular size and predicts malignant ventricular arrhythmias and sudden death. Circulation. 1995;92:231-237. 150. Karamlou T, Silber I, Lao R, et al. Outcomes after late reoperation in patients with repaired tetralogy of Fallot: the impact of arrhythmia and arrhythmia surgery. Ann Thorac Surg. 2006;81:1786-1793. 151. Turner SW, Hornung T, Hunter S. Closure of ventricular septal defects: a study of factors influencing spontaneous and surgical closure. Cardiol Young. 2002;12:357. 152. Waight DJ, Bacha EA, Khahana M, et al. Catheter therapy of Swiss cheese ventricular septal defects using the Amplatzer muscular VSD occluder. Catheter Cardiovasc Interv. 2002;55:360. 153. Seddio F, Reddy VM, McElhinney DB, et al. Multiple ventricular septal defects: how and when should they be repaired? J Thorac Cardiovasc Surg. 1999;117:134. 154. Tsang VT, Hsia TY, Yates RW, et al. Surgical repair of supposedly multiple defects within the apical part of the muscular ventricular septum. Ann Thorac Surg. 2002;73:58. 155. Rastelli G, Kirklin JW, Titus JL. Anatomic observations on complete form of persistent common atrioventricular canal with special reference to atrioventricular valves. Mayo Clin Proc. 1966;41:296. 156. Ungerleider RM. Atrial septal defects, ostium primum defects, and atrioventricular canals. In: Sabiston DC, Lyerly HK, eds. Textbook of Surgery: The Biologic Basis of Modern Surgical Practice. Philadelphia: W.B. Saunders; 1997:1993. 157. Kouchoukos NT, Blackstone EH, Doty DB, et al. Coarctation of the aorta and interrupted aortic arch. In: Kouchoukos NT, Blackstone EH, Doty DB, et al, eds. Kirklin/Barrat-Boyes Cardiac Surgery. 3rd ed. Philadelphia: Churchill Livingstone; 2003:1353. 158. Ungerleider RM, Kisslo JA, Greeley WJ, et al. Intraoperative prebypass and postbypass epicardial color flow imaging in the repair of atrioventricular septal defects. J Thorac Cardiovasc Surg. 1989;98:1146. 159. Roussin R, Belli E, Lacour-Gayet F, et al. Aortic arch reconstruction with pulmonary autograft patch aortoplasty. J Thorac Cardiovasc Surg. 2002;123:443. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 733 CHAPTER 20 Congenital Heart Disease 124. Blalock A, Hanlon CR. The surgical treatment of complete transposition of the aorta and the pulmonary artery. Surg Gynecol Obstet. 1950;90:1. 125. Senning A. Surgical correction of transposition of the great vessel. Surgery. 1959;45:966. 126. Mustard WT, Chute AL, Keith JD. A surgical approach to transposition of the great vessels with extracorporeal circuit. Surgery. 1954;36:39. 127. Jatene AD, Fontes VF, Paulista PP, et al. Successful anatomic correction of transposition of the great vessels: a preliminary report. Arq Bras Cardiol. 1975;28:461. 128. Rastelli GC. A new approach to the “anatomic” repair of transposition of the great arteries. Mayo Clin Proc. 1969;44:1. 129. Culbert EL, Ashburn DA, Cullen-Dean G, et al. Quality of life after repair of transposition of the great arteries. Circulation. 2003;108:857. 130. Dearani JA, Danielson GK, Puga FJ, et al. Late results of the Rastelli operation for transposition of the great arteries. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2001;4:3. 131. Freedom RM, Yoo SJ. Double-outlet right ventricle: pathology and angiocardiography. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2000;3:3. 132. Lev M, Bharati S, Meng CCL, et al. A concept of double outlet right ventricle. J Thorac Cardiovasc Surg. 1972;64:271. 133. Taussig HB, Bing RJ. Complete transposition of the aorta and a levoposition of the pulmonary artery. Am Heart J. 1949;37:551. 134. Belli E, Serraf A, Lacour-Gayet F, et al. Double-outlet right ventricle with non-committed ventricular septal defect. Eur J Cardiothorac Surg. 1999;15:747. 135. Kawashima Y, Matsuda H, Yagihara T, et al. Intraventricular repair for Taussig-Bing anomaly. J Thorac Cardiovasc Surg. 1993;105:591-596. 136. Rastelli GC, McGoon DC, Wallace RB. Anatomic correction of transposition of the great arteries with ventricular septal defect and subpulmonic stenosis. J Thorac Cardiovasc Surg. 1969;58:545. 137. Yasui H, Kado H, Nakano E, et al. Primary repair of interrupted aortic arch with severe stenosis in neonates. J Thorac Cardiovasc Surg. 1987;93:539-545. 138. Bradley TJ, Karamlou T, Kulik A, et al. Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle. J Thorac Cardiovasc Surg. 2007;134:967-973. 139. Brown JW, Ruzmetov M, Okada Y, et al. Surgical results in patients with double outlet right ventricle: a 20-year experience. Ann Thorac Surg. 2001;72:1630. 140. Fallot A. Contribution a l’anatomie pathologique de la maladie bleue (cyanose cardiaque) [French]. Marseille Med. 1888;25:77-403. 141. Van Praagh R, Van Praagh S, Nebesar RA, et al. Tetralogy of Fallot: underdevelopment of the pulmonary infundibulum and its sequelae. Am J Cardiol. 1970;26:25-53. 142. Need LR, Powell AJ, del Nido P, et al: Coronary echocardiography in tetralogy of Fallot: diagnostic accuracy, resource utilization, and surgical implications over 13 years. J Am Coll Cardiol. 2000;36:1371. 143. Mahle WT, McBride MG, Paridon SM. Exercise performance in tetralogy of Fallot: the impact of primary complete repair in infancy. Pediatr Cardiol. 2002;23:224. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 21 chapter Cardiac Assessment 735 Clinical Evaluation / 735 History / 735 Physical Examination / 737 Cardiac Risk Assessment in General Surgery Patients / 737 Diagnostic Studies / 738 Extracorporeal Perfusion Summary / 743 Operative Techniques and Results / 743 New Developments / 747 740 741 742 Indications / 742 Percutaneous Coronary Intervention vs. Coronary Artery Bypass Grafting / 742 Mitral Valve Disease 751 Mitral Stenosis / 751 Mitral Regurgitation / 753 Mitral Valve Operative Techniques and Results / 755 Aortic Valve Disease 756 Etiology and Pathophysiology / 765 CABG for Ischemic Cardiomyopathy / 765 Secondary Mitral Regurgitation / 765 Left Ventricular Aneurysmorrhaphy and Surgical Ventricular Restoration / 766 Mechanical Circulatory Support / 768 Right Ventricular Assist Devices and Biventricular Assist Devices / 770 Total Artificial Heart / 770 Surgery for Arryhtmias 770 Atrial Fibrillation / 771 Surgery for Pericardial Disease 772 Aortic Stenosis / 756 Aortic Insufficiency / 758 Aortic Valve Operative Techniques and Results / 761 Acute Pericarditis / 772 Relapsing Pericarditis / 773 Chronic Constrictive Pericarditis / 773 Tricuspid Valve Disease Overview and General Clinical Features / 774 Myxoma / 775 Other Benign Cardiac Tumors / 776 Malignant Cardiac Tumors / 776 Metastatic Cardiac Tumors / 776 762 Tricuspid Stenosis and Insufficiency / 762 Multivalve Disease / 764 Surgical Therapy for the Failing Heart 764 Cardiac Neoplasms 774 Epidemiology of Heart Failure / 764 CARDIAC ASSESSMENT Clinical Evaluation As with any other field in medicine, history, and physical examination form the foundation for the evaluation of a patient with acquired heart disease requiring surgical intervention. Obtaining a complete history will help identify comorbid conditions and assist in delineating the operative risks and prognosis after surgery. Physical examination not only reveals factors that may increase the complexity of surgery, such as previous surgery or peripheral or cerebral vascular disease. These may influence the operative approach but also help guide the choice and sequencing of diagnostic studies. A complete assessment of the patient allows the surgeon to make educated decisions regarding the optimal treatment strategy for the patient. History 747 General Principles / 747 Surgical Options / 747 History / 741 Etiology and Pathogenesis / 741 Risk Factors and Prevention / 741 Clinical Manifestations / 742 Preoperative Evaluation / 742 Coronary Artery Bypass Grafting Shoichi Okada, Jason O. Robertson, Lindsey L. Saint, and Ralph J. Damiano, Jr. Valvular Heart Disease History / 740 Technique / 740 Adverse Effects / 741 Myocardial Protection / 741 Coronary Artery Disease Acquired Heart Disease Symptoms suggestive of heart disease include: chest discomfort, fatigue, edema, dyspnea, palpitations, and syncope. Adequate definition of these symptoms calls for a detailed history-taking paying particular attention to onset, intensity, radiation, duration, and exacerbating/alleviating factors. The demands on the heart are determined by its loading conditions and metabolic state of the body, and symptoms are commonly accentuated with physical exertion or postural changes. Angina pectoris is the hallmark of coronary artery disease (CAD), but may occur with other cardiac pathologies which results in ischemia from a mismatch between the supply of oxygen by the coronary circulation and the metabolic demand of the myocardium. Typically, angina is described as tightness, heaviness, or dull pain, most frequently substernal in location, lasting for a few minutes. This discomfort may radiate to the left arm, neck, mandible, or epigastrium. It is most often provoked by activities that increase metabolic demand on the heart such as exercise, eating, and states of intense emotion, and is typically alleviated by rest or use of nitroglycerin. It is important to note that a significant number of patients with myocardial ischemia, particularly diabetics, females, and the elderly, may have “silent” angina or angina equivalents (dyspnea, diaphoresis, nausea, or fatigue). The overlap of these features with those VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 3 4 5 6 736 Although advances have been made in percutaneous coronary intervention techniques for coronary artery disease, survival is superior with coronary artery bypass grafting in patients with left main disease, multivessel disease, and in diabetic patients. Coronary artery bypass grafting has become increasingly safe, and improves late mortality in patients with left main or proximal left anterior descending disease, multivessel disease, and in patients with diabetes. Despite the theoretical advantages, the superiority of offpump coronary artery bypass to conventional coronary artery bypass grafting has not been clearly established and other factors likely dominate the overall outcome for either technique. Although mechanical valves offer enhanced durability over tissue valve prosthesis, they require permanent systemic anticoagulation therapy to mitigate the risk of valve thrombosis and thromboembolic sequelae, and thus are associated with an increased risk of hemorrhagic complications. Mitral valve repair is recommended over mitral valve replacement in the majority of patients with severe chronic mitral regurgitation. The decision to proceed with mitral valve repair is based on the skill and experience of the surgeon in performing repair, and on the location and type of mitral valve disease encountered at the time of operation. Although open aortic valve replacement has traditionally been the only effective treatment in patients with severe calcific aortic stenosis, transcatheter aortic valve replacement is a developing technology that has proven beneficial for the of noncardiac etiologies such as costochondritis, biliary colic, gastroesophageal reflux disease, diffuse esophageal spasm, and peptic ulcer disease, to name a few, can lead to misdiagnosis. Heart failure can occur in the left and/or right heart and respective symptoms arise from congestion of blood flow owing to the inadequacies of the cardiac pump function. Left heart failure manifests as dyspnea, usually with exertion. Orthopnea suggests worsened pulmonary congestion with increased venous return and these patients are not able to lie flat. Ascites, peripheral edema, and hepatomegaly reflect congestion in the systemic venous circulation and are prominent features of right heart failure. Peripheral edema can occur in right heart failure secondary to systemic venous congestion, or in left heart failure due to salt and fluid retention due to impaired renal perfusion. Patients with chronic suboptimal perfusion and oxygenation can also have digital clubbing and cyanosis. It is difficult to implicate cardiac disease based solely on the presence of fatigue as it is a very nonspecific symptom. However, most cardiac pathologies do result in fatigue or exercise intolerance of some degree. It is important to differentiate fatigue from exertional dyspnea which some patients may describe as “fatigue.” Dyspnea is another common symptom seen in many heart diseases. Although generally a late symptom in patients with valvular heart disease or cardiomyopathy, it may be a relatively early complaint in some patients, particularly those with 7 8 9 10 treatment of aortic stenosis in seriously ill patients that had previously been deemed high risk or inoperable. Mechanical circulatory support with newer generation continuous flow left ventricular assist devices has proven to be durable and effective both in bridging patients to transplant and as a means of “destination therapy” for patients who are not transplant candidates. Recent results for destination therapy have approached those of cardiac transplantation. Performing a biatrial Cox-Maze lesion set results in freedom from atrial fibrillation in approximately 90% of patients and is superior to both catheter-ablation and more limited lesion sets for patients with persistent atrial fibrillation or enlarged left atria. Surgical ablation of atrial fibrillation is recommended for patients referred with concomitant valvular disease and those who have previously failed or are poor candidates for catheterbased approaches. The preferred treatment for pericarditis depends on the underlying cause, although the disease typically follows a self-limited course and is best managed medically. Surgical pericardiectomy may have a role in treating relapsing pericarditis and, more commonly, chronic constrictive pericarditis.  Myxomas are the most common cardiac tumors, and, while benign, they should be promptly excised after diagnosis due to the risk of embolization, obstructive complications, and arrhythmias. mitral stenosis. As stated previously, dyspnea is also an anginal equivalent and may signal a myocardial ischemic episode. Many primary pulmonary disorders feature dyspnea as their cardinal symptom and should be evaluated simultaneously as the physiology of the heart and lungs are intimately related, and can have dramatic influences on each other. Patients typically describe palpitations as a “skipped beat” or “racing heart”. Depending on the clinical context, such as occasional premature atrial or ventricular beats in otherwise healthy individuals, these may be benign. Clinically significant arrhythmias, however, require thorough investigation. Atrial fibrillation is the most common arrhythmia and can occur alone or with concomitant cardiac pathologies. It results in an irregular, and at times, rapid heartbeat. Concurrent symptoms such as angina or lightheadedness/syncope are particularly worrisome for life threatening arrhythmias such as ventricular tachycardia or ventricular fibrillation, particularly in those with preexisting heart failure or ischemic heart disease. Syncope associated with heart disease results from abrupt reduction of cerebral perfusion. Many of the potential etiologies are serious, including sinus node dysfunction, atrioventricularconduction abnormalities, malignant arrhythmias, aortic stenosis, and hypertrophic obstructive cardiomyopathy. Any episode of syncope warrants a thorough evaluation and search for the root cause. 1 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 21-1 Table 21-2 New York Heart Association (NYHA) functional classification Canadian Cardiovascular Society (CCS) anginal classification Description I Physical activity not limited by symptoms: fatigue, palpitations, or dyspnea. II Comfortable at rest. Slight limitation of physical activity. Fatigue, palpitations, or dyspnea with ordinary physical activity. III Comfortable at rest. Marked limitation of physical activity. Fatigue, palpitations, or dyspnea with less than ordinary physical activity. IV Inability to carry out any physical activity. Symptoms may be present at rest and increase with activity. In addition to a thorough inquiry regarding the above symptoms, it is important to obtain details about the patients’ medical/surgical history, family history, social habits (with regards to alcohol and tobacco use), current medications, and a focused review of systems, including an assessment of the patients’ functional status and frailty. Specific attention should be directed to the patients’ comorbidities which not only sheds light on the patients’ general health, but also helps delineate the risks if the patient were to undergo surgery. A strong family history of coronary artery disease, myocardial infarction, hypertension, or diabetes is of particular importance as they increase the individuals’ risks. Functional Disability and Angina. With regard to heart failure, functional capacity is strongly correlated with mortality. The New York Heart Association (NYHA) functional classification is the most widely used classification system in categorizing patients based on their functional status (Table 21-1). The NYHA classification has become a basis by which to assess patient characteristics in many studies to compare patient populations. Although less commonly used, the Canadian Cardiovascular Society (CCS) angina classification is also used to incorporate anginal symptoms into the functional assessment for prognostic value (Table 21-2). Physical Examination The physical examination is an invaluable tool in directing further diagnostic studies and management of a patient with suspected heart disease. The astute clinician will detect subtle signs that may further characterize the underlying pathologic process. The general appearance of a patient is important in the clinical assessment. A pale, diaphoretic, and obviously uncomfortable patient is more likely to be in a clinically critical condition than one who is conversing comfortably with an unremarkable demeanor. In addition to basic vital signs, particular attention should be directed to the patients’ mental status and skin (color, temperature, diaphoresis) as these may be reflective of the general adequacy of perfusion. Overall frailty and dementia have also been shown to be predictors of operative and late mortality.2 Palpation of the precordium may demonstrate deviations in the point of maximal impulse indicative of ventricular Class Description I Ordinary physical activity (walking, climbing stairs) does not cause angina. Angina occurs with strenuous, rapid, or prolonged exertion during work or recreation. II Slight limitation of ordinary activity. Angina occurs with climbing stairs rapidly, walking uphill in the wind, under emotional stress, in the cold, or after meals. Walking more than 2 blocks or climbing one flight of stairs causes angina. III Marked limitation of ordinary physical activity (climbing a flight of stairs or walking 1 to 2 blocks at a normal pace). IV Inability to carry out any physical activity without discomfort. Angina may be present at rest. hypertrophy or parasternal heaves seen in right ventricular overload. Auscultation should be performed in a quiet environment as critical murmurs, rubs, or gallops may be subtle. Murmurs are characterized by their location, timing, quality, and radiation. They are typically secondary to valvular or other structural pathology and new findings require further investigation. A rub due to pericardial friction is specific and virtually pathognomonic for pericarditis. A third heart sound (S3) is generated by the rapid filling of a stiff ventricle and can be normal in young patients, but when present in older adults, is indicative of diastolic dysfunction and is pathologic. Increased contribution of the atrial pump function to ventricular filling may manifest as a fourth heart sound (S4) and is also suggestive of ventricular dysfunction. Palpation of peripheral pulses is important not only to assess the adequacy of perfusion, but the burden of coronary artery disease often correlates with the degree of peripheral arterial disease. Discovery of carotid stenosis by auscultation for carotid bruits has significant implications for operative planning. Heart disease will frequently have extracardiac manifestations and examination of the other organ systems should not be neglected. Auscultation of the lung fields may reveal rales in patients with pulmonary edema. The work of breathing may also be assessed simply by observing the patient. Jugular venous distention and hepatosplenomegaly are seen in right heart failure. Cardiac Risk Assessment in General Surgery Patients Approximately one half of the mortality in patients undergoing noncardiac surgery is due to complications which are cardiovascular in origin.3 The American College of Cardiology and American Heart Association have formed a joint task force to publish a consensus statement on guidelines and recommendations which was revised in 2007.4 The aim of these guidelines is to incorporate surgery-specific risks and patient characteristics to stratify patients in order to guide perioperative decisionmaking. Surgical procedures have been categorized based on cardiovascular risk into low and moderate risk, and vascular procedures. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease Class 737 738 UNIT II PART SPECIFIC CONSIDERATIONS Vascular procedures (aortic, peripheral vascular, and other major vascular surgery), likely due to both the nature of the procedures themselves as well as the associated cardiovascular pathology in many of these patients, carries the highest reported cardiac risk at more than 5%. Low risk procedures, including endoscopic procedures, superficial operations, cataract surgery, breast surgery, and ambulatory surgeries have a risk generally less than 1%. Intermediate risk procedures are: intraperitoneal and intrathoracic surgery, head and neck surgery, orthopedic procedures, and prostate surgery. Patient characteristics can be classified by the status of the patients’ cardiac disease, comorbid conditions, and functional capacity. Patients are considered to be at major perioperative clinical risk if they have one or more of the following active cardiac conditions: unstable coronary syndrome, decompensated heart failure, significant arrhythmias, or severe valvular heart disease. In these patients, intensive evaluation and treatment prior to surgery (unless emergent) is warranted, even if the noncardiac surgery needs to be delayed or cancelled. If the patient does not have any of the previously mentionedactive conditions, and is scheduled for a low risk surgery or if they have functional capacity greater than or equal to 4 metabolic equivalents (or METs), the official recommendation is to proceed with the planned operation. The previous guidelines contained intermediate and low cardiovascular risk profiles, but this has been replaced by cardiovascular risk factors in the update. These risk factors are: history of ischemic heart disease, history of prior or compensated heart failure, history of cerebrovascular disease, diabetes mellitus, and renal insufficiency. Based on the number of present risk factors and the surgery-specific risk, the guideline recommends pathways for further evaluation and risk management (Table 21-3). Diagnostic Studies Electrocardiogram and Chest X-ray. Electrocardiograms (ECGs) and chest X-rays are simple, noninvasive, and inexpensive diagnostic studies that are invaluable in the preoperative assessment of patients with cardiac pathology. ECGs can be useful in detecting old myocardial infarction, dilation or Table 21-3 Algorithm set forth by ACC/AHA guidelines for preoperative cardiovascular evaluation before noncardiac surgery for patients who are scheduled for nonemergent, nonlow risk surgery, no active cardiac disease, and less than 3 METs Number of Risk Factors* Recommendation 0 Proceed with planned surgery. 1–2 Control HR and proceed with planned surgery or pursue further testing if it will change management. 3–5 Pursue further testing if it will advance management. *Risk factors are: history of ischemic heart disease, history of prior or compensated heart failure, history of cerebrovascular disease, diabetes mellitus, and renal insufficiency. hypertrophy of cardiac chambers, arrhythmias, and conduction abnormalities. A stress ECG requires a patient to exercise to a target heart rate, and is used to help diagnose ischemic pathologies which may not be evident at rest. A plain film of the chest can detect pulmonary pathology, sequelae of heart failure (e.g., pulmonary edema, cardiac enlargement, pleural effusions) as well as hardware from previous procedures such as, prosthetic valves, sternal wires, pacemakers, and defibrillators. Echocardiography. Echocardiography utilizes reflected sound waves to image the heart, and is used widely due to its noninvasive nature and low cost. It is the primary diagnostic tool used to evaluate structural diseases of the heart, including: valvular pathology, septal defects, cardiomyopathies, and cardiac masses. Echocardiography is indispensable in assessing surgical prosthetics such as valves, leads, or mechanical circulatory support devices. These examinations can be performed with M-mode imaging (motion along a single line) as well as 2-D and 3-D imaging depending on the graphical information required. Doppler technology has become a standard addition to assess changes in flow patterns across both stenotic and regurgitant valves. Velocity measurements can be obtained to estimate pressure gradients across structures using the continuity equation. A common example would be the estimation of pulmonary arterial systolic pressure calculated from the regurgitant tricuspid jet profile during right ventricular systole. Transthoracic echocardiography (TTE) requires no sedation and is generally performed with the patient in a slight left lateral decubitus position. Standardized views are obtained with the ultrasound probe placed in the apical, parasternal, subcostal, and suprasternal positions. The apical four-chamber view is a useful window for visualizing all four cardiac chambers simultaneously as well as the tricuspid and mitral valves. Other windows can be obtained to assess specific structures such as the individual valve anatomy or myocardial wall segments. Dobutamine-stress echocardiography is a study similar in idea to the stress ECG which utilizes a pharmacologic agent to assess the patient for ischemia or stress-induced valvular abnormalities. A slightly invasive variant of this technology is transesophageal echocardiography (TEE) which takes advantage of the anatomic proximity of the heart to the esophagus. The exam is performed using a special endoscope with an ultrasound probe mounted on its end which is introduced orally into the esophagus under sedation. Posterior structures such as the mitral valve and left atrium are particularly well visualized. TEEs are frequently used intraoperatively during cardiothoracic surgery to assess global cardiac function, integrity of valve repairs and replacements, intracavitary thrombus and/or air, and aortic atherosclerosis or dissections which can have significant influences on operative strategy. There are some new additions to the echocardiographic armamentarium which capitalize on the strengths of ultrasound imaging. Three dimensional TEE is playing an increasing role in the preoperative and intraoperative evaluation of patients with valvular heart disease and is particularly useful in the valuation of mitral regurgitation. Tissue Doppler imaging is based on principles akin to conventional Doppler echocardiography, but attention is directed to the myocardium itself as opposed to the motion of blood to quantify abnormalities in wall motion. Strain imaging with speckle-tracking echocardiography measures the actual deformation of the myocardium by following VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ inhomogeneities inherent to the myocardium, and is a useful measure of myocardial function. Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) has a wide variety of uses in cardiac imaging depending on the pulse sequence and signal weighting. Cine-loop of the heart throughout the cardiac cycles can yield information on global chamber function and valvular pathologies. The differential response of normal and ischemic myocardium to certain pulse sequences allows imaging of myocardial perfusion using MRI. Use of contrast agents such as gadolinium can enhance scar tissue and are very useful in viability assessment. Myocardial strain imaging can also be performed using newer technologies taking advantage of radio-frequency tagging of the myocardium which deforms with the tissue and can be followed throughout the cardiac cycle. Cardiac Catheterization. Cardiac catheterization involves access to the cardiac chambers and great vessels with a peripherally inserted catheter under fluoroscopic guidance. It is a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 739 CHAPTER 21 Acquired Heart Disease Radionuclide Studies. Although ECGs are useful, inexpensive, and safe, baseline abnormalities in the ECG may limit its diagnostic capacity. In particular, ventricular rhythms, bundle-branch blocks, left ventricular hypertrophy, drug effects, and baseline ST-segment depressions can make stress ECGs uninterpretable. In this setting, myocardial perfusion imaging (MPI) using radionuclides can be utilized to assess myocardial ischemia. Thallium 201 (201Tl) was the initial radionuclide used for MPI, but due to its long half-life and relatively low photopeak, it has largely been replaced by Technetium-99m (sestamibi and tetrofosmin) which has more favorable characteristics. In the past, planar imaging with three separate two-dimensional views of the heart were obtained. Currently, it is more common to have the images acquired by single-photon emission computed tomography (SPECT) technology which detects emitted photons from 180- to 360-degrees around the patients. The signals are then processed to reconstruct multiple slices which together provide a three-dimensional view. The amount of uptake at both rest and stressed states are compared to assess ischemia and viability of the myocardium. The distribution of radionuclides depend on perfusion and therefore areas which show uptake at rest, but not during stress are concerning for ischemia. Territories that do not show uptake at rest or during stress are likely to be nonviable scar. The sensitivity and specificity of exercise SPECT are 90% and 70%, respectively.5 The image acquisition may also be gated to a simultaneously obtained ECG to assess global ventricular function. The endocardial and epicardial borders (as delineated by radionuclide uptake) are detected throughout the cardiac cycle and the ejection fraction, along with end-systolic and end-diastolic volumes, can be calculated. This study is also useful in revealing hypokinetic segments of the myocardium. One of the most significant weaknesses of SPECT imaging is that it shows regional ischemia well, but does not adequately detect global or “balanced” ischemia which can occur with diffuse CAD. Positron emission tomography (PET) scans have been used due to its ability to obtain absolute quantitative data on both myocardial perfusion and metabolism. Tracers used in PET scans can be divided into those that assess perfusion (Oxygen-15, Nitrogen-13, and Rubidiuim-82) and those that assess metabolism (Carbon-11 and Fluorine-18). The specificity of PET in detecting CAD is better than SPECT at 86% due to its superior spatial resolution.6 versatile tool used for diagnostic purposes of: cardiac chamber pressures, valvular abnormalities, wall motion assessment, and coronary artery anatomy. While some of these roles are being replaced by less invasive techniques mentioned previously, cardiac catheterization studies continue to be widely performed and is the gold standard for the assessment of coronary artery disease. A left-heart catheterization is performed by percutaneous access of the femoral, or less commonly, the radial artery. Under fluoroscopic guidance, the catheter is threaded into the aorta where a contrast aortogram may be performed. Coronary angiography requires manipulation of this catheter into the coronary ostia where contrast is directly injected. With advancement of the catheter retrograde past the aortic valve, left ventricular pressures can be obtained. This pressure is used to calculate pressure gradients across the aortic valve which becomes particularly important in the evaluation of aortic stenosis. Again, contrast injection will result in a ventriculogram used to estimate ejection fraction and visualize hypokinetic segments of the walls. Inappropriate retrograde leakage of contrast may indicate insufficiency of the aortic and/or mitral valves. Right heart catheterization is performed through a peripheral vein and the catheter is threaded into the right atrium. Rightsided pressures and structures are assessed in a similar fashion as in the left heart. Extension of the catheter into the pulmonary artery allows measurement of the pulmonary artery pressures as well as the pulmonary capillary wedge pressure (reflecting left ventricular end diastolic pressure) with an occlusive balloon. In addition to these measurements, cardiac output can be measured using thermodilution or by the Fick method using oxygen saturations of blood sampled from the various locations during the procedure. Coronary angiography provides information on hemodynamically significant stenoses in the coronary circulation as well as an anatomical roadmap for surgeons to planning revascularization. (Fig. 21-1A & B) A stenosis is considered to be significant if it narrows the lumen of the artery by 70% (or 50% in the case of left main coronary artery). There is some variability in the coronary arterial anatomy with the posterior descending artery being supplied by the right coronary artery in approximately 80% of patients (right dominant), or the left coronary artery in approximately 15% of patients (left dominant). The remaining patients have a codominant circulation where the posterior descending artery is supplied by both the right and left coronaries. An advantage of catheterization is that it offers an opportunity for interventional therapy of coronary artery disease, arrhythmias, valvular abnormalities, and other structural defects of the heart. Cardiac catheterization is generally safe, but being an invasive procedure, it is associated with complications. Overall mortality is 0.11%, and total rate of major complications, including: MI, stroke, arrhythmia, vascular injury, contrast reaction, hemodynamic instability, and cardiac perforation is usually <2%.7 Cardiac Computed Tomography. Multislice computed tomography (CT) imaging can be used to assess the coronary vasculature. The coronary calcium score is an index developed to quantify the degree of coronary atherosclerotic burden by measuring Hounsfield units in a noncontrast cardiac CT. Although this technique is quite sensitive for angiographic stenoses >50%, it remains fairly nonspecific as calcification often precedes significant luminal narrowing.8 CT coronary angiography using intravenous contrast is also utilized clinically to assess coronary pathology and is particularly useful in the emergency room to perform a “triple rule-out” for acute coronary events, asystole and hypothermia. The need for a bloodless operating field, while maintaining perfusion of heart and other organs, was evident. John Gibbon’s motivation to develop a means for extracorporeal perfusion came from a desire to safely open the pulmonary artery in a patient who suffered from a pulmonary embolus following cholecystectomy. After numerous experimental iterations, Gibbon’s cardiopulmonary bypass machine was first used clinically in 1953 to repair a large atrial septal defect in an 18-year-old female.10 Although Gibbon is credited for its invention, the development of modern cardiopulmonary bypass (CPB) is a culmination of the work of many investigators throughout the world. The early bubble oxygenators have evolved into the modern membrane oxygenators. The search for an ideal biocompatible material which minimizes the inflammatory cascade initiated by the contact of blood with the circuit components continues to this day. 740 UNIT II PART SPECIFIC CONSIDERATIONS Technique A B Figure 21-1. Cardiac catheterization angiography. A. Stenosis of right coronary artery indicated by the arrow. B. Still image of a normal left ventriculogram. pulmonary embolism, and aortic dissection in patients who present with undifferentiated chest pain. LV ejection fraction may be measured by this technique, and together with the degree of coronary stenoses, incremental prognostic value has been demonstrated in addition to routine clinical predictors.9 EXTRACORPOREAL PERFUSION History Prior to the development of extracorporeal perfusion, heart surgery was rarely performed and was limited to brief periods of The basic CPB circuit consists of the venous cannulae, a venous reservoir, pump, oxygenator, filter, and the arterial cannula. Anticoagulation is required during CPB, and 300 to 400 units/kg of heparin is given to increase the activated clotting time (ACT) to greater than 450 seconds. Once adequate anticoagulation is achieved, arterial cannulation is performed through a purse-string suture, or through a side graft which is sewn on to the native artery. The distal ascending aorta is the most common site of cannulation, but there may be concern for atheroembolization when the aorta is atherosclerotic. Other sites of cannulation include the femoral artery, axillary artery, or the distal aortic arch. Venous cannulation is performed through purse-string sutures placed on the right atrium either for a single cannula or for two separate cannulae extending into the superior and inferior vena cava, respectively. Alternatively, the venous cannula may be inserted from the femoral vein and advanced into the right atrium. Effective communication between the surgeon, the anesthesiologist, and the perfusionist is mandatory for effective cardiopulmonary bypass. Once the appropriate cannulations and connections are complete, CPB is commenced. Venous return is initiated followed by arterial flow while monitoring systemic blood pressures. At normothermia, the flow required is approximately 2.4 L/min/m2, but with hypothermia, oxygen consumption is reduced by 50% for every 10°C drop in temperature, and a flow of only 1L/min/m2 is required at 18°C. Once the heart is decompressed and hemodynamics are acceptable, ventilation is stopped. The oxygenator is adjusted to maintain a PaO2 of 150 mm Hg and normocarbia. Blood can also be filtered and returned through vents that are placed in the heart or through the cardiotomy suction used to aspirate blood from the surgical field. When the cardiac procedure is complete, the patient is rewarmed, the lungs ventilated, and the heart defibrillated if needed. The venous return to the CPB machine is gradually reduced allowing the heart to fill. The pump is also slowed while hemodynamics and global cardiac function are assessed with a TEE probe. Inotropic and vasopressor support may be used to augment cardiac function and treat hypotension. Once CPB has been stopped and stable hemodynamics achieved, the cannulae are removed. The heparin anticoagulation is reversed with protamine and hemostasis is achieved.11 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Adverse Effects Myocardial Protection CORONARY ARTERY DISEASE History The Vineberg operation, one of the initial attempts at surgical revascularization of the myocardium, was first performed in 1950s. This procedure involved implantation of the internal thoracic artery directly into the myocardium itself. While some patients were relieved of their anginal symptoms, this resulted in very little increase in coronary flow and was supplanted by methods to restore flow directly. Coronary endarterectomy was introduced by Longmire during this time period, but was met with high rates of restenosis and occlusion. The use of vein patches to repair the arteriotomy sites was described by Senning in 1961. The first saphenous vein coronary artery bypass grafting (CABG) was performed by Sabiston in 1962, but was popularized by Favalaro in 1967. In 1968, the internal thoracic artery was introduced as a bypass conduit by Green who used it to bypass the left anterior descending coronary artery.15 Etiology and Pathogenesis Atherosclerotic stenoses are the primary mechanism of coronary artery disease (CAD). The pathophysiologic process is initiated with vascular endothelial injury and is potentiated by inflammatory mechanisms, circulating lipids, toxins, and other vasoactive agents in the blood. Macrophages and platelets are attracted to this area of endothelial dysfunction inciting a local inflammatory response. During this process, macrophages infiltrate into the intimal layers and accumulate cholesterol-containing lowdensity lipoproteins. The growth factors secreted promote proliferation of smooth muscle cells within the intima and media of the arteries. Together with the accumulation of the lipid-laden macrophages, the smooth muscle hyperplasia results in an atheroma and subsequently stenosis of the vessel. These atheromas have a fibrous cap which may rupture, exposing the underlying cells and extracellular matrix which are very prothrombotic. Acute plaque rupture and thrombus formation is thought to be the main pathophysiologic mechanism responsible for acute coronary syndromes.16-18 Risk Factors and Prevention During CPB, pharmacologic agents in cardioplegic solutions may be delivered into the coronary circulation to arrest the heart allowing for a still operating target and improved myocardial protection. The most common cardioplegia consists of potassium-rich solutions that can be mixed with autologous blood and are delivered into the coronary circulation. Antegrade cardioplegia is delivered into the root of a cross-clamped aorta or directly into the individual coronary ostial via specialized catheters. A retrograde cardioplegia catheter is a balloon-cuffed Prior to the establishment of modern management strategies, the annual mortality rated from ischemic heart disease was quoted to be around 4% by the Framingham study. Since then, risk factor modification along with use of medications, such as aspirin and β-blockers, has dramatically improved survival. The major risk factors of atherosclerosis include: age, cigarette smoking, hypertension, dyslipidemias, sedentary lifestyles, obesity, and diabetes. Likely due to increased public awareness and aggressive medical management, these risk factors (with the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 741 CHAPTER 21 Acquired Heart Disease Cardiopulmonary bypass has a number of deleterious effects as various intertwining processes result in derangements in hemostasis, systemic inflammatory response, and end-organ function. Anticoagulation prior to the commencement of CPB is required as contact of blood with the artificial surfaces of the circuit can initiate a thrombogenic cascade. Generation of thrombin plays a major role in both thrombotic and bleeding phenomena during CPB. The endothelium which normally regulates the fine balance between procoagulant and anticoagulant pathways is perturbed. Fibrinogen is consumed rapidly as thrombin converts fibrinogen to fibrin while fibrinolytic mechanisms (initiated by the activated endothelium) degrade the fibrin macromolecules. Platelets are activated by the converging hemostatic pathways and are consumed. The response of the humoral and cellular immune systems partly overlap with the hemostatic pathways. The classic and alternative complement pathways are activated by CPB generating powerful chemotaxic molecules and anaphylatoxins. Monocytes, platelets, and neutrophils are activated releasing acute inflammatory mediators and cytokines which persist even after conclusion of CPB.12 These inflammatory cells also produce reactive oxidants which may have cytotoxic effects. The large quantity of unfractionated heparin used during cardiac surgery predisposes patients to developing heparin induced thrombocytopenia (HIT) with an incidence of 1% to 2%. Platelet factor-4 (PF4) is produced by platelets and avidly binds to heparin to form a heparin-PF4 complex which can be antigenic in some patients binding IgG. The IgG-heparin-PF4 complex can bind to platelets which causes release of more PF4, perpetuating the process. The earliest sign is a sudden drop of more than 50% of the platelet count, and HIT can be confirmed with an ELISA or serotonin release assay. Of the patients with HIT, 20% to 50% of patients develop thromboses in arterial or venous beds, designated as heparin induced thrombocytopenia and thrombosis (HITT), which can be life-threatening.13 The etiology of end-organ dysfunction resulting from extracorporeal circulation can mostly be categorized into one of three mechanisms. Although cardiac output and blood pressure are monitored carefully during CPB, they are surrogates for regional perfusion and cannot detect end-organ hypoperfusion directly. This can be a problem particularly with the cerebral, renal, and mesenteric circulations. With manipulation of diseased vessels and dysregulation of the native coagulation system, macroscopic and microscopic emboli are a concern despite various strategies to minimize this problem. Activated cells and circulating cytotoxic products of the immune response may cause microvascular injury and edema of other organs manifesting as neurocognitive deficits, respiratory failure, and renal injury.14 catheter that is placed through the right atrium into the coronary sinus and is used to perfuse the coronary circulation in the opposite direction through the venous circulation. This has the advantage of more uniform distribution in patients with diffuse coronary artery disease and is not dependent on a competent aortic valve for delivery. There are controversies regarding the method (antegrade retrograde vs. both), type (crystalloid vs. blood), temperature (cold vs. warm vs. tepid), and interval (continuous vs. intermittent) of cardioplegia delivery. The optimal combination is beyond the scope of this text. However, most surgeons in the United States favor cold blood potassium cardioplegia. 742 UNIT II PART exception of glucose intolerance and obesity) have recently been on the decline. Current guidelines outlined in the AHA/ACC consensus statement summarizes secondary prevention recommendations. Class I recommendations are: smoking cessation and avoidance of environmental tobacco exposure, blood pressure control to under 140/90 mm Hg (under 130/80 mm Hg in those with diabetes or chronic kidney disease), LDL cholesterol levels less than 100 mg/dL, aspirin therapy in all patients without contraindications, BMI target of less than 25 kg/m2, diabetes management with target HbA1c <7%, and encouragement of daily aerobic exercise routines. Beta-blockers are to be considered in patients with LV dysfunction and following MI or ACS. Renin-angiogensin-aldosterone system blockade in patients with hypertension, LV dysfunction, diabetes, or chronic kidney disease should also be considered.19 SPECIFIC CONSIDERATIONS Clinical Manifestations Patients with CAD may have a spectrum of presentations, including angina pectoris, myocardial infarction, ischemic heart failure, arrhythmias, and sudden death. Angina pectoris is the pain or discomfort caused by myocardial ischemia and is typically substernal and may radiate to the left upper extremity, left neck, or epigastrium. The variety of presentations can make myocardial ischemia difficult to diagnose. Characteristics of chest pain that make myocardial ischemia less likely include: pleuritic chest pain, pain reproducible by movement or palpation, or brief episodes lasting only seconds. Typical angina is relieved by rest and/or use of sublingual nitroglycerin. Differential diagnoses to be considered include, but are not limited to: musculoskeletal pain, pulmonary disorders, esophageal spasm, pericarditis, aortic dissection, gastroesophageal reflux, neuropathic pain, and anxiety. Myocardial infarction is a serious consequence of CAD occurring when ischemia results in myocardial necrosis. This may be silent and need not be preceded by angina. Necrosis may result in disruption of the myocardial integrity leading to devastating conditions such as intracardiac shunts from ventricular septal defects, acute valvular regurgitation from rupture of necrotic papillary muscles, and cardiac aneurysms which have the catastrophic potential to rupture. The ischemic insults from CAD may lead to congestive heart failure. The initial myocardial damage sets off a cascade of responses, both local and systemic. Over time, these changes can cause deleterious myocardial loading and abnormal neurohumoral responses that result in pathologic remodeling of the heart. Heart failure should be suspected in patients who present dyspnea, orthopnea, fatigue, and edema. Arrhythmias may also be a sequela of CAD. Ischemic etiologies should be investigated in patients who present with new arrhythmias. CAD may result in arrhythmias following an acute MI or as the result of ultrastructural and electrophysiologic remodeling secondary to chronic ischemic heart disease. Ischemia of the electrical conduction system may be seen as the new onset complete or partial atrioventricular conduction blocks. Preoperative Evaluation A focused history and physical examination is essential with particular attention directed to the signs, symptoms, and clinical manifestations mentioned previously. The patient’s functional status is of importance not only because it is a component of preoperative risk assessment, but also because quality of life improvement and symptomatic relief are both goals of surgical therapy. Coronary angiography is the primary diagnostic tool. The coronary anatomy and degrees of stenoses are delineated allowing for planning of surgical revascularization. Noninvasive diagnostic studies, in combination with provocative maneuvers (exercise or pharmacologic agents) offer information regarding the functional significance of ischemic disease. A stress ECG is frequently used as a screening tool with a high sensitivity. The positive predict value is 90% in patients with ST-segment depression >1mm. This test however, requires patients to achieve a certain elevation in their heart rate, and is therefore not suitable for those that cannot achieve this goal. Furthermore, baseline ECG abnormalities may render it impossible to detect typical ischemic changes with stress. Echocardiography and nuclear imaging may be performed under pharmacologic stress (with dobutamine or dipyridamole) to assess reversible ischemia and myocardial viability. Technetium99m or thallium-201 perfusion scans have an average sensitivity and specificity of 90% and 75%, respectively. Stress echocardiography has a similar sensitivity and specificity of approximately 85%.20 These studies also have the ability to assess global ventricular function in terms of LV ejection fraction which can be used to determine operative risk. CORONARY ARTERY BYPASS GRAFTING Indications A joint committee established by the American College of Cardiology and the American Heart Association have published guidelines for surgical revascularization (CABG) in CAD. The indications, categorized by presentation and angiographic disease burden as well as by treatment intention (survival improvement and symptom relief), are summarized later (Tables 21-4,5,6).21 Percutaneous Coronary Intervention vs. Coronary Artery Bypass Grafting In recent years, there have been multiple prospective randomized, controlled trials as well as retrospective studies looking at the comparative effectiveness of percutaneous coronary interventions (PCI) and CABG. Some of the representative studies are summarized here. The New York State Study (2005). A retrospective review of 59,314 patients in two of New York’s registry with multivessel (2 or more) coronary disease was performed. Of these, 37,212 patients received a CABG and the others underwent a PCI. After adjusting by means of proportional-hazards methods, CABG was associated with higher adjusted rates of long-term survival than PCI.22 Stent or Surgery Trial (2008). An international multicenter randomized controlled trial of 988 patients (n = 488 PCI, n = 500 CABG) with multivessel CAD was performed to compare revascularization strategies. At 2-year median follow-up, the PCI group had significantly higher rates of repeat revascularizations and mortality compared to the CABG group (incidence of nonfatal Q-wave myocardial infarctions were similar in both groups). The median follow-up was extended to 6-years, and a survival advantage persisted in the CABG group over the PCI group.23 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 743 Table 21-4 Data from ACC/AHA guidelines for CABG in CAD to improve survival Class of Recommendation Level of Evidence • LM I B • 3-vessel +/− proximal LAD I B • 2-vessel + proximal LAD I B • 2-vessel – proximal LAD IIa – with extensive ischemia IIb – without extensive ischemia B C • Multivessel disease with DM IIa (CABG preferred over PCI) B • Proximal LAD only IIa – with LITA for long-term benefit B • 1-vessel – proximal LAD III – Harm B • LV dysfunction IIa – LVEF 35%–50% IIb – LVEF <35% without LM disease B B • Survivor of ischemia-mediated VT I B DM = Diabetes mellitus; LITA = Left internal thoracic/mammary artery; LM = Left main coronary artery; LV = left ventricle; VT = ventricular tachycardia. Class of recommendation: I – Benefit far outweighs risks and procedure should be performed; IIa – Benefit outweighs risks and procedure is considered to be reasonable; IIb – Potential benefits may exceed risks and procedure may be considered; III – Procedure not helpful and may cause harm. Level of evidence: A – Strong; multiple supporting randomized controlled trials or meta-analyses, B – Limited; data based on a single randomized trial or nonrandomized trials, C – Very limited; based on expert consensus, case studies or standards of care. Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX Trial, 2009). Revascularization strategies, CABG vs. PCI, were compared in a 1:1 randomized prospective trial of 1800 patients with high risk coronary artery disease (left-main or triple-vessel disease). Rates of requirement for repeat revascularization and major adverse cardiac or cerebrovascular events at 12-months were lower in the CABG patients (5.9% and 12.4%, respectively) compared to PCI patients (13.5% and 17.8%, respectively). No difference in mortality was seen between the groups at 12-months.24 The ACCF and STS Database Collaboration on the Comparative Effectiveness of Revascularization Strategies (ASCERT Study, 2012). This study, performed by collaboration of the American College of Cardiology Foundation and the Society of Thoracic Surgeons, reviewed their respective national databases of patients over the age of 65 who had multivessel coronary disease (excluding those with left main disease). CABG was performed on 86,244 patients and 103,549 underwent PCI. There was no difference in adjusted mortality at 1 year, but there was a significantly lower mortality with CABG than PCI at 4 years.25 Summary PCI technology has improved over time and rates of periprocedural adverse events have decreased significantly. Management strategies must be tailored to the individual patient’s 1 clinical status and context, but CABG maintains improved long-term outcome and remains the standard of care for leftmain and multivessel coronary artery disease. Operative Techniques and Results Bypass Conduit Selection. The most important criterion in conduit selection is graft patency. The conduit with the highest patency rate (98% at 5 years and 85%–90% at 10 years) is the internal thoracic artery which is most commonly left attached proximally to the subclavian artery (although occasionally used as a free graft) and anastomosed distally to the Table 21-5 Data from ACC/AHA guidelines for CABG in CAD to improve symptoms Anatomy Associated Symptoms Class of Recommendation Level of Evidence • U  nacceptable angina with presence of ≥1 stenoses amenable to revascularization despite medical treatment I A • Complex 3-vessel CAD +/- proximal LAD involvement IIa (CABG preferred over PCI) B • U  nacceptable angina with presence of ≥1 stenoses amenable to revascularization but medical treatment is not possible IIa C • P  revious CABG with ≥1 stenoses associated with ischemia and angina despite medical treatment IIb C VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease Anatomy 744 Table 21-6 Data from ACC/AHA guidelines for CABG in CAD in specific clinical contexts Clinical Setting Class of Recommendation Level of Evidence I B I B I I B C IIa B IIa B III – Harm C Emergent CABG following acute MI UNIT II PART SPECIFIC CONSIDERATIONS • F  ailure or inability to perform PCI, anatomy suitable for CABG, persistent ischemia/ hemodynamic instability refractory to nonsurgical therapy • Patients undergoing surgical repair of postinfarction complication (e.g.,VSD, papillary or free wall rupture) • Cardiogenic shock with anatomy suitable for CABG • Life-threatening ventricular arrhythmia, ischemic in origin, with 3-vessel disease or >50% LM stenosis • Multivessel disease, recurrent angina or MI within 48 hrs of STEMI (instead of a more delayed strategy) • Age >75 with ST-elevation or new left bundle branch block who are suitable for revascularization, regardless of time between MI and cardiogenic shock. • Persistent angina with only small area of viable myocardium Survival from sudden cardiac death or sustained VT • I f thought to be due to significant CAD (amenable to revascularization). • If only scar present, and no evidence of ischemia I III- Harm B C Patients undergoing concomitant non-coronary cardiac surgery • I n presence of significant CAD (>50% LM stenosis or >70% stenosis of another major coronary artery. • LITA graft to significantly narrowed LAD or CABG of moderately diseased (>50% stenosis) coronary artery. I C IIa C I B IIa C III – Harm C Emergent CABG after failed PCI • O  ngoing ischemia, threatened occlusion with substantial myocardium at risk, or hemodynamic compromise (without coagulopathy or previous sternotomy). • Retrieval of foreign bodies (from PCI) or hemodynamic compromise with coagulopathy and without previous sternotomy. • Absence of ischemia or threatened occlusion LM = Left Main; VT = ventricular tachycardia. target coronary artery.26,27 The use of both internal thoracic arteries has been shown to increase event-free survival in a number of studies.28,29 The greater saphenous vein can be harvested using an open or endoscopic technique. In the open technique, the initial incision is made along the course of the vein on the medial aspect of the lower extremity. The vein is harvested with meticulous attention directed towards minimizing manipulation of the vein itself. The incision may be continuous or bridged in an attempt to decrease the size of the incision, but multiple bridged incisions may have the potential risk of increased conduit manipulation during harvest. Endoscopic harvest is performed by making a small incision just above and medial to the knee where the endoscope is inserted. Side branches are cauterized under endoscopic visualization using bipolar electrocautery until dissection is carried proximally until the required length of vein is mobilized. A proximal counterincision is then made to extract the venous conduit which is prepared in the standard fashion. The radial artery is another frequently used conduit. After confirmation of ulnar collateral flow to the hand by the clinical Allen’s test or a duplex ultrasound study, an incision is made from a point just proximal to the radial styloid process ending just medial and distal to the biceps tendon on the nondominant hand. With lateral retraction of the brachioradialis muscle, the radial artery is dissected sharply with care to avoid injury to the cutaneous nerves in this area and minimize manipulation of the artery itself. This artery can also be harvested using an endoscopic technique. Many studies have looked at the patency rates of the radial artery graft in comparison to the saphenous vein graft. Although some studies have resulted in equivocal data, general consensus favors the use of radial arterial grafts over vein grafts with 5 year patency rates of 98% and 86%, respectively.30,31 From a historical perspective, the anterior circulation (left main or left anterior descending artery) is generally bypassed using the internal thoracic artery and the lateral (circumflex artery) or inferior (right coronary artery) territories are bypassed using a saphenous vein or radial artery graft. These conduits may be combined to form a composite T- or Y-graft, or sewn to multiple targets as sequential grafts. Since patency is best with arterial grafts, recent data havesuggested that the best long term results are achieved with multiple or all-arterial revascularization, particularly in patients >70 years of age.32,33 Other conduits such as the gastroepiploic arteries, lesser saphenous veins, and cephalic veins have been described, but are not widely used and will not be discussed here. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Conventional Coronary Artery Bypass Grafting. Traditionally, CABGs are performed with the patient lying supine through a median sternotomy. After the patient is heparinized, cardiopulmonary bypass is initiated. The aorta is cross-clamped and cardioplegia is delivered. Once adequate myocardial protection has been achieved, coronary arteriotomies are made and distal anastomoses are performed using Prolene suture. (Fig. 21-2A & B) The proximal anastomoses are then performed directly onto the ascending aorta or onto preexisting grafts. It Conventional CABG Results Several early randomized trials have shown improved survival in patients who receive a CABG as opposed to medical therapy.34-36 A propensitymatched study identified that CABG greatly benefited patients with LV dysfunction and left main stenosis >50% compared to medical management.37 The Bypass Angioplasty Revascularization Investigation (BARI) trial demonstrated impressively superior results with CABG compared to PCI in terms of 5-year cardiac mortality (5.8% vs. 20.6%) in patients with diabetes in addition to CAD.38 In a study examining the benefits of CABG over medical management for specific CAD distributions, survival was better in patients with proximal LAD stenoses, regardless of the number of diseased vessels.39 In general, these studies show survival rates of over 90% at 5 years and approximately 75% at 10 years following CABG. The mortality and morbidity of the procedure itself has changed over time. Data from the Society of Thoracic Surgeons (STS) database accounts for 1,497,254 patients who underwent a solitary CABG from 2000 to 2009. The mortality rate of CABGs have improved significantly from 2.4% in 2000 to 1.9% in 2009 despite the relatively constant predicted mortality rate of around 2.3%. In parallel with this, postoperative complication rates have decreased as: stroke (1.6%–1.2%), bleeding requiring reoperation (2.4%–2.2%), and deep sternal wound infection (0.59%–0.37%).40 There are marked improvements in the functional status of patients receiving CABG. Patients’ 6-minute walk test distances were significantly increased 2 years postoperatively compared to their preoperative assessment.41 After 10 years, 54% of patients were free of chest pain and 31% were free of dyspnea.42 2 A B Figure 21-2. Coronary artery bypass grafting. A. Intraoperative photograph of the distal anastomoses performed between the left internal thoracic artery and left anterior descending coronary artery with a continuous 8-0 suture. B. Fifteen-year follow-up coronary angiogram of a left internal thoracic artery to left anterior descending coronary artery bypass demonstrating a widely patent free of any significant atherosclerotic stenosis. Anastomotic site is shown by the arrow. Off-pump Coronary Artery Bypass. To avoid the adverse consequences of cardiopulmonary bypass, off-pump coronary artery bypass (OPCAB) was developed and has been adopted in some centers over the past two decades. With OPCAB the heart is left beating. Performing anastomoses on the beating heart requires the use of myocardial stabilization devices which help portions of the epicardial surface to remain relatively immobile while the anastomoses are being performed. (Fig. 21-3) Carbon dioxide blower-misters are also used to clear blood from the operative site and improve visualization. Apical suction devices are used to aid in exposure, particularly of the lateral and inferior vessels. Many creative maneuvers have been developed, including patient repositioning, opening the right pleural space to allow for cardiac displacement, and creation of a pericardial cradle to minimize compromise of cardiac function while exposing the various surfaces of the heart. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 745 CHAPTER 21 Acquired Heart Disease is important to note that significant coronary stenoses can cause differential distribution of cardioplegia and myocardial protection. It is therefore recommended to use retrograde cardioplegia or to revascularize the area with the most concern for ischemia first, and give cardioplegia down the completed graft. The left internal thoracic artery to left anterior descending (LAD) graft is frequently performed last to avoid kinking or disruption of this important bypass. Once all grafts are in place, the patient is weaned from bypass. During this time, the heart is monitored closely by direct visual inspection, and transesophageal echocardiography to detect abnormalities which may signify inadequate revascularization or technical problems with the bypasses. Upon confirmation of hemostasis, chest tubes are placed, the sternum is approximated with sternal wires, and the incisions are closed. 746 UNIT II PART SPECIFIC CONSIDERATIONS Figure 21-3. Epicardial stabilizing device used during off-pump coronary anastomosis. (Reproduced with permission from Estech.) Temporary proximal occlusion of the coronary artery being grafted is necessary to provide a bloodless target. This occlusion causes temporary ischemia, and if not tolerated, coronary shunts can be employed. OPCAB Results The superiority of OPCAB over on-pump remains a controversy despite the large body of 3 CABG literature on this topic. A pooled analysis of two randomized trials, the Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 & 2), is one of several studies that have touted lower short term mortality rates with the off-pump compared to the on-pump technique.43-45 Other studies, however, have demonstrated equivocal or contrary results.46,47 Furthermore, the recent prospective and much larger ROOBY (Randomized On/Off Bypass) trial showed increased rates of adverse cardiac events with OPCAB compared to conventional CABG.48 Despite the initial enthusiasm for the theoretical advantages of avoiding cardiopulmonary bypass, consistent benefits in clinical outcome have not been observed. There does seem to be a more or less uniform trend towards decreased perioperative blood product transfusions with OPCAB compared to on-pump CABG. In terms of other measures of early outcome, postoperative renal failure, stroke, and acute MI, the superiority of OPCAB has been unclear.47,49,50 There have been questions whether the technical challenge of sewing on a beating heart leads to increased rates of graft occlusion following an OPCAB. The higher cardiac morbidity in the ROOBY trial was associated with decreased 1-year angiographic patency rates.48 However, studies with contrasting findings exist, quoting equivalent rates of graft patency for OPCAB usage.51,52 The broad variety in results may be suggestive that other factors (e.g.,surgeon skill, technical difficulty, patient factors) may be dominating the outcome rather than the use or avoidance of cardiopulmonary bypass.53 After almost two decades, OPCAB has not been widely adopted and remains less than 2% of all CABG procedures in the United States. Minimally Invasive Direct Coronary Artery Bypass. As an extension of the off-pump coronary revascularization technique, minimally invasive direct coronary artery bypass (MIDCAB) has been described. MIDCAB is performed using a left anterior mini-thoracotomy through which mobilization of the left internal thoracic and direct in situ anastomosis to the left anterior descending artery (or its diagonal branches) is performed. This technique is primarily applicable to single-vessel disease, although reports of multivessel revascularizations do exist. MIDCAB Results A review of 411 patients undergoing MIDCAB quotes an operative mortality >1%. In this study, all patients received revascularization of the LAD only, regardless of the number of diseased vessels. The 3-year mortality in patients with single-vessel disease following a MIDCAB was 3.1%, which was, not surprisingly, lower than those with multivessel disease (8.7%).54 There is an inherent selection bias in retrospective reviews comparing MIDCAB to OPCAB or conventional CABG as MIDCAB patients tend to have less extensive disease. Because of this, there have been multiple randomized controlled trials looking at the efficacy of MIDCAB compared to PCI. A metaanalysis of 5 randomized prospective trials comparing PCI to MIDCAB revascularization of isolated proximal left anterior descending artery demonstrated comparable results in terms of mortality, MI, and repeat revascularization requirement. It is worth noting however, that only one of these trials used drugeluting stents (DES) in the PCI arm.55 Hong et al showed similar efficacy with MIDCAB and DES PCI, and when this study was excluded from the meta-analysis, superiority of MIDCAB to PCI in regards to mortality, MI, and repeat revascularizations was seen.56 Although no further prospective trials have been performed to compare DES PCI and MIDCAB in this patient cohort, a retrospective review of 186 patients has demonstrated significantly higher rates of angina recurrence and major adverse cardiac events in the DES PCI group.57 Total Endoscopic Coronary Artery Bypass. With the advent of robotic surgical technology allowing stereoscopic visualization and increased instrument dexterity, total endoscopic coronary artery bypass (TECAB) has become possible. In July of 2004, the da Vinci robotic surgical system received FDA approval for use in coronary anastomoses. Extracorporeal circulation with peripheral cannulation has been used in earlier reports, but the development of mechanical stabilizers has provided the ability to perform the internal thoracic artery harvest and coronary anastomosis off-pump with use of the robotic arms only. Several studies have looked at the feasibility of TECAB, and have shown acceptable results, but this procedure has not been adopted by most surgeons due to its steep learning curve, longer operative times, and lack of demonstrable clinical benefit.58-60 Hybrid Coronary Revascularization. With the continually increasing collaboration between cardiothoracic surgeons and interventional cardiologists, hybrid coronary revascularization (HCR) combining a minimally invasive surgical technique (MIDCAB or TECAB) with PCI has become a reality. This capitalizes on a major advantage of both treatments, utilizing the durable left internal thoracic artery to left anterior descending coronary artery bypass while treating other stenoses with PCI obviating the need for a large surgical incision or cardiopulmonary bypass. HCR is not without its downsides as there are some concerns with this approach since aggressive anti-platelet therapy is required with PCI and may increase the hemorrhagic complications of surgical revascularization. A small study comparing HCR to OPCAB showed comparable graft patency and decreased hospital stay with HCR without an increase in complication rates.61 There are, however, some studies that have reported increased rates of requirement for re-intervention VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ in patients undergoing HCR, and this aspect requires further study.62,63 These procedures have not gained widespread acceptance and their clinical value remains a matter of debate. New Developments Regenerative Medicine and Tissue Engineering. Provocative investigations are being performed on the level of signaling molecules, gene therapy, stem cells, and tissue engineering to regenerate or replace damaged tissue in patients with ischemic heart disease. Growth factors, such as FGF and VEGF, are receiving focused attention due their ability to induce ingrowth of new vessels. Although concerns regarding systemic administration of these pleiotropic signaling molecules exist, early placebo-controlled clinical trials have shown some promising results with administration of these agents.67,68 Adenoviral transfection of diseased tissue with transgenes for these same growth factors has also been attempted with variable results. Research in tissue engineering has been directed at creation of vascular conduits that are resistant to atherosclerosis. Stem cells have also been infused directly into the site of injury or in the generation of new tissue around a biodegradable scaffold. Despite their potential, these technologies are still in their infancy and significant progress will be needed before more widespread clinical adoption. VALVULAR HEART DISEASE General Principles The number of patients referred for the surgical management of valvular heart disease has increased substantially in recent years, with the percentage of isolated valve procedures performed in the United States increasing from 14% of all cardiac operations in 1996, to 22% in 2006.69 In 2012, valve procedures represented over 50% of the cases performed at our institution. Although congenital and inherited etiologies represent important Surgical Options Although valve repair is increasingly indicated, especially in patients with aortic, mitral or tricuspid insufficiency, valve replacement may be necessary in certain patient populations. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 747 CHAPTER 21 Acquired Heart Disease Transmyocardial Laser Revascularization. Despite the advancement of technology and revascularization strategies, patients with end-stage coronary artery disease may not be amenable to complete revascularization. Transmyocardial laser revascularization (TMR) relies on a CO2 or holmium:yttriumaluminum-garnet (Ho:YAG) laser to create multiple transmural channels (1mm in diameter) through the myocardium. The initial concept was that these channels would serve as conduits for direct perfusion from the ventricle, but evidence suggests that the resultant angiogenesis is primarily responsible for the improved perfusion. A meta-analysis of seven randomized controlled trials comparing TMR to medical therapy for chronic angina have shown higher rates of angina improvement in the TMR but was not able to show a difference in mortality between the two groups.64 TMR is also being used as an adjunct to CABG in the treatment of extensive CAD that is not amenable to surgical revascularization alone. In a study looking at the benefits of TMR in addition to CABG, Allen et al concluded that TMR decreases angina burden when added to CABG in patients who cannot be revascularized by CABG alone.65 The current STS guidelines support the consideration of TMR in patients with ischemic myocardial territories that cannot be revascularized by PCI or CABG.66 Because of equivocal late results at most centers, this therapeutic strategy has not gained widespread acceptance. clinical entities, age-associated and acquired conditions still represent the primary causes of valvular heart disease, and are the focus of this section. The most common screening method for valvular heart disease is cardiac auscultation, with murmurs classified based primarily on their timing in the cardiac cycle, but also on their configuration, location and radiation, pitch, intensity and duration (Table 21-7).70 Although some systolic murmurs are related to normal physiologic increases in blood flow, some may indicate cardiac disease, such as valvular aortic stenosis (AS), that are important to diagnose, even when asymptomatic. Diastolic and continuous murmurs, on the other hand, are frequently pathologic in nature. Dynamic cardiac auscultation provides further evidence as to the significance and origin of many murmurs (Table 21-8).70 Although auscultation may provide initial evidence to the existence of valvular disease, associated signs and symptoms may help narrow the diagnosis. Abnormalities in the splitting of the heart sounds and additional heart sounds should be noted, as should the presence of pulmonary rales. Peripheral pulses should be checked for abnormal intensity or timing, and the presence of a jugular venous wave should be documented. Additionally, symptoms of syncope, angina pectoris, heart failure, and peripheral thromboembolism are important and may help guide diagnosis and management. Several imaging examinations are also available to aid in the diagnosis and classification of various valvular disorders. Electrocardiograms (EKGs) are widely available, and may provide information regarding ventricular hypertrophy, atrial enlargement, arrhythmias, conduction abnormalities, prior myocardial infarction, and evidence of active ischemia that would prompt further workup. Posteroanterior and lateral chest X-rays are also easy to obtain, and may yield information regarding cardiac chamber size, pulmonary blood flow, pulmonary and systemic venous pressure, and cardiac calcifications. The gold standard for the evaluation of valvular heart disease is transthoracic echocardiography (TTE). Although helpful in the noninvasive evaluation of valve morphology and function, chamber size, wall thickness, ventricular function, pulmonary and hepatic vein flow, and pulmonary artery pressures, TTE may be unnecessary for some patients with asymptomatic cardiac murmurs. Current recommendations for evaluation via TTE are listed in Table 21-9.70 Specialized examinations based on the specific findings of TTE examinations are discussed as appropriate in the following sections. Regardless of the etiology, valvular heart disease can produce a myriad of hemodynamic derangements. Left untreated, valvular stenosis and insufficiency can produce significant pressure and volume overload on the affected cardiac chamber, respectively, with mixed disease consequently causing mixed pathology. Although the heart can initially compensate for alterations in cardiac physiology, cardiac function eventually deteriorates, leading to heart failure, decreasing patient functional status, ventricular dysfunction, and eventually death. In order to optimize long-term survival, surgery is recommended in various forms of valvular heart disease, and in an increasing number of elderly and high-risk patients. 748 Table 21-7 Classification of cardiac murmurs. Murmur Condition Mechanism/Etiology Systolic murmurs UNIT II PART Holosystolic (pansystolic) VSD Flow between chambers that have widely different pressures throughout systole Mid-systolic (systolic ejection) High flow rate, MS, MR, TS, TI Often crescendo-decrescendo in configuration; occur as blood is ejected into the left and right ventricular outflow tracts Early systolic Early TI, acute MR Less common Mid to late systolic MR, MVP Soft to moderate high-pitched murmurs at the LV apex; often due to apical tethering and malcoaptation of MV leaflets; an associated click indicates prolapse of the MV leaflets SPECIFIC CONSIDERATIONS Diastolic murmurs Early high-pitched AI, PR Generally decrescendo in configuration; occur when the associated ventricular pressure drops sufficiently below that of the outflow tract Mid-diastolic MS, TS, PDA*, VSD*, Due to a relative disproportion between valve orifice size and diastolic ASD* blood flow volume; seen in normal MV and TV with increased diastolic blood flow associated with these conditions* Presystolic MS, TS Occur during the period of ventricular filling that follows atrial contraction (i.e.,only occur in sinus rhythm) Continuous murmurs Systolic and diastolic PDA Uncommon, due to shunts that persist through the end of systole and the some or all of diastole AI = aortic insufficiency; ASD = atrial septal defect; MR = mitral regurgitation; MS = mitral stenosis. MVP = mitral valve prolapse; PDA = patent ductusarteriosus; PR = pulmonic regurgitation; TI = tricuspid insufficiency; TS = tricuspid stenosis; VSD = ventricular septal defect. Table 21-8 Hemodynamic alterations in cardiac murmur intensity. Intervention Effect Respiration Right-sided murmurs increase with inspiration. Left-sided murmurs increase with expiration. Valsalva maneuver Most murmurs decrease in length and intensity. The murmur of HCM becomes louder, and the murmur of MVP becomes louder and longer. Exercise Benign flow murmurs and murmurs caused by stenotic valves become louder with isotonic and isometric exercise. The murmurs of MR, VSD, and AI also increase with isometric exercise. Positional changes Most murmurs decrease with standing; the murmur of HCM becomes louder, and the murmur of MVP becomes louder and longer. Brisk squatting and passive leg raising increases most murmurs; the murmurs of HCM and MVP diminish. Postventricular premature beat or atrial fibrillation Benign flow murmurs and stenosis at the semilunar valves increase in intensity following a ventricular premature beat or a long cycle length in atrial fibrillation. Systolic murmurs of atrioventricular valve regurgitation do not change. Pharmacologic interventions The initial hypotensive phase following inhalation of amyl nitrate decreases the murmurs of MR, VSD, and AI, and increases the murmur of AS. The later tachycardic phase following inhalation of amyl nitrate increases right-sided murmurs and the murmur of MS. The response in MVP is biphasic (softer then louder than control). Transient arterial occlusion Transient external compression of the upper extremity increases the murmurs of MR, VSD, and AI. AI = aortic insufficiency; AS = aortic stenosis; HCM = hypertrophic cardiomyopathy; MR = mitral regurgitation; MS = mitral stenosis; MVP = mitral valve prolapse; VSD = ventricular septal defect. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 749 Table 21-9 Data from ACC/AHA guidelines for echocardiographic examination in patients with cardiac murmurs. Level of Evidence • E  chocardiography is recommended for asymptomatic patients with diastolic murmurs, continuous murmurs, holosystolic murmurs, late systolic murmurs, murmurs associated with ejection clicks, or murmurs that radiate to the neck or back. I C • E  chocardiography is recommended for patients with heart murmurs and symptoms or signs of heart failure, myocardial ischemia or infarction, syncope, thromboembolism, infective endocarditis, or other clinical evidence of structural heart disease. I C • E  chocardiography is recommended for asymptomatic patients who have grade 3 or louder midpeaking systolic murmurs. I C • E  chocardiography can be useful for the evaluation of asymptomatic patients with murmurs associated with other abnormal cardiac physical findings or murmurs associated with an abnormal electrocardiogram or chest x-ray. IIa C • E  chocardiography can be useful for patients whose symptoms and/or signs are likely noncardiac in origin but in whom a cardiac basis cannot be excluded by standard evaluation. IIa C • E  chocardiography is not recommended for patients who have a grade 2 or softer midsystolic murmur identified as innocent or functional by an experienced observer. III – Harm C In some cases valve replacement can be accomplished with either mechanical or biological prostheses, and the choice of valve depends on many patient-specific factors such as age, health status, and desire for future pregnancy. Preexisting indications or contraindications to anticoagulation therapy also influence the choice of mechanical vs. tissue valve prosthesis. Current options for mechanical valve replacement include tilting disc valves and bileaflet valves. Although mechani4 cal valves are highly durable, they require permanent anticoagulation therapy to mitigate the otherwise high risk of valve thrombosis and thromboembolic sequelae.71 Due to the concordant risk of hemorrhagic complications, patient characteristics such as debility, lifestyle, and contraindications to systemic anticoagulation therapy may preclude mechanical valve replacement. Moreover, young women who are planning future pregnancies cannot take warfarin due to its teratogenic potential. Conversely, patients with other indications for systemic anticoagulation, such as other risk factors for thromboembolism (i.e., atrial fibrillation), or the existence of a mechanical prosthetic valve already in place in another position, may benefit from mechanical valve replacement. Additionally, patients with renal failure, on hemodialysis, or with hypercalcemia experience accelerated degeneration of bioprosthetic valves, and are thus, recommended to receive mechanical prostheses.72 In general, mechanical valve replacement is preferred in patients with expected long life spans who are acceptable candidates for anticoagulation therapy, in order to minimize reoperation and bleeding risks. The potential to avoid the hazards of serious bleeding complications spurred the development of valve prostheses using biological materials, which obviate the need for systemic anticoagulation therapy. As tissue valves are naturally less thrombogenic, the attendant yearly risks of both thromboembolic and anticoagulation-related complications are considerably less than with mechanical valves.73 Consequently, tissue valve replacement is generally recommended for patients averse to systemic anticoagulation therapy, with potential concerns regarding compliance or follow-up while taking anticoagulant medications, and in the case of reoperation for a thrombosed mechanical valve. However, biological valves are more prone to degeneration, especially when implanted in the mitral position, in younger patients, and in patients in renal failure, on hemodialysis, or with hypercalcemia.73 Improved manufacturing methods have made currently available tissue valves more durable than previous versions, and valve replacement with a biological prosthesis is generally preferred in patients without other indications for anticoagulation therapy, who are >60 years of age for the aortic position, and >70 years of age for the mitral position. Mechanical Valves. The first bileaflet valve was introduced in 1977. Bileaflet valves are comprised of two semicircular leaflets which open and close, creating one central and two peripheral orifices (Fig. 21-4). Bileaflet mechanical valves have demonstrated excellent flow characteristics, low risks of late valverelated complications, including valve failure, and are currently the most commonly implanted type of mechanical valve prosthesis in the world.72 Although mechanical valves necessitate systemic anticoagulation, careful monitoring of the International Normalized Ratio (INR) reduces the risk of thromboembolic events and hemorrhagic complications, and improves overall survival.74 Patients undergoing mechanical aortic valve replacement generally have a target INR of 2 to 3 times normal. Patients undergoing mechanical mitral valve replacement frequently have increased left atrial size, concomitant atrial fibrillation, and are at higher risk for thromboembolism that those undergoing mechanical aortic valve replacement, and are thus recommended to have a target INR 2.5 to 3.5 times normal. When managed appropriately, the yearly thromboembolic and bleeding risks in these patients are 1% to 2%, and 0.5% to 2%, respectively. Tissue Valves. A xenograft valve is one implanted from another species, such as porcine xenograft valves, or manufactured from tissue such as bovine pericardium. A variety of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease Class of Recommendation Clinical Setting valve areas, specifically <0.85cm2 valve area per square meter body surface area, and may affect symptomatic improvement and the hemodynamic response to exercise following surgery.75 Stentless porcine xenograft valves were developed in order to minimize the limitations in flow characteristics seen in patients with small prosthetic valve areas, and have demonstrated an increase in effective valve area of approximately 10% over stented xenografts of equivalent size.72 They can result in improved hemodynamics, both at rest and with exercise.76 The absence of a stent and sewing ring both increases the technical complexity of valve replacement, and takes advantage of the biologic mobility of the aortic valve apparatus. Though results with stentless valves seem promising, long-term durability remains to be shown, and they have not been widely adopted due to the technical complexity associated with implantation. 750 UNIT II PART SPECIFIC CONSIDERATIONS Figure 21-4. St. Jude bileaflet mechanical valve. (Photo reproduced with permission of St. Jude Medical, Inc., St. Paul, MN. All rights reserved.) xenograft tissue valves exist, and are primarily differentiated by the presence or absence of a mounting stent. Stented valves are the most commonly implanted, and the most popular valve in the United States is a stented bovine pericardial valve. The more traditional stented valves are attached to a sewing ring, which decreases the technical complexity of valve replacement compared with stentless valves (Fig. 21-5). The chief disadvantage of stented tissue valves is a smaller effective orifice area, which increases the transvalvular gradient. This effect is most pronounced in patients with small prosthetic Homografts. Homograft valves from human cadavers, also known as allografts, have been used for aortic valve replacement since the technique was originally described over 50 years ago.77 Since that time, homografts have typically been used for aortic and pulmonary valve replacements, and have been successfully harvested from brain dead organ donors and the explanted hearts of heart transplant patients. Following harvest, these valves are sterilized using an antibiotic solution, and subsequently stored in fixative or cryopreserved. Like other types of tissue valves, the risk of thromboembolic complications with homograft valves is low, and systemic anticoagulation therapy is not required. Additionally, the structure of homograft valves is naturally low-profile, allowing for larger effective valve orifices and lower postoperative transvalvular gradients compared with stented xenograft valves. Additionally, they have been shown to have some advantages in patients with endocarditis.78 The major shortcoming of homograft valves is their uncertain long-term durability in the face of significant tissue degeneration. Within one year of implantation, these valves undergo substantial loss of cellular components and subsequent Figure 21-5. Edwards’ Magna Ease stented porcine bioprosthesis. (Image reproduced with permission of Edwards Lifesciences, LLC, Irvine, CA.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ structural compromise, which may ultimately lead to valve failure.79 Although enhanced preservation techniques significantly improve cellular viability, which approach the 15-year viability of xenograft valves, the availability of these techniques has limited the use of homograft tissue valves. 751 Autografts. In 1967, Donald Ross described a procedure in Valve Repair. Valve repair offers several advantages over valve replacement, due in large part to the preservation of the patient’s native valve and subvalvular apparatus. In the case of mitral valve (MV) surgery, preservation of the mitral apparatus has been shown to lead to better postoperative left ventricular function and survival.82,83 Additionally, as there is no implanted prosthesis, the patient avoids the risks of chronic anticoagulation, infection, thromboembolic complications, and prosthetic valve failure after surgery. In the case of MV repair, freedom from reoperation and valve-related complications has been excellent in certain patient populations, even at 20-year follow-up.84 It has also been demonstrated that patients undergoing MV surgery with moderate functional tricuspid regurgitation (TR) do not experience increased perioperative complication rates when a concomitant tricuspid valve (TV) repair is performed.85 Midterm results in this group are encouraging, with greater than 98% freedom from reoperation reported by some groups at 5 years, suggesting further indications for valve repair. Despite its advantages for the patient, valve repair is generally more technically demanding than valve replacement, and may occasionally fail. Both the suitability of the patient for valve repair and the skill and expertise of the surgeon performing the operation are important when considering valve repair in the individual patient. MITRAL VALVE DISEASE Mitral Stenosis Etiology. Acquired mitral stenosis (MS) is most often caused by rheumatic fever, with approximately 60% of patients with pure MS presenting with a positive clinical history of rheumatic heart disease.70 Rarely, other conditions can cause obstruction to filling of the left ventricle (LV), mimicking MS. Acquired causes of MV obstruction include left atrial myxoma, ball valve thrombus, mucopolysaccharidosis, previous chest radiation, and severe annular calcification. Pathology. Although rheumatic heart disease is associated with a transmural pancarditis, pathological fibrosis of the valves results primarily from the endocarditic process. The damage caused by endocardial inflammation and fibrosis is progressive, causing commissural fusion, subvalvular shortening of the Figure 21-6. Mitral stenosis. The thickened, fused leaflets of the diseased mitral valve are viewed through a left atriotomy. (Image courtesy of the Centers for Disease Control and Prevention, Edwin P. Ewing, Jr.) chordae tendineae, and calcification of the valve and subvalvular apparatus.86 The resulting stenotic MV has a funnel-shaped apparatus, with a significantly narrowed orifice obliterated by interchordal and commissural fusion (Fig. 21-6). The degree of mitral stenosis should be determined preoperatively, as these pathological features may help determine the timing and type of intervention to perform.70 Pathophysiology. As the normal MV area of 4.0 to 5.0 cm2 is reduced by the rheumatic process, blood can flow from the left atrium to the left ventricle only if it is propelled by an everincreasing pressure gradient. The diastolic transmitral gradient, which is a function of the square of the transvalvular flow rate and the diastolic filling period, is a fundamental expression of the severity of MS. When the valve area is reduced to <2.5 cm2, patients may begin to experience symptoms when the transmitral gradient is exacerbated by conditions that either increase transmitral flow or decrease diastolic filling time, such as exercise, emotional stress, infection, pregnancy, or atrial fibrillation with a rapid ventricular response.87 Symptoms may begin to occur at rest with the onset of moderate stenosis, defined as a cross-sectional area of 1.0 to 1.5 cm2, and any physical exertion is typically limited by the time the MV area is <0.8 to 1.0 cm2 (Table 21-10).70 The progression of symptoms is due to the evolution of pathophysiological processes, beginning with an elevation in left atrial pressure. The increased left atrial pressure is subsequently transmitted to the pulmonary venous system, causing pulmonary edema as the hydrostatic pressure in the vessels exceeds the plasma oncotic pressure. Decreased pulmonary venous compliance exacerbates the pulmonary venous hypertension, though a concomitant decrease in microvascular permeability may preclude pulmonary edema in the chronic setting.88 Patients may also develop pulmonary arterial hypertension, owing to vasoconstriction, intimal hyperplasia, and medial hypertrophy of the pulmonary arterioles in response to the increased pulmonary venous pressure. The secondary obstruction to flow caused by reactive pulmonary arterial hypertension may serve to protect against pulmonary edema, but also exacerbates the intractable decrease in cardiac output that develops as stenosis worsens.89 Throughout the process, the left atrium becomes dilated and hypertrophied due to increased work in filling the ventricle VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease which the diseased aortic valve is replaced using the patient’s native pulmonary valve as an autograft, which is in turn replaced with a homograft in the pulmonic position.80 The procedure results in minimal transvalvular gradients, and favorable left ventricular mechanics, both at rest and during exercise. Known as the Ross procedure, this operation is particularly beneficial in children, as the pulmonary trunk grows with the child and long-term anticoagulation is not required.81 The late results of the Ross procedure are discussed later in this chapter. In addition to potential concerns with durability, performance of the Ross procedure has also been limited by its technical complexity, and the increased surgical risk associated with double valve replacement. 752 Table 21-10 Data from ACC/AHA guidelines for the classification of the severity of mitral valve disease in adults Mitral Stenosis Indicator Mild Moderate Severe Mean gradient (mm Hg)* <5 5–10 >10 Pulmonary artery systolic pressure (mm Hg) <30 30–50 >50 Valve area (cm2) >1.5 1.0–1.5 <1.0 UNIT II PART Mitral Regurgitation SPECIFIC CONSIDERATIONS Qualitative Mild Moderate Severe Angiographic grade Color Doppler jet area 1+ 2+ 3+ Small, central jet (<4 cm2 or <20% left atrial area) More than mild criteria, but Vena contracta width >0.7 cm with no severe criteria present large central jet (area >40% of left atrial area) or with a wall-impinging jet of any size, swirling in left atrium Doppler vena contracta width (cm) <0.3 0.3–0.69 ≥0.7 Regurgitant volume (ml per beat) <30 30–59 ≥60 Regurgitant fraction (%) <30 30–49 ≥50 Regurgitant orifice area (cm2) 0.2 0.2–0.39 ≥0.4 Quantitative (cath or echo) Additional essential criteria Left atrial size Enlarged Left ventricular size Enlarged *Valve gradients are flow dependent and when used as estimates of severity of valve stenosis should be assessed with knowledge of cardiac output or forward flow across the valve. against a fixed obstruction. Atrial fibrillation may develop, exacerbating the patient’s symptoms and increasing the risk of atrial thrombus and subsequent embolization. Left ventricular structure and function are typically preserved, however, owing to the protective effect of the stenotic valve. Clinical Manifestations. The sudden opening of the thickened, nonpliable valve with left atrial contraction produces an opening snap, followed by a diastolic rumble caused by rapid entry of blood into the left ventricle. When diastole is complete, the MV subsequently closes very rapidly, causing an increased first heart sound. The murmur, classically known as the auscultatory triad, is best heard at the apex. Associated mitral and tricuspid insufficiencies are heard as a pansystolic murmur radiating to the axilla, and a systolic murmur at the xiphoid process, respectively. The first clinical signs of MS are those associated with pulmonary venous congestion, namely exertional dyspnea, decreased exercise capacity, orthopnea, and paroxysmal nocturnal dyspnea. Hemoptysis, and pulmonary edema may develop as the venous hypertension worsens. Advanced MS can also cause pulmonary arterial hypertension and subsequent right heart failure, manifested as jugular venous distention, hepatomegaly, ascites, and lower extremity edema.1 As mentioned previously, atrial fibrillation may develop as left atrial pathology worsens, causing atrial stasis and subsequent thromboembolism. Patients with MS may initially present with signs of arterial embolization, even rarely with angina from coronary occlusion.1 Diagnostic Studies. All patients with a clinical history and physical exam suggestive of MS should undergo EKG and chest X-ray. Abnormalities in the EKG may include atrial fibrillation, left atrial enlargement, or right-axis deviation. Chest X-ray findings may include enlargement of the left atrium and pulmonary artery, creating a double contour behind the right atrial shadow, and obliterating the normal concavity between the aorta and left ventricle. Findings consistent with pulmonary congestion may also be present.1 The diagnostic tool of choice is TTE, which not only confirms the diagnosis of MS, but also rules out other causes of stenosis and other concomitant myocardial or valvular heart disease.90 Two-dimensional TTE can be used to calculate the MV orifice area and to determine the morphology of the MV apparatus, including leaflet mobility and flexibility, leaflet thickness and calcification, subvalvular fusion, and the appearance of the commissures. Doppler TTE can also be used in combination with various equations to estimate the hemodynamic severity of MS in terms of the mean transmitral gradient, the MV area, and the pulmonary artery systolic pressure. In most cases further examinations are not necessary. A preoperative TEE is usually unnecessary, unless there is a need to rule out left atrial appendage thrombus, the patient is being considered for percutaneous mitral balloon valvotomy, or the preoperative TTE is insufficient for diagnosis. Exercise TTE is indicated when resting TTE parameters are discordant with symptom severity.91 Routine cardiac angiography should be performed prior to valve surgery in patients with evidence of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ ischemia, decreased LV systolic function, a history of coronary artery disease or coronary risk factors, including postmenopausal status and age ≥35 in men and premenopausal women.70 Indications for Operation. Depending on the severity and the morphology of the diseased MV (Table 21-10), balloon valvuloplasty, surgical commissurotomy or repair, or MV replacement may be indicated for the treatment of MS (Table 21-11).70 Mitral Regurgitation Pathology. The MV apparatus consists of the mitral leaflets, chordae tendineae, papillary muscles, and mitral annulus, and abnormalities in any one of these components has the potential to cause MR.92 The system for classifying MR proposed by Carpentier focuses on the functional anatomic and physiologic characteristics of the MV pathology, and proposes three basic types of diseased valves based on the motion of the free edge of the leaflet relative to the plane of the mitral annulus.93 In Type I MR, valvular insufficiency occurs secondary to annular dilatation or leaflet perforation, and normal leaflet motion is maintained. Type II MR is seen in patients with mitral valve prolapse, and is due to prolapse of often thickened excessive leaflet tissue that gives the valve a “billowing” appearance, frequently in addition to ruptured or elongated chordae tendineae causing increased leaflet motion. Type III insufficiency, as seen in patients with rheumatic and ischemic heart disease, occurs from restricted leaflet motion, either during systole and diastole (Type IIIA) or during systole alone (Type IIIB). Pathophysiology. The basic pathophysiologic abnormality of MR is the retrograde flow of a portion of the LV stroke volume into the left atrium during systole due to an incompetent MV or dilated MV annulus. Acute severe MR can result from ruptured chordae tendineae, a ruptured papillary muscle, or infective endocarditis, and causes a sudden volume overload on both the left atrium and ventricle.70 Although an acute increase in preload provides a modest increase in overall stroke volume, the left atrium and ventricle are unable to fully accommodate the regurgitant volume or maintain forward stroke volume in the acute setting due to a lack of remodeling. Chronic MR generally has a more indolent course, with increasing volume overload of the left atrium and ventricle as the effective valve orifice size becomes larger. The resulting increase in left atrial and ventricular volume initially allows for an increase in the total stroke volume by Starling’s law and accommodation of the regurgitant volume, thus maintaining forward cardiac output and alleviating pulmonary congestion during the compensatory phase of chronic MR.94 However, as the left atrium becomes more dilated, the development of AF becomes more likely, disrupting atrioventricular synchrony and predisposing to thrombus formation. Additionally, chronic volume overload may lead to LV contractile dysfunction, resulting in impaired ejection and end-systolic volume increases. LV dilatation and filling pressure may also worsen throughout the 753 Clinical Manifestations. In cases of acute severe MR, patients are often very symptomatic and present with pulmonary congestion and reduced forward stroke volume. In very severe cases, patients may present with cardiogenic shock.1 Because the LV has not remodeled in the acute setting, a hyperdynamic apical impulse may not be present in the precordium. The typical systolic murmur of MR may be holosystolic or absent, with a third heart sound and/or diastolic flow murmur being the only auscultatory findings. In cases of chronic MR, patients may remain asymptomatic for long periods of time due to the compensatory mechanisms of the remodeled LV. However, once the LV begins to fail, patients become increasingly symptomatic from exertional dyspnea, decreased exercise capacity, orthopnea, and eventually pulmonary hypertension and right heart failure.1 Physical examination may demonstrate displacement of the LV apical impulse due to cardiac enlargement from chronic volume overload, and a third heart sound or early diastolic flow rumble. The characteristic auscultatory findings also include an apical systolic murmur which is variably transmitted to the axilla or the left sternal border, depending on the location of the pathology. As mentioned previously, patients may present with AF due to dilatation of the left atrium. Findings consistent with pulmonary hypertension frequently indicate late-stage disease. Diagnostic Studies. In the setting of acute heart failure, TTE should be performed and may demonstrate the anatomical location and severity of the MV pathology. However, TTE may underestimate lesion severity due to inadequate views of the color flow jet. In this case, severe MR should be suspected if hyperdynamic systolic function of the LV is visualized, and TEE may be used to confirm the diagnosis and direct repair strategies. 95 In the hemodynamically stable patient, coronary angiography should be performed preoperatively in the majority of patients so that myocardial revascularization may be performed in combination with MV surgery if necessary.70 In cases of chronic MR, EKG and chest X-ray are performed to assess rhythm status and the degree of pulmonary vascular congestion.70 An initial two-dimensional and Doppler TTE should be performed for a baseline estimation of LV and left atrial size, LV systolic function, pulmonary artery pressure, MV morphology, and MR severity.96 A central color flow jet in the setting of a structurally normal MV on TTE suggests functional MR, which may be due to LV dilatation or tethering of the posterior leaflet in patients with coronary artery disease. In the setting of organic MR, which is suggested by the presence of an eccentric color flow jet and morphological abnormalities in the MV apparatus on TTE, the presence of calcium in the annulus or leaflets, the redundancy of the leaflets, and the anatomy of the MV pathology should be assessed. Follow-up TTE is indicated on an annual or semiannual basis in patients with asymptomatic moderate to severe MR in order to assess changes from baseline parameters and direct the timing of surgery. Any abrupt change in signs or symptoms in a patient with chronic MR is also an indication for TTE examination.70 Additional preoperative studies are variably indicated in certain patient populations. Preoperative TEE is indicated in patients with poor diagnostic windows on TTE in order to VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease Etiology. The most important cause of MR in the United States is myxomatous degenerative disease of the MV, which occurs in approximately 2.4% of the population.1 Other important causes of MR include rheumatic heart disease, infective endocarditis, ischemic heart disease, and dilated cardiomyopathy. Less frequently, MR can be caused by collagen vascular diseases, trauma, previous chest radiation, the hypereosinophilic syndrome, carcinoid disease, and exposure to certain drugs.70 progression of MR, reducing cardiac output and causing congestion of the pulmonary vasculature. These changes herald LV decompensation and heart failure, and often indicate significant irreversible injury to the ventricular myocardium. 754 Table 21-11 Data from ACC/AHA guidelines for MV surgery in specific clinical contexts Class of Level of Recommendation Evidence Clinical Setting Balloon Valvotomy for Mitral Stenosis UNIT II PART SPECIFIC CONSIDERATIONS • S  ymptomatic patients (NYHA II, III, IV) with moderate or severe MS and favorable valve morphology, without left atrial thrombus or moderate to severe MR • Asymptomatic patients with moderate or severe MS, favorable valve morphology, and pulmonary hypertension (PASP >50 mm Hg at rest, >60 mm Hg with exercise), without left atrial thrombus or moderate to severe MR • Symptomatic patients (NYHA III, IV) with moderate or severe MS and favorable valve morphology, who are high risk or not candidates for surgery • Asymptomatic patients with moderate or severe MS, favorable valve morphology, and new onset atrial fibrillation, without left atrial thrombus or moderate to severe MR • Symptomatic patients (NYHA II, III, IV) with MV area >1.5 cm2 if there is evidence of hemodynamically significant MS (PASP >60 mm Hg, PAWP ≥25 mm Hg, mean MV gradient >15 mm Hg during exercise) • Symptomatic patients (NYHA III, IV) with moderate or severe MS and favorable valve morphology, as an alternative to surgery • Patients with mild MS • Patients with moderate to severe MR or left atrial thrombus I A I C IIa C IIb C IIb C IIb C III – Harm III – Harm C C I B I IIa C C IIb C III – Harm III – Harm C C I I B B I B IIa B IIa C IIa C IIb C III – Harm C III – Harm C Surgery for Mitral Stenosis* • S  ymptomatic patients (NYHA III, IV) with moderate or severe MS when: Balloon valvotomy is unavailable Balloon valvotomy is contraindicated due to thrombus or MR Valve morphology is not favorable for balloon valvotomy • Symptomatic patients with moderate to severe MS who also have moderate to severe MR • Mildly symptomatic patients (NYHA I, II) with severe MS and severe pulmonary hypertension (PASP >60 mm Hg) • Asymptomatic patients with moderate or severe MS and recurrent embolic events while receiving adequate anticoagulation, when the likelihood of successful MVr is high • MVr in the setting of mild MS • Closured commissurotomy in the setting of MVr; open commissurotomy should be performed Surgery for Mitral Regurgitation* • S  ymptomatic patients with acute severe MR • Symptomatic patients (NYHA II, III, IV) with chronic severe MR without LV dysfunction (LVEF <0.30) and/or end-systolic dimension >55 mm • Asymptomatic patients with chronic severe MR and mild to moderate LV dysfunction (LVEF 0.30–0.60) and/or end-systolic dimension ≥40 mm • Asymptomatic patients with chronic severe MR and preserved LV function (LVEF >0.60, endsystolic dimension <40 mm), when the likelihood of successful MVr is >90% • Asymptomatic patients with chronic severe MR, preserved LV function, and 1) New onset atrial fibrillation, 2) Pulmonary hypertension (PASP >50 mm Hg at rest, >60 mm Hg with exercise) • Symptomatic patients (NYHA III, IV) with chronic severe MR due to a primary abnormality of the mitral apparatus and severe LV dysfunction (LVEF <0.30, end-systolic dimension >55 mm), when the likelihood of successful MVr is high • Symptomatic patients (NYHA III, IV) with chronic severe MR secondary to severe LV dysfunction (LVEF <0.30) who remain symptomatic despite optimal medical management for heart failure, including biventricular pacing • Asymptomatic patients with MR and preserved LV function (LVEF >0.60, end-systolic dimension <40 mm), when the likelihood of successful repair is low • Isolated MV surgery in the setting of mild or moderate MR LV = left ventricular; LVEF = left ventricular ejection fraction; MR = mitral regurgitation; MS = mitral stenosis; MV = mitral valve; MVr = mitral valve repair; MVR = mitral valve replacement; NYHA = New York Heart Association; PASP = pulmonary artery systolic pressure; PAWP = pulmonary artery wedge pressure; * = mitral valve repair should be performed when possible in this population. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Indications for Operation. Based on the morphology and severity of MR (Table 21-10), MV repair, MV replacement with preservation of part or all of the mitral apparatus, or MV 5 replacement with removal of the mitral apparatus may be variably performed for the treatment of MR. As the intraoperative findings may dictate MV replacement whenever a MV repair is planned, current recommendations are for MV surgery in general (Table 21-11).70 Mitral Valve Operative Techniques and Results Mitral valve surgery is performed on the arrested heart with the assistance of cardiopulmonary bypass. Traditionally, a median sternotomy incision is used; however, the left atrium can also be approached via minimally-invasive incisions, such as a minithoracotomy or a partial sternotomy. The MV is commonly exposed through a left atrial incision placed posterior and parallel to the intra-atrial groove, or though a right atriotomy with transseptal incision. Commissurotomy. Upon opening the left atrium, the MV is visualized and the left atrium is examined for thrombus. A nerve hook or right-angle clamp is subsequently introduced beneath the commissures and used to evaluate the MV apparatus for leaflet mobility, commissural fusion, and subvalvular chordal abnormalities. The commissure is then carefully incised in a slightly anterior direction 2 to 3mm at a time, making sure with each extension of the incision that the chordae tendineae remain attached to the commissural leaflets. The commissurotomy is generally stopped 1 to 2mm from the annulus where the leaflet tissue thins, indicating the transition to normal commissural tissue. The papillary muscles are subsequently examined and incised as necessary in order to maximize the mobility of the leaflets. After the commissurotomy is complete, and the associated chordae tendineae and papillary muscles are mobilized, leaflet mobility is assessed. The anterior leaflet is grasped with forceps and brought through its complete range of motion. If subvalvular restriction or leaflet rigidity is identified, further division or excision of fused chordae and debridement of calcium may be necessary. Occasionally, the leaflets can be debrided carefully to increase mobility. Valve replacement may be more appropriate if extensive secondary mobilization is required. At the end of the procedure, competence of the valve is assessed with injection of cold saline into the ventricle. Open surgical commissurotomy has an operative risk of <1%, and has been shown to have good long term results, with freedom from reoperation as high as 88.5%, 80.3%, and 78.7% at 10, 20, and 30 years, respectively.98 The incidence of postoperative thromboembolic complications is generally <1% per patient-year, and the lack of required systemic anticoagulation precludes the development of hemorrhagic complications long-term.99 755 Mitral Valve Replacement. After exposing the valve, an incision is made in the anterior mitral leaflet at approximately the 12 o’clock position, and leaflet tissue is excised as needed. The papillary muscles are reattached to the annulus and, if possible, the posterior leaflet along with its associated subvalvular structures are preserved. The annulus is subsequently sized, and an appropriate mitral prosthesis is implanted using pledgeted horizontal mattress sutures. The annular sutures may be placed from the atrial to the ventricular side, seating the valve intra-annularly, or from the ventricular to the atrial side, seating the valve in a supra-annular position. When placing the mattress sutures, care must be taken to stay within the annular tissue, as excessively deep bites may cause injury to critical structures such as the circumflex coronary artery posterolaterally, the atrioventricular node anteromedially, or the aortic valve anterolaterally. The sutures are subsequently placed through the sewing ring, and the valve prosthesis is lowered onto the annulus, where it is secured (Fig. 21-7). The factors associated with increased operative risk for MV replacement include age, left ventricular function, emergent procedure status, NYHA functional status, previous cardiac surgery, associated coronary artery disease, and concomitant disease in another valve. However, for most patients, MV replacement is associated with an operative mortality between 2% to 6%, and 65% to 70% five-year survival.100,101 Although preservation of the mitral apparatus during MV replacement is important for subsequent left ventricular function, there appears to be no difference between complete and partial preservation with respect to 30-day and 5-year mortality.100 Mechanical valves are associated with increased durability compared to bioprosthetic valves, and have demonstrated a freedom from reoperation of 98% vs. 79% at 15 years, respectively.102 Despite these findings, the choice of prosthetic valve depends on many factors, and should be decided on a patient-by-patient basis. Mitral Valve Repair. There are many techniques available for MV repair that are variably used depending on the Figure 21-7. Mitral valve replacement. A St. Jude bileaflet mechanical valve is viewed through a left atriotomy. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease determine the severity and anatomic basis of MR, and to evaluate LV systolic function.70 Preoperative TEE is also indicated in cases when discrepancy exists between a patient’s functional status and the severity of MR on TTE, and is helpful for preoperative planning when assessing the feasibility of repair in the individual patient. Exercise stress-echocardiography may also be useful to detect LV systolic dysfunction in well-compensated patients, who may not demonstrate a rise in the end-systolic dimension of the heart or a drop in ejection fraction on routine TTE.97 Coronary angiography should be performed prior to valve surgery in patients with evidence of ischemia, decreased LV systolic function, a history of coronary artery disease or coronary risk factors, including postmenopausal status and age ≥35 in men and premenopausal women.70 756 UNIT II PART SPECIFIC CONSIDERATIONS intraoperative assessment of valvular pathology. On opening the atrium, the endocardium is examined for a jet lesion, a roughened area caused by a regurgitant jet striking the wall, in order to better localize the area of valvular insufficiency. The commissures are examined for evidence of prolapse, fusion, and malformation. The subvalvular apparatus and individual leaflets are subsequently examined, and areas of prolapse, restriction, fibrosis, and calcification are identified. Leaflet perforations are generally repaired primarily, or with a pericardial patch. The degree of annular dilation is also noted. The basic components of MV repair based on this assessment may include resection of the posterior leaflet, chordal shortening, chordal transposition, artificial chordal replacement, triangular resection of the anterior leaflet, and annuloplasty. Recent trends have been toward leaflet preservation. One of the mainstays of MV repair is triangular resection of the posterior leaflet. Excision of the diseased leaflet tissue extends down towards but generally not to the mitral annulus. After repair has been completed, valvular competency is evaluated by injecting saline into the ventricle with a bulb syringe and assessing leaflet mobility and apposition. If focal insufficiency is identified in other areas, additional procedures are performed. The anterior leaflet may be repaired via chordal shortening, chordal transposition, artificial chordal replacement, and triangular resection of the anterior leaflet. Chordal shortening has generally been abandoned in favor of chordal replacement. During chordal transposition, a resected portion of the posterior leaflet with attached chordae is transposed onto the prolapsed portion of the anterior leaflet to provide structural support, and followed with posterior leaflet repair as described above. The procedure of artificial chordal replacement uses polytetrafluoroethylene sutures to attach the papillary muscle to the free edge of the prolapsing anterior leaflet. Triangular resection with primary repair of the anterior leaflet removes the prolapsing segment of the anterior MV leaflet, while preserving adjacent chordal tissue, and may be especially helpful in patients with a ruptured chord or large amount of redundant anterior leaflet tissue. Annular dilation is generally corrected using a MV annuloplasty device, such as a ring or partial band, and is known to improve the durability of MV repair (Fig. 21-8).103 Several devices are available, and include rigid or semirigid rings that geometrically remodel the annulus, flexible rings or bands that restrict annular dilation while maintaining the physiologic sphincter motion of the annulus, and semirigid bands that provide a combination of annular remodeling and support of physiologic motion. Another technique known as the “double-orifice” or “edge-to-edge” repair was introduced in 1995, and involves tacking the free edge of the anterior leaflet to the opposing free edge of the posterior leaflet.104 This procedure effectively gives the valve a double-orifice “bow tie” configuration, and has been used as both a primary repair technique and an adjunct to other repair techniques, usually in cases of anterior leaflet pathology, or Barlow’s disease. While some groups report excellent late results, its use remains controversial. Due to the variety in operations and etiologies of MV disease, there is heterogeneity in outcomes following MV repair. In general, the operative risk for patients undergoing MV repair is generally <1%, and late results across a broad range of patients have demonstrated benefits in survival and valve-related complications, such as thromboembolic events, infective endocarditis, and anticoagulation-related hemorrhage, compared to Figure 21-8. Mitral valve repair. The narrow arrow indicates the posterior leaflet repair, and the wide arrow indicates the ring annuloplasty as viewed through a left atriotomy. MV replacement.69,84 Patients with MR due to degenerative disease have especially encouraging outcomes, demonstrating rates of survival and freedom from reoperation of >50% and >94% at 20 years, respectively.84 Historically, isolated anterior leaflet prolapse increased the risk of reoperation five-fold in this population. However, increasing experience and the expanded use of chordal replacement has greatly improved these results in recent series.105 Independent predictors of mortality have included higher NYHA class, lower left ventricular ejection fraction, and age. Older patients have demonstrated slightly worse outcomes overall, with an operative mortality of approximately 4%, and a 10-year survival of 54% in patients ≥65 years of age. However, the superiority of repair over replacement persists even for patients >80 years of age.101 Patients with rheumatic disease have also demonstrated slightly worse outcomes, with one study showing significantly better freedom from operation at 10 years in patients with nonrheumatic MV disease (88% vs. 73%, p<.005).106 Despite these differences in outcomes, MV repair remains the procedure of choice for the majority of patients with amenable MV disease. AORTIC VALVE DISEASE Aortic Stenosis Etiology. The most common cause of adult aortic stenosis (AS) is calcification of a normal trileaflet or congenital bicuspid aortic valve, particularly in patients >70 years of age. Another important cause of AS is rheumatic heart disease, which is particularly common in developing countries (Fig. 21-9). Pathology. Calcific aortic valve disease, also known as senile or degenerative disease, is an age-related disorder characterized by lipid accumulation, proliferative and inflammatory changes, upregulation of angiotensin-converting enzyme activity, oxidative stress, and infiltration of macrophages and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ T lymphocytes.107 This process, which closely resembles atherosclerotic vascular calcification, initially results in bone formation within the base of the cusps, reducing leaflet motion. Calcification progresses to involve the leaflets, and eventually results in obstructive disease, with a reduced effective valve area without signs of leaflet fusion. Pathophysiology. In general, once moderate AS is present, the average rate of progression includes an increase in jet velocity of 0.3 m/s/year, an increase in mean pressure gradient of 7 mm Hg/ year, and a decrease in valve area of 0.1 cm2/year (Table 21-12).70 Table 21-12 Data from ACC/AHA guidelines for the classification of the severity of aortic valve disease in adults Aortic Stenosis Indicator Mild Moderate Severe Jet velocity (m per s) <30 3.0–4.0 >40 Mean gradient (mm Hg)* <25 25–40 >4.0 >1.5 1.0–1.5 <1.0 Valve area (cm ) 2 <0.6 Valve area index (cm per m ) 2 2 Aortic Regurgitation Qualitative Mild Moderate Severe Angiographic grade 1+ 2+ 3–4+ Color Doppler jet width Central jet, width <25% of left ventricular outflow tract Greater than mild, but no Central jet, width >65% of signs of severe regurgitation left ventricular outflow tract Doppler vena contracta width (cm) <0.3 0.3–0.6 >0.6 Regurgitant volume (ml per beat) <30 30–59 ≥60 Regurgitant fraction (%) <30 30–49 ≥50 <0.1 0.1–0.29 ≥0.3 Quantitative (cath or echo) Regurgitant orifice area (cm ) 2 Additional essential criteria Left ventricular size Enlarged *Valve gradients are flow dependent and when used as estimates of severity of valve stenosis should be assessed with knowledge of cardiac output or forward flow across the valve. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 757 CHAPTER 21 Acquired Heart Disease Figure 21-9. Aortic stenosis. The aorta has been removed to demonstrate the thickened, fused aortic valve leaflets associated with rheumatic heart disease. (Image courtesy of the Centers for Disease Control and Prevention, Edwin P. Ewing, Jr.) In most adult patients with AS, obstruction develops gradually and includes a long latent period free from symptoms. During this time, the left ventricle typically hypertrophies in response to systolic pressure overload, and normal intracavitary volume is maintained.108 Afterload, which is defined as left ventricular systolic wall stress, and thus ejection fraction remain normal early in this process, as the increase in myocardial thickness is usually enough to counter increased intracavitary systolic pressures. Patients without a typical hypertrophic response to systolic pressure overload, or with a depressed contractile state of the myocardium, do not follow the common clinical course, but experience an early decrease in ejection fraction due to excessively increased afterload, without a compensatory response.109 Concentric left ventricular hypertrophy without chamber dilatation eventually leads to increased end-diastolic pressures and early diastolic dysfunction. Forceful atrial contraction in the face of elevated end-diastolic pressures becomes an important component of ventricular filling, even as mean left atrial and pulmonary venous pressures remain in the normal range. Disorders such as atrial fibrillation that disrupt atrial contraction typically lead to clinical deterioration. Although systolic function is generally preserved long into the natural history of the disease, left ventricular decompensation eventually occurs in the setting of longstanding increased afterload and is an indication for surgery even in the absence of other symptoms. Although concentric hypertrophy is a compensatory mechanism to maintain ejection fraction in the face of high intracavitary pressures, the hypertrophied heart becomes increasingly vulnerable to ischemic injury. Coronary blood flow may become inadequate, despite the absence of epicardial coronary artery disease.110 Coronary vasodilation is mitigated 758 by the hypertrophied myocardium, and the hemodynamic stress of exercise or tachyarrhythmias can lead to subendocardial ischemia and further systolic or diastolic dysfunction. When ischemic injuries occur, patients with ventricular hypertrophy experience larger infarcts and higher mortality rates than those without hypertrophy.111 In some patients, ventricular hypertrophy occurs in excess of what is needed to compensate for increased intracavitary pressures, creating a high-output state that is also associated with increased perioperative morbidity and mortality.112 UNIT II PART SPECIFIC CONSIDERATIONS Clinical Manifestations. The characteristic auscultatory findings of AS include a harsh, crescendo-decrescendo systolic murmur at the right second intercostal space, often with radiation to the carotid arteries.1 As the disease progresses, aortic valve closure may follow pulmonic valve closure, causing paradoxical splitting of the second heart sound. Other physical findings associated with AS include an apical impulse commonly described as a “prolonged heave,” and the presence of a narrow and sustained peripheral pulse, known as pulsus parvus et tardus. The classic symptoms of AS are exertional dyspnea, angina, and syncope.1 Although many patients are diagnosed prior to the onset of symptoms, the most common clinical presentation in patients with a known diagnosis of AS followed prospectively is worsening exertional dyspnea due to a limited capacity to increase cardiac output with exercise, and a progressive rise in end-diastolic pressures leading to pulmonary congestion. Angina occurs in over half of patients with AS, and is due to the increased oxygen demand of the hypertrophied myocardium in the setting of reduced oxygen supply secondary to coronary compression. Although some patients may have concomitant ischemic disease, angina occurs without significant epicardial coronary artery disease in half of all patients with AS. Syncope is most common during exertion, as systemic vasodilation in the setting of a fixed cardiac output causes decreased cerebral perfusion. However, at times, it may occur at rest secondary to paroxysmal atrial fibrillation and subsequent loss of atrial booster pump function. Late findings of AS include atrial fibrillation, pulmonary hypertension, systemic venous hypertension, and rarely sudden death. Diagnostic Studies. Evidence of left ventricular hypertrophy is found in approximately 85% of patients with AS on routine EKG, though the correlation between the absolute electrocardiographic voltages in precordial leads and the severity of AS is poor.1 EKG also may demonstrate signs of left atrial enlargement, and various forms and degrees of atrioventricular or intraventricular block due to calcific infiltration of the conduction system. Routine chest X-ray usually demonstrates a normal heart size, with rounding of the left ventricular border and apex. Cardiac enlargement on chest X-ray is a sign of left ventricular failure and cardiomegaly, and is a late finding. Transthoracic echocardiography is indicated in all patients with a systolic murmur graded ≥2/6, a single second heart sound, or symptoms characteristic of AS.70 Initial TTE examinations are often diagnostic, and provide an assessment of left ventricular size and function, the degree of left ventricular hypertrophy, the degree of valvular calcification, and the presence of other associated valvular disease. Doppler evaluation should be performed to define the maximum jet velocity, which is the most useful measure for following disease severity and predicting clinical outcome.1Additionally, color flow Doppler assesses the severity of the stenotic lesion by allowing calculations of the mean transvalvular pressure gradient, and effective valve orifice area (Table 21-12).70 Follow-up TTE is variably indicated depending on the severity of AS in order to assess changes from baseline parameters and direct the timing of surgery: yearly for severe AS; every 1 to 2 years for moderate AS; and every 3 to 5 years for mild AS. Any abrupt change in signs or symptoms in a patient with AS is an indication for TTE examination. Additional preoperative studies may be necessary in some patients. Rarely, when TTE images are suboptimal, TEE or fluoroscopy may be indicated to assess the degree of valve calcification and effective valve orifice area. As in other patients with valvular heart disease, coronary angiography should be performed prior to aortic valve surgery in most patients.70 Since the symptoms of AS oftentimes mimic those of ischemic disease, cardiac catheterization and coronary angiography may be necessary at the initial evaluation in patients with AS. Stress-echocardiography may also be useful in the asymptomatic patient with AS in order to elicit exercise-induced symptoms, or abnormal blood pressure responses during exertion. It is also useful in the evaluation of low-gradient AS in patients with depressed LV function. 70 However, exercise stressechocardiography is contraindicated in patients with ischemic heart disease.70 In patients with evidence of aortic root disease by TTE, chest computed tomography is useful in evaluating aortic dilatation at several anatomic levels, and is necessary for clinical decision making and surgical planning.1 Indications for Operation. Based on the severity of AS and the overall physical condition of the patient (Table 21-12), AVR may be recommended for the treatment of AS (Table 21-13).70 In patients with severe calcific AS, AVR is the only effective treatment, though controversy exists as to the timing of intervention in asymptomatic patients. Balloon valvotomy creates a modest hemodynamic effect and temporary symptom improvement in patients with calcific AS. However, the procedure has not been shown to affect long-term outcomes, and is often used in high-risk patients in which the contribution of the AS to the patients’ symptoms is a matter of debate.113 Aortic Insufficiency Etiology. The most common cause of isolated aortic insufficiency (AI) in patients undergoing AVR is aortic root disease, and represents over 50% of such patients in some studies.1 Other common causes of AI include congenital abnormalities of the aortic valve such as bicuspid aortic valve, calcific degeneration, rheumatic disease, infective endocarditis, systemic hypertension, myxomatous degeneration, dissection of the ascending aorta, and Marfan syndrome. Less common causes of AI include traumatic injuries to the aortic valve, ankylosing spondylitis, syphilitic aortitis, rheumatoid arthritis, osteogenesis imperfecta, giant cell aortitis, Ehlers-Danlos syndrome, Reiter’s syndrome, discrete subaortic stenosis, and ventricular septal defects with prolapse of an aortic cusp.70 Although most of these lesions produce chronic aortic insufficiency, rarely acute severe aortic regurgitation can result, often with devastating consequences. Pathology. Regardless of its cause, AI produces volume overload with dilation and hypertrophy of the left ventricle, and subsequent dilation of the MV annulus. Depending on the severity of AI, the left atrium may undergo dilation and hypertrophy as well. Frequently, the regurgitant jet causes endocardial lesions at the site of impact on the left ventricular wall. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 759 Table 21-13 Data from ACC/AHA guidelines for AV surgery in specific clinical contexts. Class of Recommendation Level of Evidence • Bridge to surgery in hemodynamically unstable patients with AS at high risk for AVR IIb C • Palliation in adult patients with AS, who are not candidates for AVR IIb C • Alternative to AVR in adult patients with AS III – Harm B • Symptomatic patients with severe AS I B • Severe AS in the setting of 1) Concomitant CABG 2) Concomitant valvular or aortic surgery 3) LV systolic dysfunction (LVEF <0.50) I C • Moderate AS in the setting of 1) Concomitant CABG 2) Concomitant valvular or aortic surgery IIa B IIb C • Mild AS in patients undergoing CABG, when there is high likelihood of rapid progression IIb C • A  VR for prevention of sudden death in asymptomatic patients with AS without any of the findings above III – Harm B I B I C C B • A  symptomatic patients with severe AI, normal LV systolic function (LVEF >0.50), but severe LV dilatation (end-diastolic dimension >75 mm, end-systolic dimension >55 mm) IIa B • Moderate AI in the setting of 1) Concomitant CABG 2) Concomitant surgery on the ascending aorta IIb C • A  symptomatic patients with severe AI, normal LV systolic function at rest (LVEF >0.50), and LV dilatation (end-diastolic dimension ≥70 mm, end-systolic dimension ≥50 mm) in the setting of 1) Progressive LV dilatation 2) Declining exercise tolerance 3) Abnormal hemodynamic responses to exercise IIb C • A  symptomatic patients with mild, moderate, or severe AI and normal LV systolic function (LVEF >0.50), when the degree of LV dilatation is not moderate or severe (end-diastolic dimension <70 mm, end-systolic dimension <50 mm) III – Harm B Clinical Setting Balloon Valvotomy for Aortic Stenosis • Asymptomatic patients with severe AS and   • Abnormal response to exercise   • High likelihood of rapid progression   • High likelihood of delay if surgery is withheld until time of symptom onset   • Expected operative mortality ≤1.0% Surgery for Aortic Insufficiency • Symptomatic patients with severe AI • Asymptomatic patients with chronic severe AI in the setting of 1) Concomitant CABG 2) Concomitant valvular or aortic surgery 3) LV systolic dysfunction (LVEF ≤0.50) AS = aortic stenosis; AVR = aortic valve replacement; CABG = coronary artery bypass grafting; LV = left ventricular; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association. Diseases causing AI can be classified as primary disorders of the aortic valve leaflets, and/or disorders involving the wall of the aortic root. Diseases causing dilation of the ascending aorta are a more common indication for AVR due to isolated AI, and include disorders such as age-related (degenerative) aortic dilation, cystic medial necrosis of the aorta as is seen in Marfan syndrome, aortic dilation secondary to bicuspid valves, and aortic dissection, to name a few.114 In these disorders, the aortic annulus becomes dilated, causing separation of the valve leaflets and subsequent AI. The diseased aortic wall may dissect secondarily and further escalate regurgitation across the valve, and secondary thickening and shortening of the valve VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease Surgery for Aortic Stenosis 760 UNIT II PART SPECIFIC CONSIDERATIONS cusps may occur due to undue tension placed on the valvular apparatus by the dilated aortic root. As the disease progresses, the valves become too small to close the aortic orifice, causing further aortic insufficiency and exacerbating dilation of the ascending aorta. There are also many primary valvular diseases that cause AI, generally in association with AS. One such disorder is agerelated calcific AS, which causes some degree of AI in up to 75% of patients.1 Infective endocarditis may involve the aortic valve apparatus and cause AI through direct destruction of the valve leaflets, perforation of a leaflet, or formation of vegetations that interfere with proper coaptation of the valve cusps. Rheumatic disease causes fibrous infiltration of the valve cusps and subsequent retraction of the valve leaflets, inhibiting apposition of the cusps during diastole and producing a central regurgitant jet. Patients with large ventricular septal defects or membranous subaortic stenosis may develop progressive AI, owing to a Venturi effect that results in prolapse of the aortic valve leaflets. Pathophysiology. The basic pathophysiologic abnormality of AI is the retrograde flow of a portion of the LV stroke volume into the left ventricle during diastole, producing left ventricular volume overload. Acute severe AI results most commonly from infective endocarditis, acute aortic dissection, or trauma, and causes a sudden volume overload on the left ventricle.31 Although an acute increase in preload provides a small increase in overall stroke volume due to the Starling mechanism, the left ventricle is unable to accommodate the large regurgitant volume and maintain forward stroke volume in the acute setting due to a lack of remodeling. Left ventricular end-diastolic and left atrial pressures increase dramatically, as the left ventricle is unable to develop compensatory chamber dilation. Although tachycardia develops as a compensatory mechanism to maintain forward flow, this attempt is often inadequate, and patients frequently present in heart failure and even cardiogenic shock. Moreover, subendocardial myocardial ischemia frequently develops as a result of decreased coronary diastolic perfusion pressures and increased left ventricular end-diastolic pressure, as well as increased myocardial oxygen demand due to acute dilation. In the setting of a chronic ventricular hypertrophy and preexisting diastolic dysfunction, the pressure-volume relationship is even more extreme, exacerbating the hemodynamic derangements seen in acute AI. Chronic AI generally has a more indolent course, with volume overload of the left ventricle causing compensatory increases in left ventricular end-diastolic volume and chamber compliance, and a combination of eccentric and concentric hypertrophy.115 Compensatory remodeling of the left ventricle allows for accommodation of the regurgitant volume without a significant increase in filling pressures, and maintains the preload reserve of the chamber. Eccentric left ventricular hypertrophy develops, permitting normal contractile performance across the enlarged chamber circumference and subsequent ejection of a larger total stroke volume in order to maintain forward flow, despite the regurgitant fraction.115,116 However, the enlarged chamber size results in an increase in systolic myocardial wall stress, and causes further ventricular hypertrophy. As the disease progresses, recruitment of preload reserve and compensatory hypertrophy maintains ejection fraction within the normal range despite elevated afterload, causing many patients to remain asymptomatic throughout the compensatory phase. 115,117 Eventually, left ventricular compensatory mechanisms fail and systolic dysfunction ensues. As the disease progresses, preload reserve may become exhausted, the hypertrophic response may become inadequate, and/or impaired myocardial contractility may develop so that ejection fraction begins to decline. 118 Although left ventricular systolic dysfunction related to excessive afterload is reversible early in the course, irreversible damage occurs once chamber enlargement predominates as the primary cause of diminished myocardial contractility. Clinical Manifestations. In cases of acute severe AI, patients are symptomatic and invariably present with compensatory tachycardia, often associated with acute pulmonary congestion and cardiogenic shock.1 Because the left ventricular and aortic pressures often equalize before the end of diastole, the diastolic murmur of AI may be short and/or soft. The reduced systolic pressure may attenuate the increase in peripheral pulse pressure seen in chronic AI, and early closing of the mitral valve due to elevated left ventricular end-diastolic pressures may diminish the intensity of the first heart sound in the acute setting. In patients with chronic AI, symptoms of heart failure and myocardial ischemia develop after the compensatory phase.1 Patients gradually begin to complain of exertional dyspnea, fatigue, orthopnea, and paroxysmal nocturnal dyspnea, often after significant myocardial dysfunction has developed. Angina is a common complaint late in the course, especially during sleep when heart rate slows and arterial diastolic pressure falls. Patients may also experience exertional angina secondary to diminished coronary perfusion in the setting of myocardial hypertrophy. Occasionally, the compensatory tachycardia that develops with chronic AI will cause palpitations, and the increased pulse pressure will cause a sensation of pounding in the patient’s head. Peripherally, the widened pulse pressure causes a forceful, bounding, and quickly collapsing pulse known as Corrigan’s or water-hammer pulses. Premature ventricular contractions have been reported to cause particularly troubling symptoms, owing to the heave of the volume-loaded left ventricle during the postextrasystolic beat. The classic auscultatory finding associated with AI is a high-pitched decrescendo diastolic murmur heard best in the left third intercostal space; an associated S3 gallop is often indicative of late disease. The Austin Flint murmur has also been described, and is heard as a middiastolic rumble at the apex that simulates mitral stenosis, and occurs in severe AI when the regurgitant jet impedes mitral opening. Diagnostic Studies. In the acute setting, TTE should be performed to confirm the presence and severity of aortic regurgitation, the degree of pulmonary hypertension, and the cause of valvular dysfunction.70 When aortic dissection is suspected as the cause of acute AI, TEE should be performed for diagnosis, though chest computed tomography may be substituted if more readily available.119,120 Cardiac catheterization, aortography, and coronary angiography are rarely indicated, and often delay necessary urgent surgical intervention. In cases of chronic AI, the EKG frequently demonstrates signs consistent with left axis deviation and, late in the course, intraventricular conduction defects associated with left ventricular dysfunction. On chest X-ray, the left ventricle enlarges predominantly in an inferior and leftward direction, causing marked increase in the long axis diameter of the heart, frequently with little or no change in the transverse diameter. The chest X-ray should be examined for aneurysmal dilation of the aorta.1 An initial VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Indications for Operation. Based on the morphology and severity of valve dysfunction (Table 21-12), AV repair or replacement may be performed for the treatment of AI (Table 21-13).70 Although the indications for AV repair and AV replacement do not differ, it is recommended that AV repair be performed only in those surgical centers that have developed the appropriate technical expertise, gained experience in patient selection, and demonstrated outcomes equivalent to those of valve replacement. Aortic Valve Operative Techniques and Results Aortic valve surgery has traditionally been performed through a median sternotomy incision with the assistance of cardiopulmonary bypass and moderate systemic hypothermia. However, minimally invasive incisions for aortic valve surgery have been introduced, including mini-sternotomy and mini-thoracotomy approaches. After the aorta is cross-clamped, cold blood cardioplegia is delivered antegrade through the aortic root, and/or retrograde through the coronary sinus. A left ventricular vent may be inserted through the right superior pulmonary vein to help maintain a bloodless field during the procedure, and to aid in de-airing at the conclusion of the operation. Aortic Valve Replacement. During aortic valve replacement, an aortotomy is performed, extending medially from approximately 1to 2cm above the right coronary artery and inferiorly into the noncoronary sinus, and the valve is completely excised. The annulus is thoroughly debrided of calcium deposits. After the calcium has been removed, the ventricle is copiously irrigated with saline. At this point, the annulus is sized and an appropriate prosthesis is selected. Pledgeted horizontal mattress sutures are then placed into the aortic valve annulus and subsequently through the sewing ring of the prosthetic valve, taking care to avoid damage to the coronary ostia, the conduction system, and the MV apparatus. The annular sutures may be placed from below the annulus, seating the valve supra-annularly, or from above the annulus for intra-annular placement (Fig. 21-10). The major components to increased operative risk associated with surgical AVR include age, body surface area, diabetes, renal failure, hypertension, chronic lung disease, peripheral vascular disease, neurologic events, infectious endocarditis, previous cardiac surgery, myocardial infarction, cardiogenic shock, NYHA functional status, and pulmonary hypertension. For 761 Figure 21-10. Aortic valve replacement. The stented porcine bioprosthesis as viewed through an aortotomy. most patients, the risk associated with AVR is 1% to 5%, and 5-year survival has been reported to be >80%, even in patients >70 years of age.69,121 The choice of valve is dependent on many patient-related factors, and is accompanied by the attendant postoperative risks of decreased durability, and thromboembolic vs. hemorrhagic complications for biological and mechanical valves, respectively. Aortic Valve Repair. Although aortic valve replacement is performed more commonly, AV repair may be recommended at surgical centers with extensive experience, technical expertise, and outcomes equivalent to valve replacement. 70 For patients with aortoannular ectasia, AI is due to annular dilatation and distortion of the sinotubular junction. For these patients, competence of the aortic valve can be achieved by functionally repairing the annulus in a method analogous to homograft implantation. The aneurysmal portion of the aortic root is excised, and the aortic valve is reimplanted inside a tubular Dacron graft, with concomitant reimplantation of the coronary arteries. Alternatively, the aneurysmal tissue and supravalvular tissue can be excised in their entirety, with subsequent implantation of the Dacron graft onto the superior aspect of the annulus and reimplantation of the coronary arteries. Valve-sparing root replacement for root and annular stabilization in patients with AI due to aortoannular ectasia has led to a more durable outcome than is seen with subcommissural annuloplasty or leaflet-related procedures alone. One study demonstrated equivalent overall survival between patients undergoing subcommissural annuloplasty or aortic valve repair without annuloplasty, and patients undergoing valve-sparing root replacement at 6 years. 122 However, patients that underwent valve-sparing root replacement had higher freedoms from reoperation and aortic insufficiency >2+ (100% vs. 90%, P=0.03; and 100% vs. 77%, P=0.002, respectively) at midterm follow-up. For patients with AI associated with redundant leaflet tissue, aortic valve repair may be accomplished with free margin plication or resuspension of the valve cusps, with or without triangular resection of the redundant segment. Excision of the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease TTE should be performed to confirm the diagnosis and severity of AI, assess the cause of AI (including valve morphology, and aortic root size and morphology), and assess the degree of left ventricular hypertrophy, volume, and systolic function.70 Follow-up TTE is indicated on an annual or semiannual basis in patients with asymptomatic moderate to severe AI in order to assess changes from baseline parameters and direct the timing of surgery. Any abrupt change in signs or symptoms in a patient with chronic AI is also an indication for TTE examination. Additional preoperative studies are variably indicated in certain patient populations.70 In patients with poor windows on TTE, TEE, or magnetic resonance imaging is indicated for initial and serial assessment of AI severity, and left ventricular volume and function at rest. In symptomatic patients with chronic AI, it is reasonable to proceed directly to TEE or cardiac catheterization if TTE examinations are inadequate. Exercise stress testing may be helpful for an assessment of functional capacity and symptomatic responses in patients with a history of equivocal symptoms. Coronary angiography should be performed prior to valve surgery in most patients.70 762 UNIT II PART diseased portion of the involved valve cusp improves symmetry of the valve leaflets, and annular plication of one or both commissures helps to ensure adequate coaptation. Generally, the free margins of the excised leaflets are reapproximated primarily, but in the absence of adequate cusp tissue, a triangular autologous or bovine pericardial patch may be used for cusp restoration. AV cusp repair with a free margin plication or resuspension technique has demonstrated encouraging results, both in patients with tricuspid and bicuspid aortic valves. Freedom from AV reoperation in patients with a tricuspid AV has been reported to be 89% to 92% at 10 years, with a freedom from recurrent AI >2+ of 80% to 86% at the same time point. In patients with bicuspid aortic valves, who generally represent a younger cohort of patients, 10-year survival has been reported at 94% following AV repair, with a freedom from AV reoperation of 81% at the same time point. 123 SPECIFIC CONSIDERATIONS Ross Procedure. As mentioned previously, the Ross procedure involves replacing the diseased AV with the patient’s native pulmonary valve as an autograft, which is in turn replaced with a homograft in the pulmonic position.80 The autograft may be implanted in the aortic position directly with resuspension of the valve commissures, or in association with a root replacement, which requires reimplantation of the coronary ostia. The cylinder root replacement technique is most reproducible, and involves transecting the native aorta approximately 5mm above the sinotubular ridge, with subsequent excision of the aortic valve leaflets and supra-annular tissue. The main pulmonary artery is transected at the bifurcation and the right ventricular outflow tract is incised, allowing the pulmonary valve and artery to be removed en bloc from the outflow tract. The annulus of the pulmonary autograft is sewn to the native aortic annulus with continuous or interrupted sutures, and the coronary ostia are reimplanted into the pulmonary artery graft. The pulmonary valve and right ventricular outflow tract are subsequently reconstructed using homograft tissue. The primary benefit of the Ross procedure compared to traditional AV surgery is a low risk of thromboembolism without the need for systemic anticoagulation. Although patients undergoing the Ross procedure are generally younger, perioperative mortality has been reported to be as low as 2.5% in this group, with an overall survival of 90% at 18-year follow-up.124 However, the long-term durability of the procedure is somewhat questionable. Although Ross reported a freedom from autograft replacement of 75% at 20 years, other groups have reported freedom from autograft reoperation and allograft reintervention of 51% and 82%, respectively, at 18-year follow-up.124,125 Progressive aortic insufficiency has been described as a cause of late failure in these patients, as well as calcification of the pulmonary homograft and pulmonary stenosis. Transcatheter Aortic Valve Replacement. Transcatheter aortic valve replacement (TAVR) is relatively new technology that has proven beneficial for the treatment of AS in seri6 ously ill patients who are not candidates for conventional surgery. The procedure remains the focus of ongoing clinical trials, and thus there are no published indications for operation endorsed by the American College of Cardiology or the American Heart Association. However, the Edwards SAPIEN heart-valve system that has been used thus far in the TAVR experience has been recently approved by the Food and Drug Administration for labeled-indications associated with published early results. The Edwards SAPIEN heart-valve system consists of a trileaflet bovine pericardial valve with a balloon-expandable stainless steel support frame, and can be inserted by either the transfemoral, transaortic, or transapical route. The transfemoral route involves performing a standard balloon aortic valvuloplasty, followed by transfemoral insertion of either a 22- or 24-French sheath, depending on the size of the valve selected for implantation. The balloon catheter and overlying collapsed bioprosthetic heart valve is then advanced across the native aortic valve under fluoroscopy, and deployed during rapid right ventricular pacing. If the patient’s peripheral vascular system is not amenable to femoral arterial cannulation, the transapical or transaortic route is chosen. In the transapical approach, a small intercostal incision is performed over the left ventricular apex, and a dedicated delivery catheter is inserted through the left ventricular apex and across the native aortic valve as described above. The transaortic approach is usually done through a ministernotomy. Other approaches that have been described include transaxillary, transsubclavian, and transcarotid. The particular role of each approach in a specific patient still remains to be defined, and continues to change as the technology improves. A large multicenter clinical trial has been performed on patients that were judged to be too high risk or inoperable for traditional AVR, based on assumed risks of ≥10% to 15% and ≥50% 30-day mortality, respectively. In patients that had previously been deemed inoperable, TAVR markedly reduced the rate of death from any cause (49.7% vs. 30.7%, P = <0.001), the rate of death from cardiovascular causes (41.9% vs. 19.6%, p = <.001), and the rate of repeat hospitalization (44.1% vs. 22.3%, p = <.001) at one year compared with standard medical therapy.126 Although the rates of neurological events (10.6% vs. 4.5%, P = 0.04), major vascular complications (16.8% vs. 2.2%, P = <.001), and major bleeding events (22.3% vs. 11.2%, P = 0.007) were higher in the TAVR group, these patients also experienced a significant reduction in symptoms and increased functional capacity compared with patients receiving standard medical therapy. In patients at high risk for traditional AVR, the rate of death from any cause, and from cardiovascular causes, was found to be noninferior in the TAVR group, compared with the surgical group.127 The rate of major bleeding events was higher in the surgical group (19.5% vs. 9.3%, P= <0.001) at 30 days, and patients in the TAVR group had a significantly shorter length of stay in the intensive care unit (3 vs. 5 days, P = <0.001), and a shorter index hospitalization (8 vs. 12 days, P = <.001). Although more patients in the TAVR group experienced a reduction in symptoms to NYHA class II or lower (P = <0.001), they also experienced more neurological events (8.3% vs. 4.3%, P = 0.04), and major vascular complications (11.3% vs. 3.5%, P = <.001) at one year. Although it is clear that TAVR represents a distinct set of periprocedural risks, it has demonstrated benefits in morbidity and mortality, especially in patients deemed inoperable for surgical AVR. Ongoing trials are examining the potential role of TAVR in patients with AS at moderate risk for traditional AVR. TRICUSPID VALVE DISEASE Tricuspid Stenosis and Insufficiency Etiology. Acquired tricuspid valve (TV) disease can be classified as either organic or functional, and affects approximately 0.8% of the general population.128 Tricuspid stenosis is almost VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Pathology. The changes associated with tricuspid stenosis (TS) closely resemble those associated with MS, including fusion of the commissures.128 In the case of rheumatic disease, mixed TS and TI may result from fusion and shortening of the chordae tendineae, and fusion of the commissures, causing retraction of the valve leaflets. The right atrium is frequently dilated and thickened in chronic TS, and chronic obstruction to right ventricular filling often produces signs of systemic venous congestion such as hepatomegaly and splenomegaly.1 In most cases of TI, dilation and deformation of the tricuspid annulus is the most prominent feature; the valve leaflets oftentimes appear stretched, but are otherwise pliable and normal in appearance.1 When TI is caused by carcinoid syndrome, white fibrous carcinoid plaques are found on the ventricular surfaces of the TV, causing the cusps to adhere to the underlying right ventricular wall and stenting the valve open.1 Pathophysiology. The basic pathophysiologic abnormality of both TS and severe TI is elevated right atrial pressures, producing signs of systemic congestion and right heart failure. Severe TS is marked by a valve area <1.0 cm2, and severe TI is defined as a vena contracta width of >0.7 cm in combination with systolic flow reversal in the hepatic veins.70 However, in patients with TS, a diastolic pressure gradient of only 5 mm Hg, or a TV orifice <1.5 cm2, is frequently enough to cause jugular venous distention, organomegaly, and peripheral edema. In severe cases, cardiac output is compromised, especially during exercise when the fixed obstruction prevents an increase in forward flow. Patients with severe insufficiency and pulmonary hypertension experience similar hemodynamic derangements. Clinical Manifestations. Patients with TS and severe TI develop symptoms of right heart failure associated with chronically elevated right atrial pressures.1 The classic clinical signs and symptoms of TS and severe TI are jugular venous distention, hepatomegaly, splenomegaly, ascites, and lower extremity edema. Uncomfortable fluttering in the neck has been reported in patients with TV disease, and sensations of throbbing in the eyeballs and pulsatile varicose veins have been reported to occur, especially in patients with severe TI. The low cardiac output occasionally associated with TS and severe TI can cause fatigue, weakness, and exercise intolerance in these patients. In the absence of pulmonary hypertension, dyspnea is not a prominent feature of tricuspid disease. The auscultatory findings associated with TS include a presystolic and middiastolic murmur characterized by a tricuspid opening snap that increases on inspiration. The lower left parasternal murmur of TI may be holosystolic or less than holosystolic, depending on the degree of regurgitation, may be associated with a middiastolic murmur in severe cases, and may increase on inspiration. 763 Diagnostic Studies. In patients with TV disease, chest X-ray frequently demonstrates enlargement of the right atrium and ventricle. Patients with TS demonstrate an exaggerated a wave and a diminished rate of y descent in the jugular venous pulse, while patients with TR have abnormal systolic c and v waves.1 TTE examination should be performed in patients with TV disease in order to characterize the structure and motion of the TV, the size of the tricuspid annulus, and other cardiac abnormalities that may affect TV function.70 In patients with a pulmonary artery systolic pressure >55mm Hg, TI commonly occurs in the setting of structurally normal valves; however, structural derangement of the TV apparatus is frequently present if TI is documented with a pulmonary artery systolic pressure <40mm Hg. Doppler TTE allows estimations of the severity of TI, the right ventricular systolic pressure, and the TV diastolic gradient. Indications for Operation. As an isolated lesion, mild or moderate TV disease does not require surgical correction. However, patients with severe TV disease should be considered for surgical intervention, especially in the setting of right ventricular enlargement and impaired systolic function, as this improves life expectancy and the development of sequelae such as heart failure and atrial fibrillation.128 Depending on the patient’s clinical status and the cause of TV dysfunction, TV repair and TV replacement be variably recommended for the treatment of TV dysfunction (Table 21-14).70 In patients with TI, the valve can usually be repaired with modern techniques. Operative Techniques and Results. The TV can be approached through a median sternotomy, a right thoracotomy, or minimally invasive port-based techniques. Surgery is performed with the assistance of cardiopulmonary bypass and, though TV surgery is usually performed on the beating heart, a brief period of cardioplegic arrest is rarely needed to allow for complete inspection of the interatrial septum, and close any defects that may be present. TV repair may include a suture or ring annuloplasty as well as valvuloplasty, and multiple methods have been described.128 Historically, bicuspidization of the TV was accomplished by a figure-of-eight suture plication of the annulus of the posterior leaflet; however, this technique has been essentially replaced by suture or ring annuloplasty. Suture annuloplasty is generally performed by placing 0 polypropylene pledgeted sutures along the base of the anterior and posterior leaflets, partially encircling the annulus. Ring annuloplasty can be accomplished by suturing the TV annulus to a variety of rigid or semirigid annuloplasty rings, which generally have an opening at the level of the anteroseptal commissure to avoid passing the anchoring sutures too close to the conduction system. Most surgeons favor ring over suture annuloplasty. In severe annular dilatation, augmentation of the anterior leaflet with autologous pericardium has been used with some success. Tricuspid valvuloplasty is infrequently performed and may include commissurotomy, triangular leaflet resection, primary perforation repair, and traditional leaflet repair techniques such as chordal transfer, shortening, and replacement, papillary muscle plication, tricuspid leaflet augmentation, and the edge-to-edge repair technique used in MV prolapse. For patients with functional TV disease, TV repair is generally preferred to replacement due to favorable results without the associated risks of thrombosis and anticoagulation. In the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease always a result of organic disease, namely rheumatic heart disease and endocarditis. In the case of rheumatic disease, tricuspid stenosis with or without associated insufficiency is invariably associated with mitral valve disease. Other less common causes of obstruction to right atrial emptying include congenital tricuspid atresia, right atrial tumors, and endomyocardial fibrosis. Tricuspid insufficiency, on the other hand, is most often a functional disease caused by secondary dilation of the tricuspid annulus due to pulmonary hypertension and/or right heart failure. This is most commonly caused by MV disease. Conditions such as right ventricular infarction and pulmonic stenosis can also lead to increased right ventricular pressures and functional tricuspid insufficiency (TI). The less common causes of organic TI, with or without associated stenosis, include carcinoid syndrome, radiation therapy, trauma such as repeated endomyocardial biopsy specimens, and Marfan syndrome. 764 Table 21-14 Data from ACC/AHA guidelines for TV surgery in specific clinical contexts. Class of Recommendation Level of Evidence • TVr for severe TI in patients with MV disease requiring MV surgery I B • TVR or annuloplasty for severe symptomatic primary TI IIa C • T  VR for severe TI secondary to diseased/abnormal TV leaflets not amenable to annuloplasty or TVr IIa C • Annuloplasty for less than severe TI in patients undergoing MV surgery in the setting of 1) Pulmonary hypertension 2) Tricuspid annular dilatation IIb C • T  VR or annuloplasty is not indicated in asymptomatic patients with TI, a normal MV, and a PASP <60 mm Hg III – Harm C • TVR or annuloplasty is not indicated in patients with mild primary TI III – Harm C Clinical Setting Surgery for Tricuspid Valve Disease UNIT II PART SPECIFIC CONSIDERATIONS MV = mitral valve; PASP = pulmonary artery systolic pressure; TI = tricuspid insufficiency; TV = tricuspid valve; TVr = tricuspid valve repair; TVR = tricuspid valve replacement. setting of concomitant mitral valve surgery, TV repair has not been associated with additional perioperative complications, and 5-year freedom from reoperation has been impressive at 98%.85 However, a subgroup of patients report late failure following TV repair, and this may be worse following suture annuloplasty compared with ring annuloplasty. Prosthetic valve replacement may be necessary due to extensive leaflet destruction or marked annular dilatation not amenable to repair. In some cases, the valve prosthesis may be anchored directly to the leaflet tissue instead of the valve annulus, reducing the risk of injury to the conduction system.128 If this technique is used, it should be confirmed that the residual tissue does not interfere with the movement of the prosthetic leaflets after implantation. Pledgeted sutures should be used, and may be placed on the ventricular or atrial side of the annulus. Outcomes data following TV replacement are difficult to interpret, as most reports are in patients with previous TV surgery and/or signs of severe right heart failure. Operative mortality has been over 20% in some studies. 128 One study of 87 patients undergoing TV replacement between 1194 and 2007 showed an in-hospital mortality of only 1.4%. The choice of prosthetic valve is also somewhat controversial. Though bioprosthetic valves are more durable in the tricuspid than mitral or aortic positions, valve degeneration is an important cause of bioprosthetic valve dysfunction at reoperation. The increased risk of valve thrombosis seen with mechanical valves, however, underlines the need for rigorous systemic anticoagulation. Even with these precautions, mechanical tricuspid valves are associated with an increased risk of hemorrhagic and thrombotic complications. The choice of valve is usually decided on a case-by-case basis and late outcomes have been similar with biological and mechanical valves in this position. In general, TV replacement may be a reasonable choice in select patients, though more data are needed regarding long-term outcomes in the modern era. disease, Marfan syndrome, and other connective tissue disorders.1 However, multivalve disease may also be caused by secondary valvular dysfunction due to a distal valvular lesion, as in the case of myxomatous degeneration of the mitral valve, resulting in pulmonary hypertension, dilation of the tricuspid annulus, and functional TI. If the primary pathology is corrected early in the disease course, these secondary functional changes may resolve without further intervention. In patients with multivalve disease, the clinical manifestations may be dependent on the severity of each individual valve lesion, but this is not always the case.1 In patients with concomitant mitral and tricuspid dysfunction, the prominent symptoms of dyspnea, paroxysmal nocturnal dyspnea, and orthopnea commonly associated with MV dysfunction are frequently diminished by associated TV dysfunction. Symptoms of multivalve disease are most commonly masked when valvular abnormalities are of approximately equal severity, highlighting the importance of careful examination of each valve both preoperatively and in the operating room. Surgery for multivalve disease is associated with a higher perioperative mortality than single-valve procedures, and this risk is exacerbated by factors such as pulmonary artery hypertension, age, triple-valve procedures, concomitant coronary artery bypass grafting, previous heart surgery, and diabetes.129 Failing to recognize significant concomitant valvular dysfunction at the time of surgery is also associated with higher perioperative mortality. For this reason, patients suspected of having multivalve involvement should undergo full preoperative Doppler TTE or TEE evaluation, and heart catheterization.70 In selected patients, procedures correcting multivalve disease demonstrate significant clinical improvement in symptoms and quality of life, as well as acceptable mortality and survival rates.129 Multivalve Disease Epidemiology of Heart Failure Pathology involving multiple valves is relatively common, and may result from diseases such as rheumatic fever, calcific SURGICAL THERAPY FOR THE FAILING HEART Heart failure affects approximately 5 million patients in the United States, with >550,000 new cases diagnosed annually.130 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Etiology and Pathophysiology Heart failure can be classified as acute vs. chronic, genetic vs. acquired, left-sided vs. right-sided and systolic vs. diastolic dysfunction. The underlying causes and treatments for each of these vary considerably. In the Framingham Heart Study, coronary artery disease accounted for 67% of heart failure cases, valvular heart disease accounted for 10%, and 20% of cases were attributable to primary myocardial diseases, of which dilated cardiomyopathy predominated.134 In all cases, heart failure is a progressive disorder that through complex mechanisms of ventricular remodeling, altered hemodynamics, neurohumoral activation, cytokine overexpression, and vascular and endothelial dysfunction either disrupts the ability of the myocardium to generate force or results in a loss of functioning cardiac myocytes, thereby preventing normal myocardial contraction. CABG for Ischemic Cardiomyopathy Surgical coronary revascularization is among the most commonly performed procedures for CHF. CABG is beneficial as it protects from further myocardial infarction and/or malignant ventricular arrhythmias. It is most successful when treating hibernating as opposed to infarcted myocardium. While the majority of evidence supporting CABG for patients with ischemic cardiomyopathy comes from nonrandomized, retrospective studies, the prospective, randomized, multicenter international Surgical Treatment of Ischemic Heart Failure (STICH) trial compared CABG with medical therapy to medical therapy alone. Entry criteria included an EF ≤35% with CAD and anatomy suitable for CABG. No significant difference was seen in overall mortality by study completion, but patients who underwent CABG did have fewer deaths or hospitalizations from cardiovascular causes (58% vs. 68%, P<0.001).135,136 This difference is despite the facts that only 50% of patients had myocardial viability testing, that 17% of patients in the medical therapy group underwent CABG and that 9% of patients randomized to CABG did not have surgery. Myocardial viability testing has been shown by multiple studies to be pivotal in identifying patients that will have improved outcomes following CABG for ischemic cardiomyopathy.137,138 A meta-analysis performed by Allman et al demonstrated an 80% reduction in mortality in patients who underwent revascularization with viable myocardium compared to patients who received medical therapy alone (3.2% vs. 16%, p<0.0001). Most important, in this analysis CABG had no benefit over medical therapy for patients without viable myocardium. A more recent study by Gerber et al prospectively compared CABG and medical therapy to medical therapy alone in 114 patients with CAD and low EF (24 ± 8) who underwent viability testing using delayed-enhancement cardiac MRI.139 That study demonstrated worse 3-year survival in medically treated patients with dysfunctional but viable myocardium than in medically treated patients with nonviable myocardium (48% vs. 77%, P = 0.02). This corresponded with a 4.56 hazard of death of viable myocardium when medical treatment was selected over full revascularization. In contrast, survival after CABG was not significantly different whether myocardium was viable or not (88% vs. 71%, P = NS). These studies underscore both the importance of viable myocardium as well as the adverse consequences of not offering a patient with viability surgical intervention. Patients with ischemic cardiomyopathy are a heterogeneous group, and, as with any surgery, appropriate patient selection is central to success. In one retrospective study of 96 patients with ischemic cardiomyopathy (EF ≤25%), age, and poor distal vessel quality were predictors of poor outcomes.140 Mortality in patients with poor vessel quality was 100%, compared with 90% when vessel quality was fair and 10% when it was good. Therefore, poor vessel quality should be considered a contraindication to surgical revascularization even in the presence of angina. LV size and LV dyssynchrony are also risk factors for adverse short and intermediate term outcomes. A LV end diastolic dimension of >100 mL/m2 is associated with a significantly reduced 5-year survival following CABG (85% vs. 53%, p<0.05), as well as worse 5-year freedom from recurrent CHF (85% vs. 31%).141 Moreover, LV dyssynchrony has been shown to have a significant impact on mortality in patients undergoing moderate to high risk revascularization and may compound risk in patients with nonviable myocardium.142 In patients with severe preoperative LV dyssynchrony the 30-day mortality was 27% vs. 3% in patients without significant dyssynchrony (p<0.001). Similar differences were seen with the presence of postoperative LV dyssynchrony, and outcomes were worse when patients also had fewer segments of viable myocardium. Secondary Mitral Regurgitation Secondary mitral regurgitation describes MR that results from damage to the left ventricle as a result of either ischemia or dilated cardiomyopathy rather than from a problem with the valve itself.143 Ischemic MR (IMR) typically results from systolic restriction of the mitral leaflets due to tethering of the subvalvular apparatus. This occurs mainly from regional wall motion abnormalities in areas of the LV adjacent to papillary muscle attachments. Alterations in the size and shape of the mitral annulus and posterior displacement of the posteromedial papillary muscle, which occurs primarily after an inferoposterior MI, may also contribute. Additionally, functional MR (FMR) is caused by LV dilatation and increased sphericity, which displace the papillary muscles apically and radially, creating lateral forces on the valve that lead to increased retraction of the mitral leaflets by the chordae tendineae. LV dyssynchrony may also contribute to FMR through poor coordination of the contraction of the septum and lateral walls, producing MR that may vary in intensity during the cardiac cycle. Functional MR is usually referred to as a Carpentier class I/IIIb lesion due to the presence of both annular dilatation (Carpentier type I) and systolic restriction of the mitral leaflets due to LV dysfunction (Carpentier type IIIb). Ultimately, increased regurgitation leads VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 765 CHAPTER 21 Acquired Heart Disease The disorder is the primary reason for 12 to 15 million office visits and >1 million hospitalizations each year. Overall 1-year mortality is estimated to be around 25%, but this can increase to as high as 75% for patients with more advanced heart failure (NYHA class IV).131 While heart transplantation remains the gold standard for the treatment of end stage disease, an increasing number of patients deteriorate while on the waiting list and up to 30% die before transplantation.132 The total direct and indirect costs associated with the treatment of heart failure are estimated to be $32 billion, and this is projected to increase to $70 billion by 2030.133 Advances in the surgical management of heart failure over the last decade have pushed surgery for CHF into the mainstream. As a result, there is an increasing number of patients with late- or end-stage disease who are being considered for surgical therapies. 766 UNIT II PART SPECIFIC CONSIDERATIONS to increased preload, LV wall tension, and LV work load, all of which contribute to progressive dysfunction of the LV and worsening heart failure. Several observational and population based studies have demonstrated a significant impact of secondary MR on longterm survival. Following MI, the 5-year survival rate dropped significantly from 61% in patients who did not have MR to 47% and 29% in patients with mild and moderate to severe MR, respectively.144 Similarly, in a series of 2,057 patients with symptomatic heart failure and a LVEF <40%, the 5-year survival rate for patients without MR was 54%, and it decreased to 40% in patients with moderate to severe secondary MR.145 In a cox proportional hazards analysis, increasing severity of MR was an independent predictor of decreased survival (HR = 1.23, [1.13–1.34], p = 0.0001), and this observation held for patients with both ischemic and nonischemic disease etiologies. Moreover, medical therapy and PCI have not reduced the impact of IMR on late mortality.146 Although specific recommendations to intervene for secondary MR are controversial and have not been rigorously defined, guidelines are available (Table 21-15).70,147 Some surgeons initially advocated performing only revascularization in cases of moderate ischemic MR with the idea that revascularizing viable myocardium would lead to improvements in LV function and effect reverse remodeling, ultimately contributing to a decrease in MR. While several studies have shown that MR often persists following revascularization alone, the addition of a mitral valve annuloplasty in those studies did not improve long-term functional status or survival in patients with ischemic MR.148-150 Nevertheless, other studies have shown that the persistence of MR after CABG is associated with a decreased survival rate and that CABG alone only has modest effects on reducing MR at 1 month follow-up.143 As a result, a growing number of centers have elected to repair moderate MR in this patient population. Indications for surgery in ischemic MR patients in the absence of revascularization options are even less well-defined. For patients with functional MR, the goal of mitral valve surgery is to avoid or postpone transplantation in eligible patients, but it should generally not be performed in patients with end-stage heart failure who present with low EF and limited myocardial viability. Those patients are often best suited by transplantation and/or ventricular assist device implantation. Mitral valve repair is the procedure of choice when surgery is indicated for secondary MR. Currently, recommendations are to use a semirigid or rigid annuloplasty ring to downsize the mitral annulus.143 There have also been various techniques proposed to correct the papillary muscle displacement, but most reports are single center, retrospective and small. Mitral valve replacement with preservation of the subvalvular apparatus is indicated when repair is not feasible due to severe tethering of the leaflets or massive LV dilation. Outcomes from surgery vary between centers and amongst patients in this heterogeneous group. Operative mortality ranges between 0% to 9% in most modern series.143 Generally speaking, mortality and recurrence rates are higher and long term prognosis is worse compared to outcomes for primary MR. Recurrent MR is as high as 15% to 30% in some series and 5-year mortality is between 44% to 48%.143,151,152 Some reductions in left atrial dimension and LV reverse remodeling may be achieved.153 Left Ventricular Aneurysmorrhaphy and Surgical Ventricular Restoration Pathophysiology of Ventricular Aneurysms. A transmural infarction of approximately 5% to 10% of the myocardium may result in formation of an LV aneurysm as necrotic myocardium is replaced by fibrous tissue. This usually occurs 4 to 8 weeks following the infarct. In the last decade, prompt revascularization of the culprit artery by either surgical or interventional techniques generally results in sparing of the subepicardial muscle while the subendocardial muscle remains necrotic.154 Therefore, it is not uncommon for the LV wall to show both living myocardium during thallium testing and an akinetic zone on echocardiogram or angiogram. It has been demonstrated that once more than 20% of the myocardium is necrosed there is irreversible progression to ventricular dilation and failure.155 The classic aneurysm is a 4 to 6 mm thick scar, which bulges outward in paradoxical motion as the LV contracts during systole. More than 80% develop in the anteroseptal and apical portions of the Table 21-15 Data guidelines for surgical intervention for secondary mitral regurgitation. Class of Recommendation Level of Evidence • Severe MR, LVEF >30%, undergoing CABG I C • Moderate MR, undergoing CABG, if mitral repair is feasible IIa C • Severe MR, symptomatic patients, LVEF <30%, candidate for revascularization IIa C • S  evere MR, LVEF >30%, no option for revascularization, refractory to optimal medical therapy, low comorbidity IIb C IIb C Clinical Setting Chronic Ischemic MR (ESC Guidelines) Chronic Functional MR (ESC and ACC/AHA Guidelines) • Chronic severe MR due to LV dysfunction, EF <30%, persistent NYHA class III-IV, symptoms despite optimal medical therapy MR = mitral regurgitation, ESC = European Society of Cardiology, CABG = coronary artery bypass grafting, LVEF = left ventricular ejection fraction, LV = left ventricle, ACC = American College of Cardiology, AHA = American Heart Association, NYHA = New York Heart Association. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Clinical Presentation and Diagnosis. Symptoms of LV aneurysms include angina, CHF, ventricular arrhythmias and rarely embolic phenomenon. Rupture is extremely uncommon. Patients generally present for coronary artery bypass or during evaluation of CHF or arrhythmias. While transthoracic echocardiography gives pertinent information regarding LV function, size, mitral valve function and the presence of thrombus, it is generally accepted that cardiac MRI is the best diagnostic modality to accurately identify areas of scar and viable tissue and to best define ventricular geometry.155 Surgical Treatment and Results. In 1985, Vincent Dor described a surgical technique called the endoventricular circular patch plasty that was intended to improve geometric reconstruction compared with the standard linear repair in LV aneurysm surgery. SVR is a somewhat broader term that arose from surgical repair of ventricular aneurysms and has now come to be applied to a group of surgical procedures designed to correct the effects of postinfarction ventricular remodeling. It is also sometimes referred to as surgical ventricular remodeling or reconstruction, surgical anterior ventricular endocardial reconstruction (SAVER), or the Dor procedure. SVR is specifically intended to reduce the size and sphericity of the LV by excluding akinetic and dyskinetic areas, most often by using a circular patch inserted inside the ventricle on contractile myocardium (Fig. 21-11A & B). Candidates for SVR are typically patients who have had a remote anterior or anteroseptal myocardial infarction, significant ventricular enlargement with a significant area of akinetic or dyskinetic myocardium, a discrete aneurysm, a clinical picture consistent with heart failure (LVEF <40%), retained function of the basilar and lateral portions of the heart and good right ventricular function. These patients should also be candidates for repair of any other concomitant cardiac disease. Dor currently emphasizes the importance of complete revascularization and repair of any mitral pathology at the time of operative SVR. In patients with spontaneous (13%) or inducible (25%) ventricular tachycardia (VT), it is additionally necessary to perform nonguided endocardial resection and cryoablation encircling the resected area.155 Results with this approach have been good in treating both heart failure and its sequelae, such as VT. In Dor’s series of 1150 patients, the operative mortality was dependent on the EF and ranged from 1% for patients with EF >40% to 13% for patients with EF <30%, and the 5-year survival approached 85%.155 Overall, more than 80% of survivors are either stabilized or improved, and quality of life has been shown to improve significantly by 6 months after the Dor procedure.160 This is likely due in part to the fact that the Dor procedure restores LV geometry, resulting in a mean ejection fraction increase between 10% to 15%, with significant alleviation of symptoms.155,161-163 These data are reinforced by the international RESTORE group, which examined SVR in a registry of 1198 postinfarction patients between 1998 and 2003.164 They found that 5-year overall freedom from hospital readmission for CHF was 78%. Moreover, 67% of patients had preoperative NYHA class III or IV symptoms, whereas 85% of patients were NYHA functional class I or II postoperatively. With respect to VT, Dor et al. reported on 106 patients with ischemic ventricular arrhythmias that underwent reconstruction for postinfarction LV aneurysm and visually-directed endocardiectomy plus or minus cryoablation and coronary revascularization 165. At a mean follow-up of 21.3 months, only 10.8% of patients had inducible VT and no spontaneous VT was documented. Results from similar series have also been excellent,148,163,166 but the efficacy of left ventricular restoration alone has been controversial.167,168 Inferior results seen in some series have been attributed to failure to perform endocardial resection and/or cryoablation at the border of the transitional zone, as well Figure 21-11. Surgical ventricular restoration of a ventricular aneurysm using the Dor Procedure. A. The size and sphericity of the left ventricle are reduced by excluding akinetic and dyskinetic areas. B. Most often this is completed using a circular patch inserted inside the ventricle on contractile myocardium. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 767 CHAPTER 21 Acquired Heart Disease left ventricle as a result of left anterior descending artery occlusion. The rest are inferior in location and the result of circumflex or right coronary occlusion. This patient population typically suffers from associated ventricular arrhythmias for several reasons. First, electrical dyssynchrony results from postinfarction remodeling, and triggers for ventricular arrhythmias typically occur in the scar border zone in patients with ischemic cardiomyopathy.156,157 Second, increased ventricular volume causes high wall stress and stretch, and stretch has been shown to be arrhythmogenic.158 Third, LV aneurysms represent an independent risk factor for SCD after MI.159 Surgical ventricular restoration (SVR) addresses each of these issues by removing the anatomic substrate during resection of the postinfarct scar and/or aneurysm, accomplishing volume reduction and mechanical resynchronization and relieving ischemia through complete revascularization and reduction in myocardial wall tension and oxygen demand. 768 UNIT II PART SPECIFIC CONSIDERATIONS as differences in stimulation protocols and possible inadequate volume reduction of the ventricle. Recently, a large, randomized, multicenter study, the STICH trial, has reported the conclusion that adding SVR to reduce ventricular volume to CABG does not improve symptoms or exercise tolerance and fails to lower death rate or cardiac rehospitalization compared to CABG alone135. While this trial has some shortcomings, it has resulted in a marked decrease in referrals for this procedure The main problem is that the LV volume was reduced by only 19% in the STICH trial, reflecting an inadequate repair as determined by the Surgery Therapy Committee, whose “acceptable STICH procedure” guideline required a 30% reduction at the 4-month postoperative cardiac MRI.169 Previous studies have reported an average reduction of end-systolic volume index (ESVI) of 40% with a range between 30% and 58%, suggesting that the STICH SVR procedure may have involved an inadequately small LV plication or limited intracavitary reconstruction.169 Moreover, this trial enrolled 13% of patients who had never had an MI and changed criteria such that enrollment required documented LV anterior wall dysfunction rather than demonstration of scar. This could have captured patients with hibernating myocardium that would recover following CABG alone. Dor subsequently published the results of 117 patients who would have been eligible for the STICH trial and demonstrated durable improvement in left ventricular function.170 However, this was a single-center, restrospective experience. Caution should be exercised so as not to broadly extrapolate the results of the STICH trial and inappropriately deny appropriate patients effective treatment. cardiopulmonary arrest, viral illness, pregnancy, or cardiotomy. Device therapy is intended to preserve end-organ perfusion and function and may be categorized as short- or long-term support for the left heart, the right heart, or both. In general, VADs may be used for support while the heart recovers (bridge to recovery, BTR), while the patient waits for a heart transplant (bridge to transplant, BTT) or as a final option to treat a chronic heart failure patient who is not a transplant candidate (destination therapy, DT). The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database, a joint effort by the NHLBI, FDA, CMS, academia, and industry to prospectively track patient outcomes, reported that between January 2009 and June 2010 indications for device implantation were BTR (1%), BTT (41%), bridge to decision (43%), DT (14%), and rescue therapy (0.5%).173 However, the percentage of patients receiving a VAD as destination therapy is increasing as results and devices improve. In 2011, 38% of patients had a primary device strategy of DT, whereas only 23% were considered BTT. Left ventricular assist devices (LVADs) provide support for the failing heart by unloading blood from the left ventricle and pumping it into the aorta. Cannulas may be inserted into the LV apex or the left atrium for inflow into the pump, and return is through an arterial cannula or graft sewn to either the ascending or descending aorta. For right sided devices, inflow drainage is most often from a cannula in the right atrium, and blood is returned through a graft sewn to the pulmonary artery or right ventricular outflow tract. Mechanical Circulatory Support LVADs were pulsatile devices. They provided adequate support for the heart but were limited by their large size and durability.174 More recently, continuous-flow LVADs based on rotary pump technology have been introduced. These devices are smaller, quieter, and durable enough for long term support. The two most commonly used devices today are the HeartMate II (Thoratec, Pleasanton, CA) and the HeartWare HVAD (HeartWare, Inc., Framingham, MA) (Fig. 21-12A & B, 21-13A & B). These devices differ in that the HeartMate II is implanted subdiaphragmatically, whereas the smaller HeartWare HVAD is implanted within the pericardium. Frequently used short-term support devices include the Abiomed BVS 5000 (Abiomed, Inc., Danvers, MA) and the CentriMag (Thoratec), which are both extracorporeal pumps, as well as the Impella (Abiomed), which may be inserted percutaneously. These devices are commonly used in either post-MI or postcardiotomy heart failure. They have the benefit of faster and easier insertion, making them ideal rescue devices and allowing time for patient transfer to a tertiary referral center, device weaning, transplantation, or transition to a permanent VAD as DT or BTT. Intra-aortic Balloon Pump. The intra-aortic balloon pump (IABP) is the most commonly used device for mechanical circulatory support, and it may be easily deployed in the catheterization laboratory, in the operating room or at the bedside. The device is inserted percutaneously through the femoral artery into the thoracic aorta. It is synchronized so that the balloon is inflated during diastole and deflated during systole, resulting in augmentation of diastolic perfusion of the coronary arteries and decreased afterload. Typically, this improves cardiac index and decreases both preload and myocardial oxygen consumption. The indication for use of an IABP is most often cardiogenic shock during or after cardiac catheterization or cardiac surgery. It also is indicated for preoperative stabilization of high-risk patients with either severe coronary artery disease, LV dysfunction, or refractory, unstable angina. Kang et al have reported that risk-adjusted mortality was significantly lower for selected high-risk patients undergoing open heart surgery when a preoperative IABP was used.171 Generally, an IABP is used for a few days and weaned as the patient’s condition improves. Morbidity associated with device use is typically minimal; however, in one series of 911 patients undergoing CABG who received an IABP, there was a 12% incidence of minor or major vascular complications, including an approximately 3% incidence of limb ischemia requiring thromboembolectomy. This is the most serious complication of IABP placement. To prevent this problem, frequent lower extremity neurovascular checks are necessary while an IABP is in place 172. Ventricular Assist Device Indications and Cannulation. Patients in need of ventricular assist devices (VADs) may have preexisting chronic heart failure, refractory ventricular arrhythmias, or acute heart failure following an MI, Left Ventricular Assist Devices. The first generation Bridge to Recovery. The ideal clinical situation would be for all LVADs to be temporary with the goal of myocardial recovery. However, as noted above, this is rare with only 1% of devices in the most recent INTERMACS data placed with intent for bridge to recovery.175 The LVAD Working Group Recovery Study, a prospective multicenter trial investigating myocardial recovery in BTT patients, has shown significant improvements in left ventricular ejection fraction and significant reductions in left ventricular end-diastolic diameter following support with continuous flow pumps, but myocardial recovery resulting in device explantation was still only seen in six patients (9%).176 Current data suggest that significant reverse remodeling is more likely to occur in the young and those with myocarditis.177 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ A B 769 Nevertheless, some encouraging results have been reported using a combination of treatment modalities. In a few small studies of patients with LVADs inserted for nonischemic cardiomyopathy, deliberate and aggressive medical therapy, including the β2-agonist clenbuterol resulted in successful LVAD explantation in 69% to 73% of patients,178,179 but these results have been difficult to replicate. Moreover, early results from clinical trials using stem cell therapy to treat patients with ischemic cardiomyopathy suggest that stem cells may be another adjuvant treatment with potential to aid in myocardial recovery.180,181 requirements, malignant ventricular arrhythmias, and risk for sudden death. Due to the scarcity of donor organs, the improved survival seen with LVAD usage has resulted in more patients remaining alive while on the transplantation waiting list. It is currently estimated that 35% of patients who go on to receive a heart transplant have had a previous LVAD implantation, although at more aggressive tertiary care facilities this number may be as high as 75% to 90%.131 The HeartMate II pump was evaluated as a BTT in an observational, prospective multicenter trial of 133 patients with persistent NYHA class IV heart failure despite optimal medical management who were status 1A or 1B on the transplant list.182 At 6 months, 100 patients (75%) had undergone transplantation, had cardiac recovery, or continued on mechanical support while remaining eligible for transplantation. There were significant improvements in both quality of life and functional status with Bridge to Transplant. LVADs are used as a bridge to transplant in patients who are candidates for heart transplantation but are not predicted to survive the waiting list period due to sequelae of cardiac failure, including end-organ dysfunction, rising pulmonary artery pressures, escalating inotrope A B Figure 21-13. The HeartWare HVAD system. A. Both the device controller and batteries are held in a wearable carrying case and connected to the ventricular assist device through the driveline. B. The main component is a centrifugal blood pump, called the HVAD, which is implanted within the pericardium. The only moving part in the device, the impeller, is suspended within the pump using magnets and thrust bearings. Similar to the HeartMate II, it can deliver a flow rate of up to 10 L/min. (Images reproduced with permission from HeartWare.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease Figure 21-12. The HeartMate II LVAD viewed from the (A) outside and (B) inside. The device is an axial flow, rotary pump that produces no pulsatile action. The pump contains a magnet, and the rotor assembly functions by the electromotive force generated by the motor. The result is that blood is propelled from the inflow cannula to systemic circulation at flows up to 10 L/min. (Images reprinted with the permission of Thoratec Corporation.) 770 UNIT II PART SPECIFIC CONSIDERATIONS device therapy. At 3 months, 81% of patients were in class I or II heart failure. Moreover, complications, including bleeding requiring reoperation, stroke, drive-line infection, and need for right ventricular assist device support, were significantly less frequent than with the previous generation HeartMate XVE.183 These data led to FDA approval of the HeartMate II as a BTT LVAD in 2008, and clinical use of the device increased dramatically. More recently, a multicenter, prospective trial compared the HeartWare HVAD to contemporaneously inserted devices for use as a BTT.184 This trial demonstrated noninferiority of the HeartWare HVAD, but in contrast to the 2007 trial, approximately 90% of patients in both groups were transplanted, explanted for recovery, or remained alive and eligible for transplant with LVAD support at 6 months. Most important, data suggest that patients bridged to transplant with an LVAD in the current era experience similar short- and long-term posttransplant survival and complications and do not have a higher incidence of allosensitization compared to standard cardiac transplant patients 185,186. Destination Therapy. The Randomized Evaluation of Mechanical Assistance for Treatment of Congestive Heart Failure (REMATCH) trial was conducted to compare the efficacy of LVAD insertion against optimal medical management in patients with NYHA class IV heart failure. While the pulsatile devices used in this trial had high failure rates, poor durability, and high associated mortality, there was still a clear survival benefit in patients treated with LVADs. This led to the FDA approval of the first LVADs for destination therapy in 2002.174 Subsequent trials have proven the increased efficacy of second generation devices for DT. In one such landmark trial, patients with advanced heart failure who were ineligible for transplantation were randomized in a 2:1 ratio to either a HeartMate II or HeartMate XVE.187 While both groups showed significant improvements in functional capacity and quality of life, actuarial survival at 2 years was superior for HeartMate II patients (58% vs. 24%, P=0.008) and adverse event rates were significantly lower. These data established the benefit of continuous flow LVADs over optimal medical management for end-stage heart failure, and led to FDA approval of the HeartMate II for DT in 2010. In certain populations, 2-year survival with the HeartMate II is now 80%.175 Several smaller third generation devices are in various stages of development or clinical trials. Some of these devices eliminate the drive line by using alternative energy sources, thereby removing a significant nidus for device infections. Long-term outcomes with these devices are expected to continue to improve, approaching that of cardiac transplantation and providing a viable solution to organ shortage for many patients.175 Current eligibility criteria for mechanical support as destination therapy include: (a) medically refractory NYHA class III or IV heart failure for at least 60 days, (b) peak oxygen consumption <12 ml/kg/min or failure to wean from continuous IV inotropes, (c) left ventricular ejection fraction <25%, and (d) presence of a contraindication for heart transplantation (i.e., age >65 years, irreversible pulmonary hypertension, chronic renal failure, insulin-dependent diabetes with end organ damage, or other clinically significant comorbidities).131 Once a patient has an LVAD inserted as DT, close and intensive follow-up by a multidisciplinary heart failure team is required in order to optimize medical therapy, reduce device-related morbidity and improve survival. It is also important to keep in mind that while some contraindications to transplantation are irreversible, others can 7 be modified. As such, approximately 10% of patients implanted with an initial strategy of destination therapy become BTT patients,131 and in some patients, the LVAD itself facilitates this transition. For example, an improvement in mean pulmonary vascular resistance was reported following implantation of the HeartMate II in patients with end-stage heart failure (2.1 vs. 3.6 Woods units, P<0.001).188 These data are also relevant to the 43% of patients that receive LVADs as a bridge to decision. Right Ventricular Assist Devices and Biventricular Assist Devices Most patients who present with advanced heat failure and a failing left ventricle also have some degree of right-ventricular dysfunction, but the majority of these patients do well with only an LVAD. However, implantation of an LVAD may cause acute worsening of tricuspid regurgitation and exacerbations of right-heart failure through leftward deviation of the intraventricular septum and as a result of the significant volume-loading and transfusion requirement that is often necessary to achieve adequate flows postoperatively. Overall, approximately 20% of HeartMate II BTT patients had persistent right ventricular failure (RVF) requiring either a subsequent RVAD (6%) or intravenous inotropic support for >14 days (14%), and these patients had significantly worsened 6 month survival compared to those without RVF (71% vs. 89%, P<0.001).189 Typically, mechanical right-ventricular support is temporary with intent to wean the device, and isolated right-ventricular assist devices are unusual. Biventricular support is most commonly indicated for acute cardiogenic shock after an MI or postcardiotomy heart failure. Biventricular support is temporary, although some patients may be successfully bridged to transplant or permanent left-sided assist devices. There is currently no destination therapy device for biventricular failure. Total Artificial Heart The total artificial heart (TAH, SynCardia Systems, Tucson, AZ) is currently indicated as a bridge to transplant for patients in biventricular failure, particularly for those who are critically ill and too large for extracorporeal BiVAD support. Unlike ventricular assist devices, the TAH replaces the entire heart. The ventricles of the TAH are implanted orthotopically to the atrial cuffs on the ventricular side of the AV groove, and the outflow conduits are attached to the great vessels. This approach has the benefit of obviating the hemodynamic influence of pulmonary hypertension, right heart failure, myocardial or valvular problems, cardiac arrhythmias, and inotropic agents.190 While this device has failed to reach its potential as a replacement for cardiac transplantation, the TAH has achieved favorable results as a BTT with a >70% survival in selected centers.191-193 However, at most centers results with the TAH have been suboptimal, and it is not frequently used. SURGERY FOR ARRYHTMIAS The success of catheter-based ablation and implantable cardioverter defibrillators (ICDs) has significantly diminished referrals for the surgical treatment of arrhythmias such as ventricular tachycardia, Wolff-Parkinson-White syndrome, atrial flutter, and atrioventricular nodal reentry. On the other hand, the introduction of surgical ablation modalities such as radiofrequency and cryothermal energy, has simplified the surgical treatment of atrial fibrillation (AF) and has led to a dramatic increase the in the number of surgical procedures performed annually for AF.194 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Atrial Fibrillation Medical Management. Most patients are treated medically, but the shortcomings of pharmacological management have left an important role for interventional therapies. Antiarrhythmic medications have been limited by modest efficacies and significant proarrhythmic and systemic toxicities.197 Conversely, rate control strategies leave the patient in AF, do not address the impaired hemodynamics or symptoms associated with this arrhythmia, and may render subsequent attempts at rhythm control therapies less effective for younger patients that may suffer irreversible cardiac remodeling due to the prolonged period of time in AF. Restoration of normal sinus rhythm has several potential benefits over other strategies 198-200. These include improvements in atrial systolic function, which improves cardiac output and often improves symptoms in patients with congestive heart failure; a lower risk of stroke; possible discontinuation of anticoagulation; and the benefit of potentially reversing atrial structural and/or electrical remodeling. Indications for Surgical Management. Recent consensus guidelines published by the Heart Rhythm Society state that surgical ablation for atrial fibrillation is indicated for: (a) all symptomatic AF patients undergoing other cardiac surgery; (b) selected asymptomatic AF patients undergoing cardiac surgery in which the ablation can be performed with minimal additional risk; and (c) symptomatic patients with lone AF who have failed medical therapy and prefer a surgical approach, have failed one or more attempts at catheter ablation, or are poor candidates for catheter ablation.195 At our institution, relative indications for surgical ablation in patients with permanent AF that were not included in the consensus statement are: (a) a contraindication to long term anticoagulation for patients at high A The Cox-Maze IV Procedure. The first successful operation for atrial fibrillation, the Cox-Maze procedure, was introduced clinically in 1987 by James Cox. The procedure involved the completion of a maze-like pattern of surgical incisions across both the right and left atrial that were designed to interrupt the multiple macroreentrant circuits that were thought to be responsible for AF, while still allowing propagation of the sinus impulse, restoring atrioventricular synchrony, and preserving atrial transport function. While effective at eliminating AF and reducing the risk of thromboembolism, it was not widely performed due to the fact that it was technically difficult and significantly prolonged time on cardiopulmonary bypass. In 2002, the Cox-Maze IV, was introduced. The Cox-Maze IV uses a combination of bipolar radiofrequency (RF) ablation and cryoablation to effectively replace the majority of incisions that comprise the Cox-Maze III while significantly shortening cross-clamp time and reducing operative complexity. The Cox-Maze IV is performed on cardiopulmonary bypass through either a median sternotomy, often in combination with other cardiac surgery, or a right minithoracotomy.201 In most cases, the right atrial lesion set is performed on the beating heart, whereas the left atrial lesions are performed during cardioplegic arrest (Fig. 21-14). Results from the Cox-Maze IV procedure have been excelA recent, prospective analysis of 100 consecutive lone 8 lent. Cox-Maze IV patients demonstrated postoperative freedom from AF of 93%, 90%, and 90% at 6, 12, and 24 months, respectively, and freedom from AF off antiarrhythmic drugs was 82%, 82%, and 84% at the same intervals.201 Outcomes are comparable when patients undergo concomitant cardiac surgery,202 and a propensity analysis has shown that results are similar between the traditional “cut-and-sew” maze and the Cox-Maze IV.203 This procedure is often successful in patients who are poor candidates for catheter-based ablation, such as those with large left atria and patients with long-standing persistent AF. The combination of surgical excision of the LAA and restoration of normal sinus rhythm after the Cox-Maze procedure significantly reduces stroke risk. It is our practice to stop warfarin at 3 months postoperatively in patients who are in B Figure 21-14. The Cox-Maze IV Lesion Set. A. The left atrial lesion set is comprised of right and left pulmonary vein isolation, connecting lesions between the left and right superior and inferior pulmonary veins, a lesion from the left atrial appendage excision site to the pulmonary vein and a lesion to the mitral valve annulus. B. The right atrial lesion set consists of lines of ablation along the superior and inferior vena cavae, the free wall of the right atrium and down to the tricuspid valve annulus. (From Weimar T, Bailey MS, Watanabe Y, et al. The CoxMaze IV procedure for lone atrial fibrillation: a single center experience in 100 consecutive patients. J Interv Card Electrophysiol. 2011;31: 47-54. With kind permission from Springer Science & Business Media.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 771 CHAPTER 21 Acquired Heart Disease Epidemiology of Atrial Fibrillation. Atrial fibrillation remains the most common arrhythmia in the world with an overall incidence of 0.4% to 1% that increases to 8% in those older than 80 years old.195 The most serious complication of AF is thromboembolism with resultant stroke,196 but serious morbidity and mortality may also result from hemodynamic compromise due to loss of atrial contraction, exacerbations of congestive heart failure from atrioventricular asynchrony and tachycardiainduced cardiomyopathy. risk for stroke (CHADS2 score ≥ 2) and (b) a history of stroke while on therapeutic anticoagulation. 772 UNIT II PART SPECIFIC CONSIDERATIONS normal sinus rhythm and without another indication for anticoagulation, regardless of CHADS2 score. With this approach, the stroke rate following the Cox-Maze procedure off anticoagulation has been remarkably low (annual risk = 0.2%).204 In contrast, in one report the annual rate of intracranial hemorrhage in anticoagulated patients with AF was 0.9% per year, and the overall rate of major bleeding complications was 2.3% per year.205 Left Atrial Lesion Sets. Some surgeons perform more limited ablation procedures, such as isolated pulmonary vein isolation or lesion sets that are limited to the left side of the heart. This is done in order to further reduce the complexity of the procedure and takes advantage of the fact that in most patients AF originates from the pulmonary veins and posterior left atrium. Although, there is seldom justification for limited lesion sets in experienced hands. While there is a high degree of variability in both the techniques and energy sources that have been attempted for left-sided atrial lesion sets, these procedures have all incorporated some subset of the left atrial lesion set of the Cox-Maze procedure. Pulmonary vein isolation is ubiquitously performed, and the LAA is often excised. Results differ greatly between series, but a meta-analysis of the published literature by Ad and colleagues revealed that a biatrial lesion set resulted in a significantly higher late freedom from AF compared with a left atrial lesion set alone (87% vs. 73%, P = 0.05).206 These results are not surprising, as our intraoperative mapping experience with such patients showed a distinct region of stable dominant frequency in the left atrium only 30% of the time.207 The dominant frequency was located in the right atrium 12% of the time and moved during the recording period in almost half of all patients. It must also be kept in mind that recurrent right atrial flutter is a known complication of performing only the left atrial lesions. When it does occur, atrial flutter can be treated with catheter-based ablation; however, recurrent left atrial flutter can be very difficult to ablate. Pulmonary Vein Isolation. Pulmonary vein isolation (PVI) is an attractive therapeutic option due to the fact that it can be performed off of cardiopulmonary bypass (CPB) through small or thoracoscopic incisions. The results of PVI have been variable and highly dependent on patient selection since outcomes are consistently worse in patients with longstanding persistent AF. In a study from Edgerton et al, only 56% of patients were free from AF at 6 months (35% off antiarrhythmic drugs), and with concomitant procedures, the success rate of PVI has been even lower.208 Several devices are available to close the LAA at the time of PVI. These include staplers and epicardial clips that can be placed without the need for CPB. While surgical PVI has had poorer results than a Cox-Maze procedure, it has had superior results to catheter-based PVI. The Atrial Fibrillation Catheter Ablation Versus Surgical Ablation Treatment (FAST) Trial, which was a two center, randomized clinical trial, compared catheter-based ablation to thoracoscopic PVI in patients with antiarrhythmic drug-refractory AF and either left atrial dilatation and hypertension or failed prior catheterablation.209 This study demonstrated that the 12-month freedom from AF and antiarrhythmic drugs was 37% for the catheter ablation group and 66% for the PVI group (P = 0.0022). SURGERY FOR PERICARDIAL DISEASE Acute Pericarditis Pericarditis is characterized by infiltration of the cellular and fibrous pericardium by inflammatory cells. The exact incidence and prevalence of pericarditis is unknown, but it is estimated that pericarditis is found in approximately 1% of autopsies and accounts for up to 5% of presentations of nonischemic chest pain.210,211 The etiologies of acute pericarditis are diverse and may result from primary pericardial disorders or occur secondary to a systemic illness.212 In developed countries, 80% to 90% of cases are now considered idiopathic or related to a viral pathogen, but nonviral infection, autoimmune diseases, myocardial infarction, radiation, malignancy, endocrinopathy, myocarditis, aortic dissection, uremia, trauma, pharmacological side effects, and previous cardiothoracic surgery must be included in the differential diagnosis. The relative incidences of peri-infarction pericarditis, which was once common, and postcardiac injury syndrome have been dramatically reduced with the advent of thrombolytics and coronary angioplasty.212 Clinical Presentation and Diagnosis. Diagnosis of acute pericarditis typically requires the identification of at least two of four cardinal features (Table 21-16). The presentation may be confused with several more common cardiopulmonary conditions, particularly myocardial infarction, making a careful history and physical critical. Patients with pericarditis classically complain of sudden onset, retrosternal pain that may be pleuritic in nature. The pain may also be positional, with alleviation of pain when the patient is upright and leaning forward. Pain from pericarditis is typically sharp or stabbing, as opposed to the dull pain or pressure that is common with angina, and it typically does not crescendo. While both conditions cause pain that often radiates to the neck, arms, and shoulders, pericarditis pain may uniquely radiate to the trapezius ridge due to innervation from the phrenic nerve.213,214 The presence of a pericardial friction rub is pathognomonic for pericarditis, but it tends to vary in intensity over time and may be absent in 15% to 65% of patients.213,215 As such, the sensitivity of this physical finding is dependent on the frequency and quality of auscultation. A pericardial friction rub is best heard at the left lower sternal border and is typically described as a high-pitched scratchy or squeaky sound with a triphasic cadence corresponding to the movement of the heart during atrial systole, ventricular systole, and early ventricular diastole. However, it may be monophasic or biphasic in up to 50% of patients. Electrocardiogram (EKG) changes typically progress through four stages representing global subepicardial myocarditis and subsequent recovery. Pericarditis patients may have concave ST deflections with diffuse changes, spanning the leads of multiple coronary artery distributions, but ST segment abnormalities are absent in 20% to 40% of patients.216,217 Acute pericarditis should not result in the development of infarct patterns, such as Q-waves or loss of R-waves, and T-wave inversions from pericarditis tend to result later in the disease process after the ST segment has returned to baseline. Table 21-16 Features of acute pericarditis. • Pleuritic and positional, retrosternal chest pain • Pericardial friction rub • EKG changes: diffuse ST elevation and PR depression • Pericardial effusion EKG = Electrocardiogram. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Treatment. The preferred treatment depends on the underlying cause of the pericarditis. The disease usually follows a selfand benign course and can be successfully treated 9 limited with a short course of nonsteroidal anti-inflammatory agents (NSAIDs). Some patients may require judicious use of steroids or IV antibiotics. In cases of purulent pyogenic pericarditis, surgical exploration and drainage are occasionally necessary. Rarely, accumulation of fluid in the pericardium may lead to tamponade, requiring prompt evacuation of the pericardial space. While pericardiocentesis will typically suffice, surgical drainage may be required for thick, viscous, or clotted fluid or in patients with significant scarring from previous surgeries. More commonly, surgical intervention is required to manage recurrent disease. Relapsing Pericarditis As many as one-third of patients with acute pericarditis will develop at least one episode of relapse.212 While many of these patients can be treated medically during their initial relapse and do not experience further episodes, a subset of patients experience chronic relapsing pericarditis that can significantly impact their quality of life. Recurrence may develop either from the original etiology or from an autoimmune process that occurs as a consequence of damage from the initial episode. Relapsing pericarditis normally responds to a longer course of NSAIDS ± colchicine. While steroids may induce rapid symptomatic response, their use should be limited to patients who have multiple relapses and are unresponsive to first-line agents, as several studies have suggested that steroid administration may favor relapse.219 Pericardiectomy may be considered a last resort treatment in patients with relapsing pericarditis who are severely symptomatic despite optimal medical management, are unable to tolerate steroids or have recurrence with tamponade. Evidence for this approach is lacking, as few studies have described pericardiectomy in this population.220-222 The largest study and the only one to compare surgical treatment with medical management for patients with persistent relapsing pericarditis was a report of 184 patients from the Mayo Clinic.221 About 58 patients were identified as having undergone a pericardiectomy after failed medical treatment, whereas the remainder were treated with medical management only. Compared to medical treatment only, pericardiectomy resulted in significantly fewer relapses (8.6% vs. 28.6%, P = 0.009) at long term follow-up, as well as a nonsignificant trend towards less medication and corticosteroid usage. Of note, 80% of patients in the pericardiectomy group who had relapses reported significant improvements in their symptoms and had fewer relapses than before pericardiectomy. No perioperative deaths were observed, and only 2 patients (3%) had major complications. Hence, at experienced centers pericardiectomy may be a safe and viable option in select patients with relapsing pericarditis. 773 Chronic Constrictive Pericarditis Etiology, Pathology, and Pathophysiology. Constrictive pericarditis can occur after any pericardial disease process but remains a rare outcome of recurrent pericarditis. It results when chronic pericardial scarring and fibrosis cause adhesion of the visceral and parietal layers and resultant obliteration of the pericardial space. While the pericardium is often grossly thickened with either focal or diffuse calcification in chronic disease, constriction may occur with normal pericardial thickness in approximately 20% of cases.212,223 In developed nations, idiopathic causes and cardiac surgery (accounting for almost 40% of cases in some series) are the predominant underlying etiologies, followed by mediastinal radiation, pyogenic infections (i.e., Staphylococcus), and other miscellaneous causes. Tuberculosis is an additional common cause in immunosuppressed patients and in developing or underdeveloped countries. Clinically, pericardial constriction limits diastolic filling of the ventricles and mimics right heart failure since the rightsided chambers are more affected by a rise in filling pressures. Subsequent increases in central venous pressure result in the progressive development of hepatomegaly, ascites, peripheral edema, abdominal pain, dyspnea on exertion, anorexia, and nausea (in part due to hepatic and bowel congestion). In many patients, these symptoms develop insidiously over a course of years. Since many of these symptoms are similar to those seen in patients with restrictive cardiomyopathy, the distinction between the two entities is difficult, but it remains critical because the treatment is completely different for restriction. The primary difference is that restrictive cardiomyopathy is defined by a nondilated ventricle with a rigid myocardium that causes a significant decrease in myocardial compliance, which is not seen in constrictive pericarditis. Clinical and Diagnostic Findings. Classic physical exam findings include jugular venous distention with Kussmaul’s sign, diminished cardiac apical impulses, peripheral edema, ascites, pulsatile liver, a pericardial knock, and, in advanced disease, signs of liver dysfunction, such as jaundice or cachexia. The “pericardial knock” is an early diastolic sound that reflects a sudden impediment to ventricular filling, similar to an S3 but of higher pitch. Several findings are characteristic on noninvasive and invasive testing. CVP is often elevated 15 to 20 mm Hg or higher. EKG commonly demonstrates nonspecific low voltage QRS complexes and isolated repolarization abnormalities. Chest X-ray may demonstrate calcification of the pericardium, which is highly suggestive of constrictive pericarditis in patients with heart failure, but this is present in only 25% of cases.219 Cardiac CT or MRI (cMRI) typically demonstrate increased pericardial thickness (>4 mm) and calcification, dilation of the inferior vena cava, deformed ventricular contours, and flattening or leftward shift of the ventricular septum. Pericardial adhesions may also be seen on tagged cine MRI studies. As discussed, it is most important to distinguish pericardial constriction from restrictive cardiomyopathy, which is best done with either echocardiography or right heart catheterization. Findings favoring constriction on echocardiography include respiratory variation of ventricular septal motion and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 21 Acquired Heart Disease Echocardiography is routinely performed in the evaluation of acute pericarditis. Its role is primarily to assess for a pericardial effusion.Although, in a patient who can be demonstrated to have previously had normal cardiac function, it may be used to exclude segmental wall motion abnormalities that may suggest ischemia. The remaining work-up should attempt to determine the underlying cause of the pericarditis and should be directed by the history and physical. Most inflammatory markers and laboratory tests are nonspecific, but C-reactive protein (CRP) may be useful in predicting recurrence risks and in guiding the duration of anti-inflammatory medications.218 Rarely, other imaging modalities, such as CT scanning, pericardial biopsies, or pericardiocentesis may aid in diagnosis. 774 mitral inflow velocity, preserved or increased mitral annulus early diastolic filling velocity, and increased hepatic vein flow reversal with expiration.212,219 Cardiac catheterization will show increased atrial pressures, equalization of end-diastolic pressure and early ventricular diastolic filling with a subsequent plateau, called the “square-root sign.” Additional findings upon catheterization that would favor constriction include respiratory variation in ventricular filling and increased ventricular interdependence, manifest as a discordant change in the total area of the LV and RV systolic pressure curve with respiration. UNIT II PART SPECIFIC CONSIDERATIONS Surgical Treatment. Transient constrictive pericarditis may occur weeks to months after an initial injury and follows a self-limiting course of weeks to a few months. These patients are best treated with medical therapy alone. They often lack calcification of their pericardium, and the degree of late gadolinium enhancement of the pericardium on cardiac MRI has shown promise in predicting which patients may have resolution of the process.224 Still, there is no ideal way to distinguish these patients from those who will develop chronic constrictive pericarditis, which is permanent. Therefore, if a newly diagnosed patient is hemodynamically stable, it is recommended that conservative management is attempted for two to three months prior to performing a pericardiectomy.223 Surgical therapy should not be delayed indefinitely, however, as results are improved when the operation is performed earlier in the course of the disease. Additional factors that predict adverse longterm outcomes include older age and prior ionizing radiation, as well as cardiopulmonary and renal dysfunction.219 Surgery should therefore be approached cautiously in patients with very advanced, “end-stage” constrictive pericarditis, patients with mixed constrictive-restrictive disease (often from radiation), and those with significant myocardial or renal dysfunction, as those patients are at increased risk from surgery and may not experience improvement of symptoms. In order to minimize recurrence following pericardiectomy, complete pericardial resection is desirable. This is typically performed through either a median sternotomy or left anterolateral thoracotomy while on cardiopulmonary bypass. Radical pericardiectomy involves wide resection of the constricting pericardium from the anterior surface of the heart between the phrenic nerves and the diaphragmatic surface. Decortication of the right atrium and vena cavae is not universally performed, but doing so improves the risk of persistent disease or relapse.225,226 The extent of myocardial involvement may also affect long-term outcomes, and, thus, the depth of decortication is an important consideration.225 Even when an adequate pericardiectomy is performed, epicardial sclerosis can cause persistent hemodynamic instability or a delayed response to surgery. Sclerotic epicardium is often thin and nearly transparent, but in cases of severe chronic constrictive pericarditis it can be difficult to remove it without injury to the heart. Surgical Results. While most patients experience significant improvement in their symptoms following pericardiectomy, symptomatic relief may take several months. Since there is a significant perioperative morbidity and mortality, pericardiectomy is best performed by experienced surgeons at high-volume centers. Between 1970 and 1985, the operative mortality was reported to be 12%, but a lower mortality of approximately 4% to 8% was noted between 1977 and 2006 at several experienced centers.223,226-230 Long-term survival is in part determined by etiology of the disease. In a report from the Cleveland Clinic, seven-year survival rates following pericardiectomy for idiopathic, postsurgical, and radiation-induced constrictive pericarditis were 88%, 66%, and 27%, respectively.227 Results are worst for radiationinduced disease because ionizing radiation is often associated with myocardial injury as well as pericardial disease. Despite the risks, many patients experience significant benefits from surgical treatment. In one large series, 83% of patients were reported to be free of symptoms at last followup.230 This is in agreement with other studies that have shown a significant improvement in NYHA functional status from class III/IV preoperatively to class I/II following pericardiectomy in >95% of patients.226,228-230 CARDIAC NEOPLASMS Overview and General Clinical Features Cardiac neoplasms are rare, with an incidence ranging from 0.001% to 0.3% in autopsy studies and a 0.15% incidence in major echocardiographic series.231,232 Benign cardiac tumors are most common and account for 75% of primary neoplasms. Approximately 50% of benign cardiac tumors are myxomas, with the remainder being papillary fibroelastomas, lipomas, rhabdomyomas, fibromas, hemangiomas, teratomas, lymphangiomas, and others, in order of decreasing frequency. Most malignant primary cardiac tumors are sarcomas (angiosarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, and liposarcoma), with a small incidence of malignant lymphomas. Metastatic cardiac tumors, while still infrequent, have been reported to occur 100-fold more often than primary lesions. Clinical Presentation. The clinical presentation of cardiac neoplasms varies greatly depending on the location of the tumor, as well as its size, rate of growth, invasiveness, and friability. While as many as 10% of patients are asymptomatic, most manifest some combination of symptoms from the classic triad resulting from blood flow obstruction, tumor embolization, and constitutional symptoms.233,234 Systemic manifestations of disease include fever, myalgias, chills, night sweats, weight loss, and fatigue and occur in up to one-third of patients. Obstruction of cardiac blood flow accounts for the majority of presenting symptoms.234 When the tumor is located in the left atrium, symptoms tend to mimic mitral valve disease with dyspnea and pulmonary edema; although more severe presentations with syncopal episodes, hypotension, and sudden cardiac death have been reported from temporary valve orifice occlusion. When the tumor is located in the right atrium, symptoms may mimic right heart failure and include hepatomegaly, ascites, and peripheral edema. Outflow tract obstruction is rare but may be caused by large ventricular tumors.235 Tumor lysis and embolization may also lead to neurologic presentations such as stroke, retinal artery occlusion, or cerebral aneurysms, particularly in the case of pedunculated tumors and those with frond-like projections.236 Embolic tumor cells are able to lodge and penetrate distant vessel walls via subintimal growth, which leads to weakening of the arterial wall and subsequent aneurysm formation. This has been documented as late as five years out from successful primary myxoma resection.237 Alternatively, embolic implants may metastasize and create space occupying lesions. While rare, myxomatous tumor emboli have also been identified in the coronary arteries, common iliac and femoral arteries, kidney, spleen, pancreas, and liver.236 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Diagnosis and Characterization of Cardiac Masses. Transthoracic echocardiography is the mainstay imaging technique for the detection of cardiac tumors.234 However, echocardiography is limited by dependence on an acoustic window, suboptimal visualization of extracardiac extension, and poor soft-tissue visualization. Transesophageal echocardiography is generally only beneficial for small localized tumors due to its limited field of view. Cardiac MRI is therefore the current standard for delineating the anatomical extent of the tumor and assessing the paracardiac space and great vessels. Advantages of cMRI over CT scans include better soft-tissue evaluation without the need for iodinated contrast and no exposure to ionizing radiation. It is important in the initial workup to distinguish a cardiac tumor from an intracardiac thrombus, which may be common in the atria of patients with AF and can mimic echocardiographic features of atrial myxomas. This determination is critical, as an atrial thrombus may be expected to resolve with anticoagulation, whereas a tumor requires surgical intervention. Moreover, anticoagulation can potentially increase the risk of peripheral embolization in patients with cardiac tumors. Delayed enhancement cMRI is the best modality to separate these two entities. cMRI may show vascularization, areas of necrosis, hemorrhage, or calcification in cardiac tumors that are not present in thrombi. Myxoma Pathology and Genetics. Cardiac myxomas are the most common cardiac tumor and are characterized by several distinguishing features. About 75% of the time, they arise 10 from the interatrial septum near the fossa ovalis in the left atrium.238 Most others will develop in the right atrium, but, less commonly, they can arise from valvular surfaces and the walls of other cardiac chambers. Macroscopically, these tumors are pedunculated with a gelatinous consistency, and the surface may be smooth (65%), villous, or friable.233 Size varies greatly with these tumors and ranges from 1 to 15 cm in diameter. Internally, myxomas are heterogeneous and often contain hemorrhage, cysts, necrosis, or calcification. Histologically, these tumors contain cells that arise from a multipotent mesenchyme and are contained within a mucopolysaccharide stroma.239 While the majority of myxomas occur spontaneously with the highest incidence in women aged 40 to 60 years old, approximately 7% of cases are familial as part of Carney complex.233 Carney complex is an autosomal dominant disorder characterized by two or more of the following conditions: atrial and extracardiac myxomas, schwannomas, cutaneous lentiginosis, spotty pigmentation, myxoid fibroadenomas of the breast, endocrine overactivity (pituitary adenomas or primary adrenal hyperplasia with Cushing’s syndrome), and testicular tumors. Compared to sporadic myxomas, those that occur as part of Carney complex are more commonly found in the right atrium (37% vs. 18%) or one of the ventricles (25% vs. 0%), more often multicentric (33% vs. 6%) and more likely to recur (20% vs. 3%).238 They also present earlier at an average age of 24 years old (range 4–48 years). Pathophysiology. Larger tumors are more likely to be associated with cardiovascular symptoms from obstruction, and embolic symptoms tend to occur from organized thrombi present on friable or villous tumors (Fig. 21-15). The relative frequencies of symptoms was illustrated by a series of 112 patients who reported cardiovascular symptoms (67%), most commonly resembling mitral valve obstruction; systemic embolization (29%); neurologic deficits (20%); and constitutional symptoms (34%).233 Similar incidences of symptoms have been reported in other large studies. Treatment. Cardiac myxomas should be promptly excised after diagnosis due to the significant risk of embolization and cardiovascular complications, including sudden death. Resection may be performed through either a median sternotomy or a minimally invasive right thoracotomy while on cardiopulmonary bypass. Care is taken not to manipulate the tumor before cross clamping of the aorta in order to avoid embolization. Left atrial tumors may be approached through a standard left atriotomy.240 Exposure of large tumors attached to the interatrial septum may be facilitated by an additional parallel incision in the right atrium, but this is rarely necessary. An ideal resection encompasses both the tumor and a portion of the cardiac wall or interatrial septum to which it is attached. In order to prevent recurrence, a full thickness excision of the attachment site is Figure 21-15. Massive left atrial myxoma. A. Intraoperative echocardiogram of a large left atrial mass, diagnosed preoperatively as a left atrial myxoma. The mass can be seen prolapsing through the mitral valve orifice causing intermittent symptoms of mitral stenosis. B. The resected specimen. The neck of the mass that was obstructing the mitral orifice is clearly delineated. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 775 CHAPTER 21 Acquired Heart Disease Certain clinical features may be helpful in distinguishing benign from malignant primary cardiac tumors234 Malignant tumors, primarily sarcomas, do not demonstrate a gender preference and tend to present after the fourth decade of life. They are often multifocal within the right atrium, and intramyocardial invasion can lead to refractory congestive heart failure, arrhythmias, hemopericardium, and ischemia. Conversely, benign tumors, primarily myxomas, are typically unifocal in the left atrium, have a 3:1 female preference, and occur in younger patients. Arrhythmias and pericardial effusions are very rare in this population. 776 UNIT II PART preferred, but partial thickness excisions and cryoablation of the base have been performed with good late results.240 The defect created in the atrial septum can either be repaired primarily or with a small patch. Finally, patients with valvular involvement may require additional valvular reconstruction or replacement, and rare cases of cardiac autotransplantation (with atrial reconstruction) or transplantation have been reported as strategies for complex cases of recurrent atrial myxoma.241,242 Short- and long-term results following excision are excellent for benign cardiac myxomas. Operative mortality is low, and the probability of disease-free survival at 20 years has been reported to be as high as 92% for benign, sporadic myxomas.233,240 Risk of recurrence is significantly higher for familial cases. Other Benign Cardiac Tumors SPECIFIC CONSIDERATIONS There are several benign cardiac tumors apart from myxomas that are infrequent but have distinct pathophysiologic features.234 Papillary fibroelastomas are the second most common primary cardiac tumor, representing approximately 8% of all cases. These tumors typically occur in more elderly patients; are small (<1 cm in diameter) sessile, pedunculated masses that arise from the mitral or aortic valves; and frequently result in embolization. Fibroelastomas can almost always be resected with preservation of the native valve leaflets, and cryoablation of the valve leaflet after resection can help prevent recurrence. Lipomas are encapsulated tumors that usually arise from the epicardium and remain asymptomatic in most patients. Hemangiomas, which may arise from any cardiac structure, including the pericardium, account for 2% of benign cardiac tumors, and atrioventricular node tumors, which often lead to sudden cardiac death from heart block and ventricular fibrillation, are exceedingly rare. In children, rhabdomyomas are the most common primary cardiac tumor, whereas fibromas are the most commonly resected cardiac tumor. Rhabdomyomas are myocardial hamartomas that are often multicentric in the ventricles. About 50% of cases are associated with tuberous sclerosis, and while resection is occasionally necessary, most disappear spontaneously. Fibromas are congenital lesions that one-third of the time are found in children younger than one-year old. These tumors, conversely, are ordinarily solitary lesions found in the inner interventricular septum, and they may present with heart failure, cyanosis, arrhythmias, syncopal episodes, chest pain, or sudden cardiac death. Malignant Cardiac Tumors Primary cardiac malignancies are very rare, but when they occur they tend to have a right-sided predominance and frequently demonstrate extracardiac extension and involvement.234,243 Malignant cardiac tumors include angiosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, and primary cardiac lymphomas. Angiosarcomas are aggressive, rapidly invading adjacent structures, and 47% to 89% of patients present with lung, liver, or brain metastases by the time of diagnosis. Leiomyosarcomas are sessile masses with a mucous appearance that are typically found in the posterior wall of the left atrium. Rhabdomyosarcomas are bulky (>10 cm in diameter) tumors that usually occur in children and do not have a predilection for any particular chamber. They frequently invade nearby cardiac structures and are multicentric in 60% of cases. Finally, while not as frequent as secondary cardiac lymphomas, primary cardiac lymphomas are increasing in frequency due to lymphoproliferative disorders caused by Epstein-Barr virus in immunosuppressed patients. The absence of necrotic foci in lymphomas can be used to differentiate these tumors from cardiac sarcomas. Metastatic Cardiac Tumors Cardiac metastases have been found in approximately 10% of autopsies performed for malignant disease.234 Secondary cardiac tumors, unlike primary tumors, are therefore relatively common. They may arise from direct extension of mediastinal tumors, hematological spread, intracavitary extension from the inferior vena cava or lymphatic extension, although the latter is the most common mechanism. While they can occur with most any primary tumor, they are generally observed late in the course of disease. Malignant melanomas have a high potential for cardiac involvement, but other soft tissue tumors such as lung cancer, breast cancer, sarcomas, renal carcinoma, esophageal cancer, hepatocellular carcinoma, and thyroid cancer may all progress to cardiac involvement. Cardiac metastases may also develop from leukemia and lymphoma in 25% to 40% of cases.244 Metastatic cardiac tumors are typically found in random locations, excluding the valvular tissue where lymphatics are absent, and they may be multifocal or diffusely extend along the epicardial surface. Signs of malignant cardiac involvement in cancer patients include pericardial effusion or tamponade, tachyarrhythmias, and heart failure symptoms. Workup is similar to other cardiac tumors. Treatment is generally with combined chemotherapy and radiation and is rarely effective. REFERENCES Entries highlighted in bright blue are key references. 1. Braunwald E, Bonow RO. 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Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation. 2012;126:S54-S64. 181. Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of allogeneic vs. autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308:2369-2379. 182. Miller LW, Pagani FD, Russell SD, et al. Use of a continuousflow device in patients awaiting heart transplantation. N Engl J Med. 2007;357:885-896. 183. Frazier OH, Rose EA, Oz MC, et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg. 2001;122:1186-1195. 184. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation. 2012;125: 3191-3200. 185. John R, Pagani FD, Naka Y, et al. Post-cardiac transplant survival after support with a continuous-flow left ventricular assist device: impact of duration of left ventricular assist device support and other variables. J Thorac Cardiovasc Surg. 2010;140:174-181. 186. Pal JD, Piacentino V, Cuevas AD, et al. Impact of left ventricular assist device bridging on posttransplant outcomes. Ann Thorac Surg. 2009;88:1457-1461; discussion 1461. 187. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med. 2009;361:2241-2251. 188. John R, Liao K, Kamdar F, Eckman P, Boyle A, ColvinAdams M. Effects on pre- and posttransplant pulmonary hemodynamics in patients with continuous-flow left ventricular assist devices. J Thorac Cardiovasc Surg. 2010;140: 447-452. 189. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 781 CHAPTER 21 Acquired Heart Disease 154. Bogaert J, Maes A, Van de Werf F, et al. Functional recovery of subepicardial myocardial tissue in transmural myocardial infarction after successful reperfusion: an important contribution to the improvement of regional and global left ventricular function. Circulation. 1999;99:36-43. 155. Dor V, Sabatier M, Montiglio F, Civaia F, DiDonato M. Endoventricular patch reconstruction of ischemic failing ventricle. A single center with 20 years experience. Advantages of magnetic resonance imaging assessment. Heart Fail Rev. 2004;9:269-286. 156. Fenoglio JJ Jr. Pham TD, Harken AH, Horowitz LN, Josephson ME, Wit AL. Recurrent sustained ventricular tachycardia: structure and ultrastructure of subendocardial regions in which tachycardia originates. Circulation. 1983;68:518-533. 157. Scherlag BJ, el-Sherif N, Hope R, Lazzara R. Characterization and localization of ventricular arrhythmias resulting from myocardial ischemia and infarction. Circ Res. 1974;35: 372-383. 158. Koilpillai C, Quinones MA, Greenberg B, et al. Relation of ventricular size and function to heart failure status and ventricular dysrhythmia in patients with severe left ventricular dysfunction. Am J Cardiol. 1996;77:606-611. 159. Hassapoyannes CA, Stuck LM, Hornung CA, Berbin MC, Flowers NC. Effect of left ventricular aneurysm on risk of sudden and nonsudden cardiac death. Am J Cardiol. 1991;67: 454-459. 160. Sartipy U, Albage A, Lindblom D. Improved health-related quality of life and functional status after surgical ventricular restoration. Ann Thorac Surg. 2007;83:1381-1387. 161. Isomura T. Surgical left ventricular reconstruction. Gen Thorac Cardiovasc Surg. 2011;59:315-325. 162. Maxey TS, Reece TB, Ellman PI, et al. Coronary artery bypass with ventricular restoration is superior to coronary artery bypass alone in patients with ischemic cardiomyopathy. J Thorac Cardiovasc Surg. 2004;127:428-434. 163. Mickleborough LL, Merchant N, Ivanov J, Rao V, Carson S. Left ventricular reconstruction: Early and late results. J Thorac Cardiovasc Surg. 2004;128:27-37. 164. Athanasuleas CL, Buckberg GD, Stanley AW, et al. Surgical ventricular restoration: the RESTORE Group experience. Heart Fail Rev. 2004;9:287-297. 165. Dor V, Sabatier M, Montiglio F, Rossi P, Toso A, Di Donato M. Results of nonguided subtotal endocardiectomy associated with left ventricular reconstruction in patients with ischemic ventricular arrhythmias. J Thorac Cardiovasc Surg. 1994;107:1301-1307; discussion 1307-1308. 166. Sartipy U, Albage A, Straat E, Insulander P, Lindblom D. Surgery for ventricular tachycardia in patients undergoing left ventricular reconstruction by the Dor procedure. Ann Thorac Surg. 2006;81:65-71. 167. Matthias Bechtel JF, Tolg R, Graf B, et al. High incidence of sudden death late after anterior LV-aneurysm repair. Eur J Cardiothorac Surg. 2004;25:807-811. 168. O’Neill JO, Starling RC, Khaykin Y, et al. Residual high incidence of ventricular arrhythmias after left ventricular reconstructive surgery. J Thorac Cardiovasc Surg. 2005;130:1250-1256. 169. Buckberg GD, Athanasuleas CL. The STICH trial: misguided conclusions. J Thorac Cardiovasc Surg. 2009;138: 1060-1064e2. 170. Dor V, Civaia F, Alexandrescu C, Sabatier M, Montiglio F. Favorable effects of left ventricular reconstruction in patients excluded from the Surgical Treatments for Ischemic Heart Failure (STICH) trial. J Thorac Cardiovasc Surg. 2011;141:905-916, 16 e1-e4. 171. Kang N, Edwards M, Larbalestier R. Preoperative intraaortic balloon pumps in high-risk patients undergoing open heart surgery. Ann Thorac Surg. 2001;72:54-57. 782 190. 191. 192. UNIT II PART 193. SPECIFIC CONSIDERATIONS 195. 194. 196. 197. 198. 199. 200. 201. 202. 203. 204. 205. 206. 207. 208. ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg. 2010;139:1316-1324. Neragi-Miandoab S. A ventricular assist device as a bridge to recovery, decision making, or transplantation in patients with advanced cardiac failure. Surg Today. 2012;42:917-926. Copeland JG, Smith RG, Arabia FA, et al. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004;351:859-867. El-Hamamsy I, Jacques F, Perrault LP, et al. Results following implantation of mechanical circulatory support systems: the Montreal Heart Institute experience. The Can J Cardiol. 2009;25:107-110. Meyer A, Slaughter M. The total artificial heart. Panminerva Med. 2011;53:141-154. Gammie JS, Haddad M, Milford-Beland S, et al. Atrial fibrillation correction surgery: lessons from the Society of Thoracic Surgeons National Cardiac Database. Ann Thorac Surg. 2008;85:909-914. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm 2012;(4):632-696 e21. Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention. Ann Intern Med. 1999;131:688-695. Zimetbaum P. Antiarrhythmic drug therapy for atrial fibrillation. Circulation. 2012;125:381-389. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109:1509-1513. Cox JL, Ad N, Palazzo T. Impact of the maze procedure on the stroke rate in patients with atrial fibrillation. J Thorac Cardiovasc Surg. 1999;118:833-840. Feinberg MS, Waggoner AD, Kater KM, Cox JL, Lindsay BD, Perez JE. Restoration of atrial function after the maze procedure for patients with atrial fibrillation. Assessment by Doppler echocardiography. Circulation. 1994;90:II285-II292. Weimar T, Bailey MS, Watanabe Y, et al. The Cox-maze IV procedure for lone atrial fibrillation: a single center experience in 100 consecutive patients. J Interv Card Electrophysiol. 2011;31:47-54. Damiano RJ Jr., Schwartz FH, Bailey MS, et al. The Cox maze IV procedure: predictors of late recurrence. J Thorac Cardiovasc Surg. 2011;141:113-121. Lall SC, Melby SJ, Voeller RK, et al. The effect of ablation technology on surgical outcomes after the Cox-maze procedure: a propensity analysis. J Thorac Cardiovasc Surg. 2007;133:389-396. Pet M, Robertson JO, Bailey M, et al. The impact of CHADS(2) score on late stroke after the Cox maze procedure. J Thorac Cardiovasc Surg. 2013;146(1):85-9. Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med. 1996;156:409-416. Barnett SD, Ad N. Surgical ablation as treatment for the elimination of atrial fibrillation: a meta-analysis. J Thorac Cardiovasc Surg. 2006;131:1029-1035. Schuessler RB, Kay MW, Melby SJ, Branham BH, Boineau JP, Damiano RJ Jr. Spatial and temporal stability of the dominant frequency of activation in human atrial fibrillation. J Electrocardiol. 2006;39:S7-S12. Edgerton JR, Edgerton ZJ, Weaver T, et al. Minimally invasive pulmonary vein isolation and partial autonomic denervation for surgical treatment of atrial fibrillation. Ann Thorac Surg. 2008;86:35-38; discussion 39. 209. Boersma LV, Castella M, van Boven W, et al. Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): a 2-center randomized clinical trial. Circulation. 2012;125:23-30. 210. Imazio M, Trinchero R. Clinical management of acute pericardial disease: a review of results and outcomes. Ital Heart J. 2004;5:803-817. 211. Launbjerg J, Fruergaard P, Hesse B, Jorgensen F, Elsborg L, Petri A. Long-term risk of death, cardiac events, and recurrent chest pain in patients with acute chest pain of different origin. Cardiology. 1996;87:60-66. 212. Dudzinski DM, Mak GS, Hung JW. Pericardial diseases. Curr Probl Cardiol. 2012;37:75-118. 213. Lange RA, Hillis LD. Clinical practice. Acute pericarditis. N Engl J Med. 2004;351:2195-2202. 214. Spodick DH. Acute pericarditis: current concepts and practice. JAMA. 2003;289:1150-1153. 215. Imazio M, Demichelis B, Parrini I, et al. Day-hospital treatment of acute pericarditis: a management program for outpatient therapy. J Am Coll Cardiol. 2004;43:1042-1046. 216. Bruce MA, Spodick DH. Atypical electrocardiogram in acute pericarditis: characteristics and prevalence. J Electrocardiol. 1980;13:61-66. 217. Salisbury AC, Olalla-Gomez C, Rihal CS, et al. Frequency and predictors of urgent coronary angiography in patients with acute pericarditis. Mayo ClinProc. 2009;84:11-15. 218. Imazio M, Brucato A, Maestroni S, et al. Prevalence of C-reactive protein elevation and time course of normalization in acute pericarditis: implications for the diagnosis, therapy, and prognosis of pericarditis. Circulation. 2011;123:1092-1097. 219. Khandaker MH, Espinosa RE, Nishimura RA, et al. Pericardial disease: diagnosis and management. Mayo Clinic Proc. 2010;85:572-593. 220. Fowler NO. Recurrent pericarditis. Cardiol Clin. 1990;8: 621-626. 221. Khandaker MH, Schaff HV, Greason KL, et al. Pericardiectomy vs. Medical Management in Patients With Relapsing Pericarditis. Mayo Clinic Proc. 2012;87:1062-1070. 222. Tuna IC, Danielson GK. Surgical management of pericardial diseases. Cardiol Clin. 1990;8:683-696. 223. Azam S, Hoit BD. Treatment of pericardial disease. Cardiovasc Ther. 2011;29:308-314. 224. Feng D, Glockner J, Kim K, et al. Cardiac magnetic resonance imaging pericardial late gadolinium enhancement and elevated inflammatory markers can predict the reversibility of constrictive pericarditis after anti-inflammatory medical therapy: a pilot study. Circulation. 2011;124:1830-1837. 225. Ariyoshi T, Hashizume K, Taniguchi S, et al. Surgical experience with chronic constrictive pericarditis. Gen Thorac Cardiovas Surg. 2012;60:796-802. 226. Chowdhury UK, Subramaniam GK, Kumar AS, et al. Pericardiectomy for constrictive pericarditis: a clinical, echocardiographic, and hemodynamic evaluation of two surgical techniques. Ann Thorac Surg. 2006;81:522-529. 227. Bertog SC, Thambidorai SK, Parakh K, et al. Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy. J Am Coll Cardiol. 2004;43:1445-1452. 228. DeValeria PA, Baumgartner WA, Casale AS, et al. Current indications, risks, and outcome after pericardiectomy. Ann Thorac Surg. 1991;52:219-224. 229. Ghavidel AA, Gholampour M, Kyavar M, Mirmesdagh Y, Tabatabaie MB. Constrictive pericarditis treated by surgery. Tex Heart Inst J. 2012;39:199-205. 230. Ling LH, Oh JK, Schaff HV, et al. Constrictive pericarditis in the modern era: evolving clinical spectrum and impact on outcome after pericardiectomy. Circulation. 1999;100:1380-1386. 231. Abushaban L, Denham B, Duff D. 10 year review of cardiac tumours in childhood. Br Heart J. 1993;70:166-169. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 239. Pucci A, Gagliardotto P, Zanini C, Pansini S, di Summa M, Mollo F. Histopathologic and clinical characterization of cardiac myxoma: review of 53 cases from a single institution. Am Heart J. 2000;140:134-138. 240. Bakaeen FG, Reardon MJ, Coselli JS, et al. Surgical outcome in 85 patients with primary cardiac tumors. Am J Surg. 2003;186:641-647; discussion 647. 241. Gammie JS, Abrishamchian AR, Griffith BP. Cardiac autotransplantation and radical bi-atrial resection for recurrent atrial myxoma. Ann Thorac Surg. 2007;83:1545-1547. 242. Goldstein DJ, Oz MC, Michler RE. Radical excisional therapy and total cardiac transplantation for recurrent atrial myxoma. Ann Thorac Surg. 1995;60:1105-1107. 243. Putnam JB Jr., Sweeney MS, Colon R, Lanza LA, Frazier OH, Cooley DA. Primary cardiac sarcomas. Ann Thorac Surg. 1991;51:906-910. 244. Neragi-Miandoab S, Kim J, Vlahakes GJ. Malignant tumours of the heart: a review of tumour type, diagnosis and therapy. Clin Oncol (R Coll Radiol). 2007;19:748-756. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 783 CHAPTER 21 Acquired Heart Disease 232. Reynen K. Frequency of primary tumors of the heart. Am J Cardiol. 1996;77:107. 233. Pinede L, Duhaut P, Loire R. Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases. Medicine. 2001;80:159-172. 234. Castillo JG, Silvay G. Characterization and management of cardiac tumors. Semin Cardiothorac Vasc Anesth. 2010; 14:6-20. 235. Kusano KF, Ohe T. Cardiac tumors that cause arrhythmias. Card Electrophysiol Rev. 2002;6:174-177. 236. Lee VH, Connolly HM, Brown RD Jr. Central nervous system manifestations of cardiac myxoma. Arch Neurol. 2007;64:1115-1120. 237. Jean WC, Walski-Easton SM, Nussbaum ES. Multiple intracranial aneurysms as delayed complications of an atrial myxoma: case report. Neurosurgery. 2001;49:200-202; discussion 202-203. 238. Jain D, Maleszewski JJ, Halushka MK. Benign cardiac tumors and tumorlike conditions. Ann Diagn Pathol. 2010;14:215-230. This page intentionally left blank VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 22 chapter Anatomy of the Aorta Thoracic Aortic Aneurysms 785 785 Causes and Pathogenesis / 786 Clinical History / 789 Clinical Manifestations / 789 Diagnostic Evaluation / 789 Treatment / 791 Aortic Dissection Thoracic Aneurysms and Aortic Dissection Scott A. LeMaire, Raja R. Gopaldas, and Joseph S. Coselli Pathology and Classification / 806 Causes and Clinical History / 809 Clinical Manifestations / 809 Diagnostic Evaluation / 810 Treatment / 812 Outcomes 806 Repair of Distal Aortic Aneurysms / 819 Treatment of Acute Descending Aortic Dissection / 820 816 Conclusions Acknowledgments 820 820 Repair of Proximal Aortic Aneurysms / 817 Treatment of Acute Ascending Aortic Dissection / 819 ANATOMY OF THE AORTA THORACIC AORTIC ANEURYSMS The aorta consists of two major segments—the proximal aorta and the distal aorta—whose anatomic characteristics affect both the clinical manifestations of disease in these segments and the selection of treatment strategies for such disease (Fig. 22-1). The proximal aortic segment includes the ascending aorta and the transverse aortic arch. The ascending aorta begins at the aortic valve and ends at the origin of the innominate artery. The first portion of the ascending aorta is the aortic root, which includes the aortic valve annulus and the three sinuses of Valsalva; the coronary arteries originate from two of these sinuses. The aortic root joins the tubular portion of the ascending aorta at the sinotubular ridge. The transverse aortic arch is the area from which the brachiocephalic branches arise. The distal aortic segment includes the descending thoracic aorta and the abdominal aorta. The descending thoracic aorta begins distal to the origin of the left subclavian artery and extends to the diaphragmatic hiatus, where it joins the abdominal aorta. The descending thoracic aorta gives rise to multiple bronchial and esophageal branches, as well as to the segmental intercostal arteries, which provide circulation to the spinal cord. The volume of blood that flows through the thoracic aorta at high pressure is far greater than that found in any other vascular structure. For this reason, any condition that disrupts the integrity of the thoracic aorta, such as aortic dissection, aneurysm rupture, or traumatic injury, can have catastrophic consequences. Historically, open surgical repair of such conditions has been an intimidating undertaking associated with significant morbidity and mortality. Strategies for protecting the brain and spinal cord during such repairs have become critical in preventing devastating complications. In recent years, endovascular therapy for thoracic aortic disease in selected patients has become accepted practice, producing fewer adverse outcomes than traditional approaches do. Aortic aneurysm is defined as a permanent, localized dilatation of the aorta to a diameter that is at least 50% greater than is normal at that anatomic level.1 The annual incidence of thoracic aortic aneurysms is estimated to be 5.9 per 100,000 persons.2 The clinical manifestations, methods of treatment, and treatment results in patients with aortic aneurysms vary according to the cause and the aortic segment involved. Causes of thoracic aortic aneurysms include degenerative disease of the aortic wall, aortic dissection, aortitis, infection, and trauma. Aneurysms can be localized to a single aortic segment, or they can involve multiple segments. Thoracoabdominal aortic aneurysms, for example, involve both the descending thoracic aorta and the abdominal aorta. In the most extreme cases, the entire aorta is aneurysmal; this condition is often called mega-aorta. Aortic aneurysms can be either “true” or “false.” True aneurysms can take two forms: fusiform and saccular. Fusiform aneurysms are more common and can be described as symmetrical dilatations of the aorta. Saccular aneurysms are localized outpouchings of the aorta. False aneurysms, also called pseudoaneurysms, are leaks in the aortic wall that are contained by the outer layer of the aorta and/or the periaortic tissue; they are caused by disruption of the aortic wall and lead blood to collect in pouches of fibrotic tissue. Aneurysms of the thoracic aorta consistently increase in size and eventually progress to cause serious complications. These include rupture, which is usually a fatal event. Therefore, aggressive treatment is indicated in all but the poorest surgical candidates. Small, asymptomatic thoracic aortic aneurysms can be followed, especially in high-surgical-risk patients, and can be treated surgically later if symptoms or complications develop, or if progressive enlargement occurs. Meticulous control of hypertension is the primary medical treatment for patients with small, asymptomatic aneurysms. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Key Points 1 2 Part II 3 4 Assessing urgency of repair is essential to developing the appropriate management plan. Although emergent repair carries greater operative risk than does elective repair, any inappropriate delay of repair risks death. The clinical progression of an aortic aneurysm is continued expansion and eventual rupture. Hence, regular noninvasive imaging studies, as part of a lifelong surveillance plan, are necessary to ensure long-term patient health. Even small asymptomatic aneurysms should be routinely imaged to assess overall growth and yearly rate of expansion. Endovascular repair devices are approved for the treatment of descending thoracic aortic aneurysms, and some of the newer devices are also approved for the treatment of aortic trauma and penetrating aortic ulcer. Practice guidelines were recently published that have helped to standardize the decision-making process and select an appropriate surgical intervention, as well as to standardize the use of imaging studies for patients with thoracic aortic disease. 5 6 7 8 Ascending aortic aneurysms that are symptomatic or >5.5 cm should be repaired. This threshold is lowered for patients with connective tissue disorders. Surgical repair involves the development of a patient-­ tailored plan based on careful preoperative medical evaluation. When appropriate, optimizing a patient’s health status—to mitigate existing comorbidities—is important before surgical intervention. The development and use of surgical adjuncts like antegrade selective cerebral perfusion and cerebrospinal fluid drainage have significantly reduced the morbidity rates traditionally associated with complex aortic repair. Proximal aortic dissection is a life-threatening condition, and immediate operative repair is generally indicated, although definitive aortic repair may be delayed until after severe malperfusion has been treated. nancy. An emergency operation is performed for any patient in whom a ruptured aneurysm is suspected. Patients with thoracic aortic aneurysm often have coexisting aneurysms of other aortic segments. A common cause of death after repair of a thoracic aortic aneurysm is rupture of a different aortic aneurysm. Therefore, staged repair of multiple aortic segments often is necessary. As with any major operation, careful preoperative evaluation for coexisting disease and subsequent medical optimization are important for successful surgical treatment. An alternative to traditional open repair of a descending thoracic aortic aneurysm is endovascular stent grafting. Certain anatomic criteria need to be satisfied for this treatment option to be considered, including the presence of at least a 2-cm landing zone of healthy aortic tissue proximally and distally to the aneurysm to be excluded. Although data on long-term outcomes are still lacking, endovascular repair of a descending thoracic aortic aneurysm has become an accepted practice that produces excellent midterm results. Causes and Pathogenesis General Considerations. The normal aorta derives its elastic- Figure 22-1. Illustration of normal thoracic aortic anatomy. The brachiocephalic vessels arise from the transverse aortic arch and are used as anatomic landmarks to define the aortic regions. The ascending aorta is proximal to the innominate artery, whereas the descending aorta is distal to the left subclavian artery. 786 Elective resection with graft replacement is indicated in asymptomatic patients with an aortic diameter of at least twice normal in the involved segment (5–6 cm in most thoracic segments). Elective repair is contraindicated by extreme operative risk due to severe coexisting cardiac or pulmonary disease and by other conditions that limit life expectancy, such as malig- ity and tensile strength from the medial layer, which contains approximately 45 to 55 lamellae of elastin, collagen, smooth muscle cells, and ground substance. Elastin content is highest within the ascending aorta, as would be expected because of its compliant nature, and decreases distally into the descending and abdominal aorta. Maintenance of the aortic matrix involves complex interactions among smooth muscle cells, macrophages, proteases, and protease inhibitors. Any alteration in this delicate balance can lead to aortic disease. Thoracic aortic aneurysms have a variety of causes (Table 22-1). Although these disparate pathologic processes differ in biochemical and histologic terms, they share the final common pathway of progressive aortic expansion and eventual rupture. Hemodynamic factors clearly contribute to the process of aortic dilatation. The vicious cycle of increasing diameter and increasing wall tension, as characterized by Laplace’s law VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Causes of thoracic aortic aneurysms Nonspecific medial degeneration Aortic dissection Genetic disorders Marfan syndrome Loeys-Dietz syndrome Ehlers-Danlos syndrome Familial aortic aneurysms Aneurysms-Osteoarthritis syndrome Congenital bicuspid aortic valve Bovine aortic arch Poststenotic dilatation Infection Aortitis Takayasu arteritis Giant cell arteritis Rheumatoid aortitis Trauma (tension = pressure × radius), is well established. Turbulent blood flow is also recognized as a factor. Poststenotic aortic dilatation, for example, occurs in some patients with aortic valve stenosis or coarctation of the descending thoracic aorta. Hemodynamic derangements, however, are only one piece of a complex puzzle. Atherosclerosis is commonly cited as a cause of thoracic aortic aneurysms. However, although atherosclerotic disease often is found in conjunction with aortic aneurysms, the notion that atherosclerosis is a distinct cause of aneurysm formation has been challenged. In most thoracic aortic aneurysms, atherosclerosis appears to be a coexisting process, rather than the underlying cause. Research into the pathogenesis of abdominal aortic aneurysms has focused on the molecular mechanisms of aortic wall degeneration and dilatation. For example, imbalances between proteolytic enzymes (e.g., matrix metalloproteinases) and their inhibitors contribute to abdominal aortic aneurysm formation. Building on these advances, current investigations are attempting to determine whether similar inflammatory and proteolytic mechanisms are involved in thoracic aortic disease, in hope of identifying potential molecular targets for pharmacologic therapy. Nonspecific Medial Degeneration. Nonspecific medial degeneration is the most common cause of thoracic aortic disease. Histologic findings of mild medial degeneration, including fragmentation of elastic fibers and loss of smooth muscle cells, are expected in the aging aorta. However, an advanced, accelerated form of medial degeneration leads to progressive weakening of the aortic wall, aneurysm formation, and eventual dissection, rupture, or both. The underlying causes of medial degenerative disease remain unknown. Aortic Dissection. An aortic dissection usually begins as a tear in the inner aortic wall, which initiates a progressive separation of the medial layers and creates two channels within the aorta. This event profoundly weakens the outer wall. As the most common catastrophe involving the aorta, dissection represents a major, distinct cause of thoracic aortic aneurysms and is discussed in detail in the second half of this chapter. Genetic Disorders. Marfan Syndrome Marfan syndrome is an autosomal dominant genetic disorder characterized by a specific connective tissue Loeys-Dietz Syndrome Loeys-Dietz syndrome is phenotypically distinct from Marfan syndrome. It is characterized as an aneurysmal syndrome with widespread systemic involvement. Loeys-Dietz syndrome is an aggressive, autosomal dominant condition that is distinguished by the triad of arterial tortuosity and aneurysms, hypertelorism (widely spaced eyes), and bifid uvula or cleft palate. It is caused by heterozygous mutations in the genes encoding TGF-β receptors.7,8 Patients with LoeysDietz syndrome—including young children—are at increased risk of aortic rupture and aortic dissection; diameter-based thresholds of repair tend to be lower for patients with this syndrome than for patients with other connective tissue disorders. Ehlers-Danlos Syndrome Ehlers-Danlos syndrome includes a spectrum of inherited connective tissue disorders of collagen synthesis. The subtypes represent differing defective steps of collagen production. Vascular type Ehlers-Danlos syndrome is characterized by an autosomal dominant defect in type III collagen synthesis, which can have life-threatening cardiovascular manifestations. Spontaneous arterial rupture, usually involving the mesenteric vessels, is the most common cause of death in these patients. Thoracic aortic aneurysms and dissections are less commonly associated with Ehlers-Danlos syndrome, but when they do occur, they pose a particularly challenging surgical problem because of the reduced integrity of the aortic tissue.9 An Ehlers-Danlos variant of periventricular heterotopia associated with joint and skin hyperextensibility and aortic dilation has been described as being caused by mutations in the gene encoding filamin A (FLNA), an actinbinding protein that links the smooth muscle cell contractile unit to the cell surface.10 Familial Aortic Aneurysms Families without the heritable connective tissue disorders described earlier also can be affected by genetic conditions that cause thoracic aortic aneurysms. In fact, it is estimated that at least 20% of patients with thoracic aortic aneurysms and dissections have a genetic predisposition to them. The involved mutations are characterized by autosomal dominant inheritance with decreased penetrance and variable expression. Thus far, mutations involving the genes for TGF-β receptors (TGFβR1 and TGFβR2), TGF-β2, β-myosin (MYH11 and MYLK), and α-smooth muscle cell actin (ACTA2) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 787 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection defect that leads to aneurysm formation. The phenotype of patients with Marfan syndrome typically includes a tall stature, high palate, joint hypermobility, eye lens disorders, mitral valve prolapse, and aortic aneurysms. The aortic wall is weakened by fragmentation of elastic fibers and deposition of extensive amounts of mucopolysaccharides (a process previously called cystic medial degeneration or cystic medial necrosis). Patients with Marfan syndrome have a mutation in the fibrillin gene located on the long arm of chromosome 15. The traditionally held view is that abnormal fibrillin in the extracellular matrix decreases connective tissue strength in the aortic wall and produces abnormal elasticity, which predisposes the aorta to dilatation from wall tension caused by left ventricular ejection impulses.3 More recent evidence, however, shows that the abnormal fibrillin causes degeneration of the aortic wall matrix by increasing the activity of transforming growth factor beta (TGF-β).4 Between 75% and 85% of patients with Marfan syndrome have dilatation of the ascending aorta and annuloaortic ectasia (dilatation of the aortic sinuses and annulus).5 Such aortic abnormalities are the most common cause of death among patients with Marfan syndrome.6 Marfan syndrome also is frequently associated with aortic dissection. Table 22-1 788 UNIT II Part SPECIFIC CONSIDERATIONS have been identified as causes of familial thoracic aortic aneurysms and dissection.11-13 ACTA2 mutations are present in approximately 14% of families with familial thoracic aortic aneurysms and dissections. Aneurysms-Osteoarthritis Syndrome Aneurysms-osteoarthritis syndrome is a recently identified autosomal dominant disorder. Patients with this syndrome suffer from aortic and arterial aneurysms, arterial tortuosity, aortic dissection, mild craniofacial abnormalities, and early onset osteoarthritis. Aneurysms-osteoarthritis syndrome is caused by mutations in the gene encoding SMAD3, a transcription factor for TGF-β. Affected patients have a high incidence of aortic dissection, which often occurs in a mildly dilated aorta (4–4.5 cm) and causes sudden death.14 Congenital Bicuspid Aortic Valve Bicuspid aortic valve is the most common congenital malformation of the heart or great vessels, affecting up to 2% of Americans.15 Compared to patients with a normal, trileaflet aortic valve, patients with bicuspid aortic valve have an increased incidence of ascending aortic aneurysm formation and, often, a faster rate of aortic enlargement.16 The location of the fused leaflet, or raphe, may be predictive of aortic dilation and other abnormalities.17 About 50% to 70% of adults with bicuspid aortic valve, but without significant valve dysfunction, have echocardiographically detectable aortic dilatation.18,19 This dilatation usually is limited to the ascending aorta and root.20 Dilation occasionally is found in the arch and only rarely in the descending or abdominal aorta. In addition, aortic dissection occurs 10 times more often in patients with bicuspid valves than in the general population.21 Recent findings suggest that aneurysms associated with bicuspid aortic valve have a fundamentally different pathobiologic cause than aneurysms that occur in patients with trileaflet valves.22 Although the exact mechanism responsible for aneurysm formation in patients with bicuspid aortic valve remains unclear, evidence suggests that these patients have a congenital connective tissue abnormality that predisposes the aorta to medial degeneration.22-28 For example, fibrillin 1 content is significantly lower and matrix metalloproteinase activity is significantly higher in the aortic media in patients with bicuspid aortic valve than in persons with a normal, tricuspid aortic valve.22-24 Further, the process of medial degeneration in patients with bicuspid aortic valve may be exacerbated by the presence of chronic turbulent flow through the deformed valve. Bovine aortic arch Bovine aortic arch—a common origin of the innominate and left common carotid arteries—has been considered a normal anatomic variant. Recent studies from Yale University have identified a higher prevalence of bovine aortic arch in patients with thoracic aortic disease; an association was found between this anomaly and a generalized increase in aortic aneurysmal disease (without any predisposition to a particular aortic region). However, bovine aortic arch was not associated distinctly with bicuspid aortic valve or aortic dissection, but with a higher mean aortic growth rate: 0.29 cm/year in patients with bovine aortic arch, compared with 0.09 cm/year in controls. Therefore, bovine aortic arch may be better characterized as a precursor of aortic aneurysm than as a simple normal anatomic variant.29 Further studies are needed to delineate the underlying mechanism for this association. Infection. Primary infection of the aortic wall resulting in aneurysm formation is rare. Although these lesions are termed mycotic aneurysms, the responsible pathogens usually are bacteria rather than fungi. Bacterial invasion of the aortic wall may result from bacterial endocarditis, endothelial trauma caused by an aortic jet lesion, or extension from an infected laminar clot within a preexisting aneurysm. The most common causative organisms are Staphylococcus aureus, Staphylococcus epidermidis, Salmonella, and Streptococcus.30,31 Unlike most other causes of thoracic aortic aneurysms, which generally produce fusiform aneurysms, infection often produces saccular aneurysms located in areas of aortic tissue destroyed by the infectious process. Although syphilis was once the most common cause of ascending aortic aneurysms, the advent of effective antibiotic therapy has made syphilitic aneurysms a rarity in developed nations. In other parts of the world, however, syphilitic aneurysms remain a major cause of morbidity and mortality. The spirochete Treponema pallidum causes an obliterative endarteritis of the vasa vasorum that results in medial ischemia and loss of the elastic and muscular elements of the aortic wall. The ascending aorta and arch are the most commonly involved areas. The emergence of HIV infection in the 1980s was associated with a substantial increase in the incidence of syphilis in both HIV-­ positive and HIV-negative patients. Because syphilitic aortitis often presents 10 to 30 years after the primary infection, the incidence of associated aneurysms may increase in the near future. Aortitis. In patients with preexisting degenerative thoracic aortic aneurysms, localized transmural inflammation and subsequent fibrosis can develop. The dense aortic infiltrate responsible for the fibrosis consists of lymphocytes, plasma cells, and giant cells. The cause of the intense inflammatory reaction is unknown. Although the severe inflammation is a superimposed problem rather than a primary cause, its onset within an aneurysm can further weaken the aortic wall and precipitate expansion. Systemic autoimmune disorders also cause thoracic aortitis. Aortic Takayasu arteritis generally produces obstructive lesions related to severe intimal thickening, but associated medial necrosis can lead to aneurysm formation. In patients with giant cell arteritis (temporal arteritis), granulomatous inflammation may develop that involves the entire thickness of the aortic wall, causing intimal thickening and medial destruction. Rheumatoid aortitis is an uncommon systemic disease that is associated with rheumatoid arthritis and ankylosing spondylitis. The resulting medial inflammation and fibrosis can affect the aortic root, causing annular dilatation, aortic valve regurgitation, and ascending aortic aneurysm formation. Pseudoaneurysms. Pseudoaneurysms of the thoracic aorta usually represent chronic leaks that are contained by surrounding tissue and fibrosis. By definition, the wall of a pseudoaneurysm is not formed by intact aortic tissue; rather, the wall develops from organized thrombus and associated fibrosis. Pseudoaneurysms can arise from primary defects in the aortic wall (e.g., after trauma or contained aneurysm rupture) or from anastomotic or cannulation site leaks that occur after cardiovascular surgery. Anastomotic pseudoaneurysms can be caused by technical problems or by deterioration of the native aortic tissue, graft material, or suture. Commonly, they occur in patients with Marfan syndrome.32 Tissue deterioration usually is related to either progressive degenerative disease or infection. Improvements in sutures, graft materials, and surgical techniques have decreased the incidence of thoracic aortic pseudoaneurysms. Should thoracic aortic pseudoaneurysms occur, they typically require expeditious surgical or other intervention because they are associated with a high incidence of morbidity and rupture. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Clinical History Local Compression and Erosion. Initially, aneurysmal Clinical Manifestations In many patients with thoracic aortic aneurysms, the aneurysm is discovered incidentally when imaging studies are performed for unrelated reasons. Therefore, patients often are asymptomatic at the time of diagnosis. However, thoracic aortic aneurysms that initially go undetected eventually create symptoms and signs that correspond with the segment of aorta that is involved. These aneurysms have a wide variety of manifestations, including compression or erosion of adjacent structures, aortic valve regurgitation, distal embolism, and rupture. Aortic Valve Regurgitation. Ascending aortic aneurysms can cause displacement of the aortic valve commissures and annular dilatation. The resulting deformation of the aortic valve leads to progressively worsening aortic valve regurgitation. In response to the volume overload, the heart remodels and becomes increasingly dilated. Patients with this condition may present with progressive heart failure, a widened pulse pressure, and a diastolic murmur. Distal Embolization. Thoracic aortic aneurysms—particularly those involving the descending and thoracoabdominal aorta—are commonly lined with friable, atheromatous plaque and mural thrombus. This debris may embolize distally, causing occlusion and thrombosis of the visceral, renal, or lowerextremity branches. Rupture. Patients with ruptured thoracic aortic aneurysms often experience sudden, severe pain in the anterior chest (ascending aorta), upper back or left chest (descending thoracic aorta), or left flank or abdomen (thoracoabdominal aorta). When ascending aortic aneurysms rupture, they usually bleed into the pericardial space, producing acute cardiac tamponade and death. Descending thoracic aortic aneurysms rupture into the pleural cavity, producing a combination of severe hemorrhagic shock and respiratory compromise. External rupture is extremely rare; saccular syphilitic aneurysms have been observed to rupture externally after eroding through the sternum. Diagnostic Evaluation Diagnosis and characterization of thoracic aneurysms require imaging studies, which also provide critical information that VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 789 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Treatment decisions in cases of thoracic aortic aneurysm are guided by our current understanding of the clinical history of these aneurysms, which classically is characterized as progressive aortic dilatation and eventual dissection, rupture, or both. An analysis by Elefteriades of data from 1600 patients 1 with thoracic aortic disease has helped quantify these well-recognized risks.33 Average expansion rates were 0.07 cm/y in ascending aortic aneurysms and 0.19 cm/y in descending thoracic aortic aneurysms. As expected, aortic diameter was a strong predictor of rupture, dissection, and mortality. For thoracic aortic aneurysms >6 cm in diameter, annual rates of catastrophic complications were 3.6% for rupture, 3.7% for dissection, and 10.8% for death. Critical diameters, at which the incidence of expected complications significantly increased, were 6.0 cm for aneurysms of the ascending aorta and 7.0 cm for aneurysms of the descending thoracic aorta; the corresponding risks of rupture after reaching these diameters were 31% and 43%, respectively.34 Certain types of aneurysms have an increased propensity for expansion and rupture. For example, aneurysms in patients with Marfan or Loeys-Dietz syndrome dilate at an accelerated rate and rupture or dissect at smaller diameters than non–connective tissue disorder-related aneurysms. Before the era of surgical treatment for aortic aneurysms, this aggressive form of aortic disease resulted in an average life expectancy of 32 years for Marfan patients; aortic root complications caused the majority of deaths.35 Saccular aneurysms, which commonly are associated with aortic infection and typically affect only a discrete small section of the aorta, tend to grow more rapidly than fusiform aneurysms, which are associated with more widespread degenerative changes and generally affect a larger section of the aorta. One common clinical scenario deserves special attention. A moderately dilated ascending aorta (i.e., 4–5 cm) often is encountered during aortic valve replacement or coronary artery bypass operations. The clinical history of these ectatic ascending aortas has been defined by several studies. Michel and colleagues36 studied patients whose ascending aortic diameters were >4 cm at the time of aortic valve replacement; 25% of these patients required reoperation for ascending aortic replacement. Prenger and colleagues37 reported that aortic dissection occurred in 27% of patients who had aortic diameters of >5 cm at the time of aortic valve replacement. Recently, attention has been directed toward whether or not a mildly dilated aortic root should be replaced in patients with bicuspid aortic valve who are undergoing isolated valve replacement, and at what threshold to intervene. Although this is a controversial issue, many surgeons believe that the tendency toward late aortic dilatation in these patients warrants aggressive treatment.38,39 Current practice guidelines indicate that such early replacement should be considered in these patients when the ascending aorta is 4.0 to 4.5 cm.40 expansion and impingement on adjacent structures causes mild, chronic pain. The most common symptom in patients with ascending aortic aneurysms is anterior chest discomfort; the pain is frequently precordial in location but may radiate to the neck and jaw, mimicking angina. Aneurysms of the ascending aorta and transverse aortic arch can cause symptoms related to compression of the superior vena cava, the pulmonary artery, the airway, or the sternum. Rarely, these aneurysms erode into the superior vena cava or right atrium, causing acute high-output failure. Expansion of the distal aortic arch can stretch the recurrent laryngeal nerve, which results in left vocal cord paralysis and hoarseness. Descending thoracic and thoracoabdominal aneurysms frequently cause back pain localized between the scapulae. When the aneurysm is largest in the region of the aortic hiatus, it may cause middle back and epigastric pain. Thoracic or lumbar vertebral body erosion typically causes severe, chronic back pain; extreme cases can present with spinal instability and neurologic deficits from spinal cord compression. Although mycotic aneurysms have a peculiar propensity to destroy vertebral bodies, spinal erosion also occurs with degenerative aneurysms. Descending thoracic aortic aneurysms may cause various degrees of airway obstruction, manifesting as cough, wheezing, stridor, or pneumonitis. Pulmonary or airway erosion presents as hemoptysis. Compression and erosion of the esophagus cause dysphagia and hematemesis, respectively. Thoracoabdominal aortic aneurysms can cause duodenal obstruction or, if they erode through the bowel wall, gastrointestinal bleeding. Jaundice due to compression of the liver or porta hepatis is uncommon. Erosion into the inferior vena cava or iliac vein presents with an abdominal bruit, widened pulse pressure, edema, and heart failure. 790 UNIT II Part guides the selection of treatment options. Although the best choice of imaging technique for the thoracic and thoracoabdominal aorta is somewhat institution-specific, varying with the availability of imaging equipment and expertise, efforts have been made to standardize key elements of image acquisition and reporting. Recent practice guidelines40 recommend that aortic imaging reports plainly state the location of aortic abnormalities (including calcification and the extent to which abnormalities extend into branch vessels), the maximum external aortic diameters (rather than internal, lumen-based diameters), internal filling defects, and any evidence of rupture. Whenever possible, all results should be compared to those of prior imaging studies. SPECIFIC CONSIDERATIONS Plain Radiography. Plain radiographs of the chest, abdomen, or spine often provide enough information to support the initial diagnosis of thoracic aortic aneurysm. Ascending aortic aneurysms produce a convex shadow to the right of the cardiac silhouette. The anterior projection of an ascending aneurysm results in the loss of the retrosternal space in the lateral view. An aneurysm may be indistinguishable from elongation and tortuosity.41 Above all, chest radiographs (CXRs) may appear normal in patients with thoracic aortic disease and, thus, cannot exclude the diagnosis of aortic aneurysm. Aortic root aneurysms, for example, often are hidden within the cardiac silhouette. Plain CXRs may reveal convexity in the right superior mediastinum, loss of the retrosternal space, or widening of the descending thoracic aortic shadow, which may be highlighted by a rim of calcification outlining the dilated aneurysmal aortic wall. Aortic calcification also may be seen in the upper abdomen on a standard radiograph made in the anteroposterior or lateral projection (Fig. 22-2). Once a thoracic aortic aneurysm is detected on plain radiographs, additional studies are required to define the extent of aortic involvement. Echocardiography and Abdominal Ultrasonography. Ascending aortic aneurysms are commonly discovered during echocardiography in patients presenting with symptoms or signs of aortic valve regurgitation. Both transthoracic and transesophageal echocardiography provide excellent visualization of the ascending aorta, including the aortic root.42 Transesophageal echocardiography also allows visualization of the descending thoracic aorta but is not ideal for evaluating the transverse aortic arch (which is obscured by air in the tracheobronchial tree) or the upper abdominal aorta. Effective echocardiography requires considerable technical skill, both in obtaining adequate images and in interpreting them. This imaging modality has the added benefit of assessing cardiac function and revealing any other abnormalities that may be present. During ultrasound evaluation of a suspected infrarenal abdominal aortic aneurysm, if a definitive neck cannot be identified at the level of the renal arteries, the possibility of thoracoabdominal aortic involvement should be suspected and investigated by using other imaging modalities. Caution should be exercised while interpreting aneurysm dimensions from ultrasound imaging because intraluminal measurements are often reported, whereas external measurements are usually used in other imaging modalities. Computed Tomography. Computed tomographic (CT) scanning is widely available, provides visualization of the entire thoracic and abdominal aorta, and permits multiplanar and 3-dimensional aortic reconstructions. Consequently, CT is the most common—and arguably the most useful—imaging modality for evaluating thoracic aortic aneurysms.43 In addition to establishing the diagnosis, CT provides information about Figure 22-2. Chest radiographs showing a calcified rim (arrows) in the aortic wall of a thoracoabdominal aortic aneurysm. A. Anteroposterior view. B. Lateral view. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ disease or diabetes).44 If possible, surgery is performed ≥1 day after contrast administration to allow time to observe renal function and to permit diuresis of the contrast agent. If renal insufficiency occurs or is worsened, elective surgery is postponed until renal function returns to normal or stabilizes. Magnetic Resonance Angiography. Magnetic resonance angiography (MRA) is becoming widely available and can facilitate visualization of the entire aorta. This modality produces aortic images comparable to those produced by contrastenhanced CT but does not necessitate exposure to ionizing radiation. In addition, MRA offers excellent visualization of branch vessel details, and it is useful in detecting branch vessel stenosis.45 However, MRA is limited by high expense and a susceptibility to artifacts created by ferromagnetic materials, and gadolinium—the contrast agent for MRA—may be linked to nephrogenic systemic fibrosis and acute renal failure in patients with advanced renal insufficiency.46 Furthermore, the MRA environment is not appropriate for many critically ill patients, and unlike CT imaging, MRA imaging is suboptimal in patients with extensive aortic calcification. Invasive Aortography and Cardiac Catheterization. Figure 22-3. Current practice guidelines40 seek to standardize the reporting of aortic diameters by indicating key locations of measurement. These include (1) the sinuses of Valsalva, (2) the sinotubular junction, (3) the mid-ascending aorta, (4) the proximal aortic arch at the origins of the innominate artery, (5) the mid-aortic arch, which is between the left common carotid and left subclavian arteries, (6) the proximal descending thoracic aorta, which begins at the isthmus (approximately 2 cm distal to the origins of the left subclavian artery), (7) the mid-descending thoracic artery, (8) the aorta at the diaphragm, and (9) the abdominal aorta at the origins of the celiac axis. (Used with permission of Baylor College of Medicine.) 791 Although catheter-based contrast aortography was previously considered the gold standard for evaluating thoracic aortic disease, cross-sectional imaging (i.e., CT and MRA) has largely replaced this modality. Technologic improvements have enabled CT and MRA to provide excellent aortic imaging while causing less morbidity than catheter-based studies do, so CT and MRA are now the primary modes for evaluating thoracic aortic disease. Today, the use of invasive aortography in patients with thoracic aortic disease is generally limited to those undergoing endovascular therapies or when other types of studies are contraindicated or have not provided satisfactory results. Unlike standard aortography, cardiac catheterization continues to play an important role in diagnosis and preoperative planning, especially in patients with ascending aortic involvement. Proximal aortography can reveal not only the status of the coronary arteries and left ventricular function but also the degree of aortic valve regurgitation, the extent of aortic root involvement, coronary ostial displacement, and the relationship of the aneurysm to the arch vessels. The value of the information one can obtain from catheterbased diagnostic studies should be weighed against the established limitations and potential complications of such studies. A key limitation of aortography is that it images only the lumen and may therefore underrepresent the size of large aneurysms that contain laminated thrombus. Manipulation of intraluminal catheters can result in embolization of laminated thrombus or atheromatous debris. Proximal aortography carries a 0.6% to 1.2% risk of stroke. Other risks include allergic reaction to contrast agent, iatrogenic aortic dissection, and bleeding at the arterial access site. In addition, the volumes of contrast agent required to adequately fill large aneurysms can cause significant renal toxicity. To minimize the risk of contrast nephropathy, patients receive periprocedural intravenous (IV) fluids for hydration, mannitol for diuresis, and acetylcysteine.47,48 As with contrast-enhanced CT, surgery is performed ≥1 day after angiography whenever possible to ensure that renal function has stabilized or returned to baseline. Treatment Selecting the Appropriate Treatment. Once a thoracic ­aortic aneurysm is detected, management begins with patient VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 22 Thoracic Aneurysms and Aortic Dissection an aneurysm’s location, extent, anatomic anomalies, and relationship to major branch vessels. CT is particularly useful in determining the absolute diameter of the aorta, especially in the presence of a laminated clot, and also detects aortic calcification. Contrast-enhanced CT provides information about the aortic lumen and can detect mural thrombus, aortic dissection, inflammatory periaortic fibrosis, and mediastinal or retroperitoneal hematoma due to contained aortic rupture. To increase consistency and ensure uniform reporting, current practice guidelines suggest that measurements be taken perpen2 dicular to blood flow and at standard anatomic locations40 (Fig. 22-3); this should reduce the likelihood of erroneous measurements, especially during serial imaging surveillance. The major disadvantage of contrast-enhanced CT scanning is the possibility of contrast-induced acute renal failure in patients who are at risk (e.g., patients with preexisting renal 792 UNIT II Part SPECIFIC CONSIDERATIONS education, particularly if the patient is asymptomatic, because aortic disease may progress rapidly and unexpectedly in some patients. A detailed medical history is collected, a physical examination is performed, and a systematic review of medical records is carried out to clearly assess the presence or absence of pertinent symptoms and signs, despite any initial denial of symptoms by the patient. Signs of genetic diseases such as Marfan syndrome or Loeys-Dietz syndrome are thoroughly reviewed. If clinical criteria are met for such a genetic condition, confirmatory laboratory tests are conducted. Patients with such genetic diseases are best treated in a dedicated aortic clinic where they can be appropriately followed up. Surveillance imaging and aggressive blood pressure control are the mainstays of initial management for asymptomatic patients. When patients become symptomatic or their aneurysms grow to meet certain size criteria, the patients become surgical candidates. Although long-term data are still lacking, endovascular therapy has become an accepted treatment for thoracic aortic aneurysms.49 Its role in treating proximal aortic disease and thoracoabdominal aortic aneurysms remains experimental. Nonetheless, endoluminal stenting is approved by the U.S. Food and Drug Administration for the treatment of isolated descending thoracic aortic aneurysms, and some newer devices are approved for the treatment of blunt aortic injury and penetrating aortic ulcer. In practice, however, the off-label application 3 of aortic stent grafts is widespread and accounts for well over half their use.50 Endovascular approaches may be helpful in emergent aneurysm repair, such as for patients with aortic rupture.51 Recently, endovascular therapy has evolved to include hybrid repairs, which combine open “debranching” techniques (to reroute branching vessels) with endovascular aortic repair. Despite these advances, for the repair of aneurysms with proximal aortic involvement and of thoracoabdominal aortic aneurysms, open procedures remain the gold standard and preferred approach. Determination of the Extent and Severity of Disease. Crosssectional imaging with reconstruction is critical when one is evaluating a thoracic aneurysm, determining treatment strategy, and planning necessary procedures. Note that, commonly, patients with a thoracic aortic aneurysm also have a remote aneurysm.2 In such cases, the more threatening lesion usually is addressed first. In many patients, staged operative procedures are necessary for complete repair of extensive aneurysms involving the ascending aorta, transverse arch, and descending thoracic or thoracoabdominal aorta.52 When the descending segment is not disproportionately large (compared with the proximal aorta) and is not causing symptoms, the proximal aortic repair is carried out first. An important benefit of this approach is that it allows treatment of valvular and coronary artery occlusive disease at the first operation. Proximal aneurysms (proximal to the left subclavian artery) usually are addressed via a sternotomy approach. Aneurysms involving the descending thoracic aorta are evaluated in terms of criteria (described later) for potential endovascular repair; those unsuitable for an endovascular approach are repaired with open techniques through a left thoracotomy. A CT scan can reveal detailed information about aortic calcification and luminal thrombus. These details are important in preventing embolization during surgical manipulation. Indications for Operation Thoracic aortic aneurysms are repaired to prevent fatal rupture. Therefore, on the basis of the natural history studies and other data, practice guidelines for thoracic aortic disease40 recommend elective operation in 4 asymptomatic patients when the diameter of an ascending aortic aneurysm is >5.5 cm, when the diameter of a descending thoracic aortic aneurysm is >6.0 cm, or when the rate of dilatation is >0.5 cm/y. In patients with connective tissue disorders such as Marfan and Loeys-Dietz syndromes, the threshold for operation is based on a smaller aortic diameter (4.0–5.0 cm for the ascending aorta and 5.5 to 6.0 cm for the descending thoracic aorta). For women with connective tissue disorders who are considering pregnancy, prophylactic aortic root replacement is considered because the risk of aortic dissection or rupture increases at an aortic diameter of 4.0 cm or greater. For lowrisk patients with chronic aortic dissection, descending t­ horacic repair is recommended at an aortic diameter of 5.5 cm or greater. For patients undergoing aortic valve replacement or repair, 5 smaller ascending aortic aneurysms (>4.5 cm) are considered for concomitant repair. The acuity of presentation is a major factor in decisions about the timing of surgical intervention. Many patients are asymptomatic at the time of presentation, so there is time for thorough preoperative evaluation and improvement of their current health status, such as through smoking cessation and other optimization programs. In contrast, patients who present 6 with symptoms may need urgent operation. Symptomatic patients are at increased risk of rupture and warrant expeditious evaluation. The onset of new pain in patients with known aneurysms is especially concerning, because it may herald significant expansion, leakage, or impending rupture. Emergent intervention is reserved for patients who present with aneurysm rupture or superimposed acute dissection.53 Open Repair vs. Endovascular Repair As noted earlier, endovascular repair of thoracic aortic aneurysms has become an accepted treatment option in selected patients, particularly patients with isolated degenerative descending thoracic aortic aneurysms; in fact, practice guidelines recommend that endovascular repair be strongly considered for patients with descending thoracic aneurysm at an aortic diameter of 5.5 cm (which is slightly below the 6.0-cm threshold for open repair).40 For endovascular repairs to produce optimal outcomes, several anatomic criteria must be met. For one, the proximal and distal neck diameters should fall within a range that will allow proper sealing. Also, the proximal and distal landing zones should ideally be at least 20 mm long so that an appropriate seal can be made. Note that the limiting structures proximally and distally are the brachiocephalic vessels and celiac axis, respectively. Another anatomic limitation for this therapy relates to vascular access: The femoral and iliac arteries have to be wide enough to accommodate the large sheaths necessary to deploy the stent grafts, although newer devices use a smaller sheath (or are “sheathless” self-deployed stent grafts) to accommodate smaller arteries. Tortuosity of the iliac vessels and abdominal aorta can make these procedures technically challenging. Occasionally, a “side graft” anastomosed to the iliac artery through a retroperitoneal incision is used because of poor distal access. When any of these anatomic criteria are not met, an open approach is preferable to an endovascular approach. Of note, attempts have been made to extend the use of endovascular therapy to aortic arch aneurysms and thoracoabdominal aortic aneurysms. Although reports of purely endovascular repair of the aortic arch remain limited, Greenberg and colleagues54 have reported their experience with a large series of VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Preoperative Assessment and Preparation. Given the impact of comorbid conditions on perioperative complications, a careful preoperative assessment of physiologic reserve is critical in assessing operative risk. Therefore, most patients undergo a thorough evaluation—with emphasis on cardiac, pulmonary, and renal function—before undergoing elective surgery.56,57 Cardiac Evaluation Coronary artery disease is common in patients with thoracic aortic aneurysm and is responsible for a substantial proportion of early and late postoperative deaths in such patients. Similarly, valvular disease and myocardial dysfunction have important implications when one is planning anesthetic management and surgical approaches for aortic repair. Transthoracic echocardiography is a satisfactory noninvasive method for evaluating both valvular and biventricular function. Dipyridamole-thallium myocardial scanning identifies regions of myocardium that have reversible ischemia, and this test is more practical than exercise testing in older patients with concomitant lower-extremity peripheral vascular disease. Cardiac catheterization and coronary arteriography are performed in patients who have evidence of coronary disease—as indicated by either the patient’s history or the results of noninvasive studies—­ or who have a left ventricular ejection fraction of ≤30%. If significant valvular or coronary artery disease is identified before a proximal aortic operation, the disease can be addressed directly during the procedure. Patients who have asymptomatic distal aortic aneurysms and severe coronary occlusive disease undergo percutaneous transluminal angioplasty or surgical revascularization before the aneurysmal aortic segment is replaced. Pulmonary Evaluation Pulmonary function screening with ­arterial blood gas measurement and spirometry is routinely performed before thoracic aortic operations. Patients with a forced expiratory volume in 1 second of >1.0 L and a partial pressure of carbon dioxide of <45 mmHg are considered surgical candidates. In suitable patients, borderline pulmonary function can be improved by implementing a regimen that includes smoking cessation, weight loss, exercise, and treatment of bronchitis for a period of 1 to 3 months before surgery. Although surgery is not withheld from patients with symptomatic aortic aneurysms and poor pulmonary function, adjustments in operative technique should be made to maximize these patients’ chances of recovery. In such patients, preserving the left recurrent laryngeal nerve, the phrenic nerves, and diaphragmatic function is particularly important. Renal Evaluation Renal function is assessed preoperatively by measuring serum electrolyte, blood urea nitrogen, and creatinine levels. Information about kidney size and perfusion can be obtained from the imaging studies used to evaluate the aorta. Obtaining accurate information about baseline renal function has important therapeutic and prognostic implications. For example, perfusion strategies and perioperative medications are adjusted according to renal function. Patients with severely impaired renal function frequently require at least temporary hemodialysis after surgery. These patients also have a mortality rate that is significantly higher than normal. Patients with thoracoabdominal aortic aneurysms and poor renal function secondary to severe proximal renal occlusive disease undergo renal artery endarterectomy, stenting, or bypass grafting during the aortic repair. Operative Repair. Proximal Thoracic Aortic Aneurysms Open Repair Traditional open operations to repair proximal aortic aneurysms—which involve the ascending aorta, transverse aortic arch, or both—are performed through a midsternal incision and require cardiopulmonary bypass. The best choice of aortic replacement technique depends on the extent of the aneurysm and the condition of the aortic valve. The spectrum of operations (Fig. 22-4) ranges from simple graft replacement of the tubular portion of the ascending aorta (Fig. 22-4A) to graft replacement of the entire proximal aorta, including the aortic root, and reattachment of the coronary arteries and brachiocephalic branches. The options for treating aortic valve disease, repairing aortic aneurysms, and maintaining perfusion during repair procedures each deserve detailed consideration (Table 22-2). Aortic Valve Disease and Root Aneurysms Many patients undergoing proximal aortic operations have aortic valve disease that requires concomitant surgical correction. When such disease is present and the sinus segment is normal, separate repair or replacement of the aortic valve and graft replacement of the tubular segment of the ascending aorta are carried out. In such cases, mild to moderate valve regurgitation with annular dilatation can be addressed by plicating the annulus with mattress sutures placed below each commissure, thereby preserving the native valve. In patients with more severe valvular regurgitation or with valvular stenosis, the valve is replaced with a stented biologic or mechanical prosthesis. Mechanical prostheses necessitate following a lifelong anticoagulation regimen. Separate replacement of the aortic valve and ascending aorta is not performed in patients with Marfan syndrome, because progressive dilatation of the remaining sinus segment eventually leads to complications that necessitate reoperation. Therefore, patients with Marfan syndrome or those with annuloaortic ectasia require some form of aortic root replacement.58 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 793 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection purely endovascular thoracoabdominal aortic repairs. Additionally, there have been numerous reports of small series of offlabel, experimental hybrid procedures that involve debranching the aortic arch or the visceral vessels of the abdominal aorta, followed by endovascular exclusion of the aneurysm. The majority of hybrid approaches involve repairing the aortic arch. In its simplest form, hybrid arch repair involves an open bypass from the left subclavian to the left common carotid artery, which is followed by deliberate coverage of the origins of the left subclavian artery by the stent graft. In its most complex form, hybrid arch repair involves rerouting all of the brachiocephalic vessels, followed by proximal placement of the stent graft in the ascending aorta and extending repair distally into the aortic arch and descending thoracic aorta. The patients who theoretically may benefit more from an endovascular approach than from traditional open techniques are those who are of advanced age or have significant comorbidities. For example, the open repair of a descending thoracic aortic aneurysm can result in significant pulmonary morbidity. Therefore, patients with borderline pulmonary reserve may better tolerate an endovascular procedure than standard open repair. In contrast, patients with significant intraluminal atheroma may be better served by an open approach because of the risk of embolization and stroke posed by catheter manipulation. Similarly, patients with connective tissue disorders generally are not considered candidates for elective endovascular repair. Endovascular repair in patients with connective tissue disorders has produced poor results, which are mainly due to progressive dilatation, stent graft migration, and endoleak.55 794 UNIT II Part SPECIFIC CONSIDERATIONS A B C E F G H I J D K Figure 22-4. Illustrations of proximal aortic repairs in which the native aortic root is left intact. A. Graft replacement of the tubular portion of the ascending aorta with the aortic arch left intact. B. Hemiarch beveled graft replacement, in which the ascending aorta and a portion of the lesser curvature of the aortic arch are replaced. C. A modified hemiarch with additional graft replacement of the innominate artery. D. Patch repair of the aortic arch. E. Traditional total arch replacement using an island approach to reattach the brachiocephalic vessels. F. The branched graft approach, which replaces the brachiocephalic vessels by following their original anatomic location. G. The elephant trunk approach with a concomitant island brachiocephalic artery reattachment. Contemporary Y-graft arch repairs include H. the single Y-graft approach, I. the double Y-graft approach, J. the elephant trunk approach with a single Y-graft, and K. the elephant trunk approach with a double Y-graft. (Used with permission of Baylor College of Medicine.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 22-2 Options for open surgical repair of proximal aortic ­aneurysms In many cases, the aortic root is replaced with a mechanical or biologic graft that has both a valve and an aortic conduit. Currently, three graft options are commercially available: composite valve grafts, which consist of a bileaflet mechanical valve attached to a polyester tube graft; aortic root homografts, which are harvested from cadavers and cryopreserved; and stentless porcine aortic root grafts.59,60 Another option for surgeons is to construct a bioprosthetic composite valve graft during the operation by suturing a stented tissue valve to a polyester graft tube. Although select patients may be offered the Ross procedure, in which the patient’s pulmonary artery root is excised and placed in the aortic position and then the right ventricular outflow tract is reconstructed by using a cryopreserved pulmonary homograft, this option is rarely used. This is largely because it is a technically demanding procedure, and there are concerns about the potential for autograft dilatation in patients with connective tissue disorders.61 An additional option is valve-sparing aortic root replacement, which has evolved substantially during the past decade.62 The valve-sparing technique that is currently favored is called aortic root reimplantation and involves excising the aortic sinuses, attaching a prosthetic graft to the patient’s annulus (Fig. 22-5), and resuspending the native aortic valve inside VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 795 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Options for treating aortic valve disease Aortic valve annuloplasty (annular plication) Aortic valve replacement with mechanical or biologic prosthesis Aortic root replacement    Composite valve graft    Aortic homograft    Stentless porcine root    Pulmonary autograft (Ross procedure)    Valve-sparing techniques Options for graft repair of the aortic aneurysm Patch aortoplasty Ascending replacement only Beveled hemiarch replacement Total arch replacement with reattachment of brachiocephalic branches Total arch replacement with bypass grafts to the brachiocephalic branches (Y-graft approaches) Elephant trunk technique with island reattachment Elephant trunk technique with Y-graft approach Perfusion options Standard cardiopulmonary bypass Profound hypothermic circulatory arrest without adjuncts Hypothermic circulatory arrest with adjuncts    Retrograde cerebral perfusion    Antegrade cerebral perfusion    Balloon perfusion catheters    Right axillary artery cannulation    Innominate artery cannulation    Combined antegrade and retrograde cerebral perfusion the graft. The superior hemodynamics of the native valve and the avoidance of anticoagulation are major advantages of the valve-sparing approach. Long-term results in carefully selected patients have been excellent.63 Although the durability of this procedure in patients with either Marfan syndrome or ­bicuspid aortic valve has been questioned, reports suggest that longterm durability is possible for patients with Marfan syndrome who undergo the procedure at experienced centers.64,65 Further, acceptable midterm outcomes have been reported for patients with bicuspid aortic valve.66 Patients who have structural leaflet deterioration or excessive annular dilatation are typically deemed unsuitable for valve-sparing repair. Regardless of the type of conduit used, aortic root replacement requires reattaching the coronary arteries to openings in the graft. In the original procedure described by Bentall and De Bono,67 this was accomplished by suturing the intact aortic wall surrounding each coronary artery to the openings in the graft. The aortic wall was then wrapped around the graft to establish hemostasis. However, this technique frequently produced leaks at the coronary reattachment sites that eventually led to pseudoaneurysm formation. The Cabrol modification, in which a separate, small tube graft is sutured to the coronary ostia and the main aortic graft, achieves tension-free coronary anastomoses and reduces the risk of pseudoaneurysm formation.68 Kouchoukos’s button modification of the Bentall procedure is currently the most widely used technique.69 The aneurysmal aorta is excised, and buttons of aortic wall are left surrounding both coronary arteries, which are then mobilized and sutured to the aortic graft (Fig. 22-6). The coronary suture lines may be reinforced with polytetrafluoroethylene felt or pericardium to enhance hemostasis. When the coronary arteries cannot be mobilized adequately because of extremely large aneurysms or scarring from previous surgery, the Cabrol technique or a related modification can be used. Another option, originally described by Zubiate and Kay,70 is the construction of bypass grafts by using interposition saphenous vein or synthetic grafts. Aortic Arch Aneurysms Several options are also available for handling aneurysms that extend into the transverse aortic arch (Fig. 22-4). The surgical approach depends on the extent of involvement and the need for cardiac and cerebral protection. Saccular aneurysms that arise from the lesser curvature of the distal transverse arch and that encompass <50% of the aortic circumference can be treated by patch graft aortoplasty. For fusiform aneurysms, when the distal portion of the arch is a reasonable size, a single, beveled replacement of the lower curvature (hemiarch) is performed. More extensive arch aneurysms require total replacement involving a distal anastomosis to the proximal descending thoracic aorta and separate reattachment of the brachiocephalic branches. The brachiocephalic vessels are reattached to one or more openings made in the graft, or if these vessels are aneurysmal, they are replaced with separate, smaller grafts. Recently, Y-graft approaches to aortic arch repair have been introduced71 that essentially debranch the brachiocephalic vessels and move them forward. This permits the distal anastomosis to be brought forward and aids in hemostasis. When the aneurysm involves the entire arch and extends into the descending thoracic aorta, it is approached by using Borst’s elephant trunk technique of staged total arch replacement.72 The distal anastomosis may be constructed by using a collared graft to accommodate any discrepancy in aortic diameter73 and is performed such that a portion of the graft is 796 A D C B UNIT II Part H SPECIFIC CONSIDERATIONS G F E L K J I Figure 22-5. Illustration of our current valve-sparing procedure for replacing the aortic root and ascending aorta for treatment of A. aortic root aneurysm. B. The ascending aorta is opened after cardiopulmonary bypass and cardioplegic arrest are established and the distal ascending aorta is clamped. The diseased aortic tissue (including the sinuses of Valsalva) is excised. Buttons of surrounding tissue are used to mobilize the origins of the coronary arteries. C. A synthetic graft is sewn to the distal ascending aorta with continuous suture. D. After the distal anastomosis is completed, six sutures reinforced with Teflon pledgets are placed in the plane immediately below the aortic valve annulus. E. The subannular sutures are placed through the base of a synthetic aortic root graft, which is then is parachuted down around the valve. F. After the root graft is cut to an appropriate length, the valve commissures and leaflets are positioned within the graft. The annular sutures are then tied. G. Each of the three commissures is then secured near the top of the graft. H. The supra-annular aortic tissue is sewn to the graft in continuous fashion. I. The button surrounding the origin of the left main coronary artery is sewn to an opening cut in the root graft. J. The two aortic grafts are sewn together with continuous suture. K. The button surrounding the origin of the right coronary artery is sewn to an opening cut in the root graft. L. The completed valve-sparing aortic root replacement and graft repair of the ascending aorta is shown. (Used with permission of Baylor College of Medicine.) left suspended within the proximal descending thoracic aorta (Fig. 22-7). During a subsequent operation, this “trunk” is used to facilitate repair of the descending thoracic aorta through a thoracotomy incision. This technique permits access to the distal portion of the graft during the second operation without the need for dissection around the distal transverse aortic arch; this reduces the risk of injuring the left recurrent laryngeal nerve, esophagus, and pulmonary artery if an open approach is used at the second stage. As described in the section on hybrid repair of arch aneurysms (see later), the elephant trunk can be completed VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ by using a hybrid endovascular approach (Fig. 22-8) in certain settings. Cardiopulmonary Bypass Perfusion Strategies Like the operations themselves, perfusion strategies used during proximal aortic surgery depend on the extent of the repair. Aneurysms that are isolated to the ascending segment can be replaced by using standard cardiopulmonary bypass and distal ascending aortic clamping. This provides constant perfusion of the brain and other vital organs during the repair. Aneurysms involving the transverse aortic arch, however, cannot be clamped during the repair, which necessitates the temporary withdrawal of cardiopulmonary bypass support; this is called circulatory arrest. To protect the brain and other vital organs during the circulatory arrest period, hypothermia must be initiated before pump flow is stopped. However, hypothermia is not without risk, and coagulopathy is associated with deep levels of hypothermia (below 20°C), which have been traditionally used in open arch repair. Recently, more moderate levels of hypothermia (often between 22°C and 24°C) have been introduced that appear to decrease risks associated with deep hypothermia while still providing sufficient brain protection. Nonetheless, although brief periods of circulatory arrest generally are well tolerated, even this recently modified technique continues to have substantial limitations; as the duration of circulatory arrest VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 797 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Figure 22-6. Illustration of a modified Bentall procedure for replacing the aortic root and ascending aorta. The aortic valve and entire ascending aorta, including the sinuses of Valsalva, have been replaced by a mechanical composite valve graft. The coronary arteries with buttons of surrounding aortic tissue have been mobilized and are being reattached to openings in the aortic graft. increases, the well-recognized risks of brain injury and death increase dramatically. Additionally, some authors have raised the concern that reducing the degree of hypothermia narrows the safety margin that deep hypothermia provides, because it increases the risk of ischemic complications involving the spinal cord, kidneys, and other organs that now receive less hypothermic protection.74 Because of the inherent complexity of aortic arch repairs and their general tendency to require longer periods of hypothermic circulatory arrest, two cerebral perfusion strategies— retrograde cerebral perfusion (RCP) and antegrade cerebral perfusion (ACP)—were developed to supplement this process by delivering cold, oxygenated blood to the brain and further reduce the risks associated with repair. Retrograde cerebral perfusion involves directing blood from the cardiopulmonary bypass circuit into the brain through the superior vena cava.75 However, RCP is thought to be less beneficial than ACP,76 and although it may be helpful in the retrograde flushing of air and debris from the arch, most centers have stopped using RCP. In contrast, ACP delivers blood directly into the brachiocephalic arteries to maintain cerebral flow. Although its use was cumbersome in the past, contemporary ACP techniques (Fig. 22-9) have been simplified and commonly involve cannulating either the right axillary artery or the innominate artery and subsequent connection to the cardiopulmonary bypass circuit.77,78 Often, a small section of graft is used as a conduit to ease cannulation, but there remains a small procedure-related risk of brachial plexus or vascular injury. Upon initiation, cold blood is delivered into the brain via the right common carotid artery. Note that, with this technique, blood flow to the left side of the brain requires an intact circle of Willis. Methods to help determine the adequacy of unilateral ACP to deliver cerebral cross-circulation include preoperative imaging and intraoperative monitoring. Our preferred method of intraoperative monitoring is brain near-infrared spectroscopy (NIRS), which measures cerebral oxygenation. If NIRS monitoring indicates inadequate perfusion, an additional perfusion catheter can be inserted into the left common carotid artery to provide blood flow to the left side of the brain. Because of the use of more moderate levels of hypothermia, some groups supplement ACP with additional perfusion strategies that provide flow to the descending aorta during arch repair.79,80 Endovascular Repair Experience with purely endovascular treatment of proximal aortic disease remains limited and only investigational. The unique anatomy of the aortic arch and the need for uninterrupted cerebral perfusion pose difficult challenges. There are reports of the use of “homemade” grafts to exclude arch aneurysms; however, these grafts are highly experimental at this time. For example, in 1999, Inoue and colleagues81 reported placing a triple-branched stent graft in a patient with an aneurysm of the aortic arch. The three brachiocephalic branches were positioned by placing percutaneous wires in the right brachial, left carotid, and left brachial arteries. The patient underwent two subsequent procedures: surgical repair of a right brachial pseudoaneurysm and placement of a distal stent graft extension to control a major perigraft leak. Since then, efforts to employ endovascular techniques in the treatment of the proximal aorta have been essentially limited to the use of approved devices for off-label indications, such as the exclusion of pseudoaneurysms in the ascending aorta. Hybrid Repair Unlike purely endovascular approaches, hybrid repairs of the aortic arch have entered the mainstream clinical 798 A F D UNIT II Part B E SPECIFIC CONSIDERATIONS G C Figure 22-7. Illustration of a contemporary Y-graft approach to total arch replacement for aortic arch aneurysm. A. The proximal portions of the brachiocephalic arteries are exposed. B. The first two branches of the graft are sewn end-to-end to the transected left subclavian and left common carotid arteries. The proximal ends of the transected brachiocephalic arteries are ligated. C. A balloon-tipped perfusion cannula is placed inside the double Y-graft and used to deliver antegrade cerebral perfusion. After systemic circulatory arrest is initiated, the innominate artery is clamped, transected, and sewn to the distal end of the main graft. D. The proximal aspect of the Y-graft is clamped. This directs flow from the axillary artery to all three brachiocephalic arteries. The arch is then replaced with a collared elephant trunk graft. E. The distal anastomosis between the elephant trunk graft and the aorta is created between the innominate and left common carotid arteries. The collared graft accommodates any discrepancy in aortic diameter. F. The aortic graft is clamped, and a second limb from the arterial inflow tubing of the cardiopulmonary bypass circuit is used to deliver systemic perfusion through a side-branch of the arch graft while the proximal portion of the ascending aorta is replaced. Once the proximal aortic anastomosis is completed, the main trunk of the double Y-graft is cut to an appropriate length, and the beveled end is then sewn to an oval opening created in the right anterolateral aspect of the ascending aortic graft, which completes the repair G. (Adapted from LeMaire et al,73 Fig. 2. Used with permission. Copyright The Society of Thoracic Surgeons.) arena, although they remain controversial. Hybrid arch repairs involve some form of “debranching” of the brachiocephalic vessels (which are not unlike Y-graft approaches), followed by endovascular exclusion of some or all of the aortic arch (Fig. 22-10). Although this technique has many variants, they often involve sewing a branched graft to the proximal ascending aorta with the use of a partial aortic clamp. The branches of the graft are then sewn to the arch vessels. Once the arch is “debranched,” the arch aneurysm can be excluded with an endograft. Commonly, a zone 0 approach (Fig. 22-11) is undertaken, in which the proximal end of the endograft lies between the ascending aorta and the origins of the innominate artery. Other hybrid approaches aim to extend repair into the distal arch and descending thoracic aorta (see later). The arguments for using a hybrid approach to treat aortic arch aneurysms include the elimination of cardiopulmonary bypass, circulatory arrest, and cardiac ischemia, although in practice, these adjuncts are frequently used during hybrid proximal aortic repairs.82 It is not yet clear whether hybrid repairs are as durable as traditional ones because little mid- or long-term data have been published, and no large-scale studies have compared hybrid and traditional repairs. Procedure-related risks include the risk of embolization and stroke due to wire and device manipulation within the aortic arch (this risk appears to be greatest in zone 0 repairs83), retrograde acute aortic dissection,84 type I endoleak,85 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 799 B C Figure 22-8. Illustration of Borst’s elephant trunk technique using a contemporary Y-graft approach. A. Stage 1: The proximal repair includes replacing the ascending aorta and entire arch, with Y-graft reattachment of the brachiocephalic vessels. The distal anastomosis is facilitated by using a collared elephant trunk graft to accommodate the larger diameter of the distal aorta. A section of the graft is left suspended within the proximal descending thoracic aorta. B. Stage 2: The distal repair uses the floating “trunk” for the proximal anastomosis. C. An alternate “hybrid” approach may be used in patients with less extensive distal aortic disease. Endovascular stent grafts are placed within the elephant trunk to complete the repair. (Used with permission of Baylor College of Medicine.) and paraplegia.24 Some centers have begun to replace a small section of the ascending aorta such that the endograft does not land in native aortic tissue, because this may reduce the risk of iatrogenic dissection.84 In a recent expert consensus document, the recommendation was to limit direct stenting of the aortic arch to patients who fall into the high surgical risk ­category. These are patients with significant comorbidities such as chronic pulmonary disease.86 Distal Thoracic Aortic Aneurysms Open Repair In patients with descending thoracic or thoracoabdominal aortic aneurysms, several aspects of treatment—including Figure 22-9. Illustration of a contemporary technique for delivering antegrade cerebral perfusion during aortic arch repair. A. A graft sewn to the right axillary artery is used to return oxygenated blood from the cardiopulmonary bypass circuit. B. After adequate hypothermia is established, the innominate artery is occluded with a tourniquet (inset) so that flow is diverted to the right common carotid artery, which maintains cerebral circulation. (Images adapted from Gravlee GP, Davis RF, Stammers AH, et al, eds. Cardiopulmonary Bypass: Principles and Practice, 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008, Chap. 32, Fig. 1A,B. Copyright Wolters Kluwer Health.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 22 Thoracic Aneurysms and Aortic Dissection A 800 Undeployed endograft UNIT II Part 5-French sheath SPECIFIC CONSIDERATIONS Stiff guidewire Marked pigtail catheter A B C Delivery sheath Figure 22-10. Illustration of a hybrid arch repair. A. A distal arch aneurysm, which extends into the proximal aspect of the descending thoracic aorta, is shown. B. The brachiocephalic vessels are debranched onto a double Y-graft, and a separate graft is used as a conduit for antegrade endovascular deployment of the stent-graft. C. The completed repair. The proximal landing zone of the endograft is within zone 0. (Used with permission from Baylor College of Medicine.) Left common carotid artery Right common carotid artery Left subclavian artery Innominate artery Landing Zone Classifications Figure 22-11. Illustration of the Criado landing zones, which are used to describe aortic anatomy during thoracic endovascular repair. The arch is the short segment that includes the origins of the three brachiocephalic arteries—the innominate artery, the left common carotid artery, and the left subclavian artery. Zone 0 includes the ascending aorta and the origin of the innominate artery. Zone 1 includes the origin of the left common carotid artery. Zone 2 includes the left subclavian artery origin. Zone 3 is a short section of the aorta that comprises the 2 cm immediately distal to the origin of the left subclavian artery, and Zone 4 begins where Zone 3 ends. (Used with permission from Baylor College of Medicine.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 22-12. Illustration of the Crawford classification of thoracoabdominal aortic aneurysm repair based on the extent of aortic replacement. (Reproduced with permission from Coselli et al,232 Fig. 1. Copyright The Society of Thoracic Surgeons.) Table 22-3 801 Current strategy for spinal cord and visceral protection during repair of distal thoracic aortic aneurysms All extents • Permissive mild hypothermia (32°C–34°C, nasopharyngeal) • Moderate heparinization (1 mg/kg) • Aggressive reattachment of segmental arteries, especially between T8 and L1 • Sequential aortic clamping when possible • Perfusion of renal arteries with 4°C crystalloid solution when possible Crawford extent I and II thoracoabdominal repairs • Cerebrospinal fluid drainage • Left heart bypass during proximal anastomosis • Selective perfusion of celiac axis and superior mesenteric artery during intercostal and visceral anastomoses operations. Therefore, several aspects of the operation are devoted to minimizing spinal and renal ischemia (Table 22-3). Our multimodal approach to spinal cord protection includes expeditious repair to minimize aortic clamping time, moderate systemic heparinization (1.0 mg/kg) to prevent smallvessel thrombosis, mild permissive hypothermia (32°C–34°C [89.6°–93.2°F] nasopharyngeal temperature), and reattachment of segmental intercostal and lumbar arteries. As the aorta is replaced from proximal to distal, the aortic clamp is moved sequentially to lower positions along the graft to restore perfusion to newly reattached branch vessels. During extensive thoracoabdominal aortic repairs (i.e., Crawford extent I and II repairs), cerebrospinal fluid drainage is used. The ben7 efits of this adjunct, which improves spinal perfusion by reducing cerebrospinal fluid pressure, have been confirmed in a prospective, randomized trial performed by our group. 87 Motor evoked potentials are used by some groups to monitor the spinal cord throughout the operation.88,89 Left heart bypass, which provides perfusion of the distal aorta and its branches during the clamping period, is also used during extensive thoracoabdominal aortic repairs.90-92 Because left heart bypass unloads the heart, it is also useful in patients with poor cardiac reserve. Balloon perfusion cannulas connected to the left heart bypass circuit can be used to deliver blood directly to the celiac axis and superior mesenteric artery during their reattachment. The potential benefits of reducing hepatic and bowel ischemia include reduced risks of postoperative coagulopathy and bacterial translocation, respectively. Whenever possible, renal protection is achieved by perfusing the kidneys with cold (4°C [39.2°F]) crystalloid. In a randomized clinical trial, reduced kidney temperature was found to be associated with renal protection, and the use of cold crystalloid independently predicted preserved renal function.93 Hypothermic circulatory arrest can also be used during descending thoracic or thoracoabdominal aortic repairs.94 At our center, the primary indication for this approach is the inability to clamp the aorta because of rupture, extremely large aneurysm size, or extension of the aneurysm into the distal transverse aortic arch, or because a prior endovascular repair hinders clamping.55 As discussed previously, complete repair of extensive aneurysms involving the ascending aorta, transverse arch, and VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 22 Thoracic Aneurysms and Aortic Dissection preoperative risk assessment, anesthetic management, choice of incision, and use of protective adjuncts—are dictated by the overall extent of aortic involvement. By definition, descending ­thoracic aortic aneurysms involve the portion of the aorta between the left subclavian artery and the diaphragm. Thoracoabdominal aneurysms can involve the entire thoracoabdominal aorta, from the origin of the left subclavian artery to the aortic bifurcation. Surgical repair of thoracoabdominal aortic aneurysms is categorized by the extent of aortic replacement according to the Crawford classification scheme (Fig. 22-12). Extent I thoracoabdominal aortic aneurysm repairs involve most of the descending thoracic aorta, usually beginning near the left subclavian artery, and extend down into the suprarenal abdominal aorta. Extent II repairs also begin near the left subclavian artery but extend distally into the infrarenal abdominal aorta, and they often reach the aortic bifurcation. Extent III repairs extend from the lower descending thoracic aorta (below the sixth rib) and into the abdomen. Extent IV repairs begin at the diaphragmatic hiatus and often involve the entire abdominal aorta. Descending thoracic aortic aneurysms are repaired through a left thoracotomy. In patients with thoracoabdominal aortic aneurysms, the thoracotomy is extended across the costal margin and into the abdomen. Use of a double-lumen endobronchial tube allows selective ventilation of the right lung and deflation of the left lung. Transperitoneal exposure of the thoracoabdominal aorta is achieved by performing medial visceral rotation and circumferential division of the diaphragm. During a period of aortic clamping, the diseased segment is replaced with a polyester tube graft. Important branch arteries—including intercostal arteries and the celiac, superior mesenteric, and renal arteries— are reattached to openings made in the side of the graft. Visceral and renal artery occlusive disease is commonly encountered during aneurysm repair; options for correcting branch vessel stenosis include endarterectomy, direct arterial stenting, and bypass grafting. Clamping the descending thoracic aorta causes ischemia of the spinal cord and abdominal viscera. Clinically significant manifestations of hepatic, pancreatic, and bowel ischemia are relatively uncommon. However, both acute renal failure and spinal cord injury resulting in paraplegia or paraparesis remain major causes of morbidity and mortality after these 802 descending thoracic aorta generally requires staged operations. In such procedures, when the descending or thoracoabdominal component is symptomatic (e.g., causes back pain or has ruptured) or is disproportionately large (compared with the ascending aorta), the distal segment is treated during the initial operation, and repair of the ascending aorta and transverse aortic arch is performed as a second procedure. A reversed elephant trunk repair, in which a portion of the proximal end of the aortic graft is inverted down into the lumen, can be performed during the first operation; this technique facilitates the second-stage repair of the ascending aorta and transverse aortic arch (Fig. 22-13).95 Although spinal cord ischemia and renal failure receive the most attention, several other complications warrant consideration. The most common complication of extensive repairs is pulmonary dysfunction. With aneurysms adjacent to the left subclavian artery, the vagus and left recurrent laryngeal nerves are often adherent to the aortic wall and thus are susceptible to injury. Vocal cord paralysis should be UNIT II Part SPECIFIC CONSIDERATIONS Figure 22-13. Illustration of the reversed elephant trunk technique using a traditional “island” approach to total aortic arch replacement. A. Stage 1: The distal aorta is repaired through a left thoracoabdominal approach. The aneurysm is opened after the aorta is clamped between the left common carotid artery and the left subclavian artery, which is also clamped. Before the proximal anastomosis is performed, the end of the graft is partly invaginated to leave a “trunk” for the subsequent repair. Proximal intercostal arteries are oversewn. B. After the proximal suture line is completed, the clamps are repositioned to restore blood flow to the left subclavian artery. The repair is completed by reattaching patent intercostal arteries to an opening in the side of the graft and creating a beveled distal anastomosis at the level of the visceral branches. C. Stage 2: The proximal aorta is repaired through a median sternotomy. The aortic arch is opened under hypothermic circulatory arrest. The “trunk” is pulled out and used to replace the aortic arch and ascending aorta. This eliminates the need for a new distal anastomosis and simplifies the procedure. Circulatory arrest and operative time, along with their attendant risks, are reduced. D. The completed two-stage repair of the entire thoracic aorta. (Reproduced with permission from Coselli JS, LeMaire SA, Carter SA, et al: The reversed elephant trunk technique used for treatment of complex aneurysms of the entire thoracic aorta. Ann Thorac Surg 2005; 80:2166, Figs. 2, 3, 7, and 8. Copyright The Society of Thoracic Surgeons.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Endovascular Repair Descending Thoracic Aortic Aneurysms Stent graft repair of descending thoracic aortic aneurysms has become an accepted treatment option for selected patients.86 Although aortic repair with a self-fixing endoprosthesis was reported by Volodos97 in the mid-1980s, it was the report by Parodi and associates98 of using endovascular stent grafting to repair abdominal aortic aneurysms that helped popularize this approach. Only 3 years after this seminal report was published, Dake and colleagues99 reported performing endovascular descending thoracic aortic repair with “homemade” stent grafts in 13 patients. Although endografting was initially approved to treat degenerative descending thoracic aortic aneurysms, recently some newer devices have been approved for use in blunt aortic injury, as well as for penetrating aortic ulcers (see Penetrating Aortic Ulcer discussed later). However, in practice, off-label use of stent-grafts is exceedingly common, and they are frequently used in patients with aortic dissection or ruptured aneurysm. Although the use of stent-grafts in cases of aortic infection is not ideal, patients with fistula or mycotic aneurysm may be treated endovascularly as a bridge to open repair. Reporting standards to uniformly describe the endovascular repair process have been recently introduced,100 as have guidelines for the use of endovascular repair in thoracic aortic disease.40 In elderly patients with severe comorbidity and patients who have undergone previous complex thoracic aortic procedures, endovascular repair is a particularly attractive alternative to standard surgical procedures. The patients tend to have a lower incidence of intraoperative complications, a shorter length of stay, and a higher likelihood of being discharged to home than those who undergo open repair.49 As mentioned previously, appropriate patient selection depends on specific measurements taken from preoperative CT angiograms. To protect patients against spinal cord ischemia during these endovascular repairs, many surgeons use cerebrospinal Figure 22-14. Illustration of a thoracoabdominal aortic aneurysm repair in a patient with a patent left internal thoracic artery–to–left anterior descending coronary artery graft. The proximal anastomosis is being performed while the aorta is clamped between the left common carotid and subclavian arteries. Myocardial perfusion is maintained through the carotidsubclavian bypass graft. (Reproduced with permission from Jones et al,96 Fig. 2. Copyright The Society of ­Thoracic Surgeons.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 803 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection s­ uspected in patients who have postoperative hoarseness, and the presence of nerve damage should be confirmed by endoscopic examination. Vocal cord paralysis can be treated effectively by direct cord medialization (type 1 thyroplasty). Injury to the esophagus during the proximal anastomosis can have catastrophic consequences. Carefully separating the proximal descending thoracic aorta from the underlying esophagus before performing the proximal anastomosis minimizes the risk of a secondary aortoesophageal fistula. In patients who have previously undergone coronary artery bypass with a left internal thoracic artery graft, clamping proximal to the left subclavian artery can precipitate severe myocardial ischemia and cardiac arrest. When the need to clamp at this location is anticipated in these patients, a left common carotid to subclavian bypass is performed to prevent cardiac complications (Fig. 22-14).96 804 UNIT II Part SPECIFIC CONSIDERATIONS fluid drainage. The first step in the repair procedure is to obtain appropriate vascular access for the insertion of the thoracic stent graft. If the femoral artery will not accommodate the necessary sheath, then an iliac artery is exposed. A graft can be sewn to the iliac artery in an end-to-side fashion to facilitate the deployment of the endograft. After 5000 to 10,000 units of heparin are administered, a guidewire and the delivery sheath are typically inserted into the access artery under fluoroscopic guidance; recently, sheathless stent-grafts have been introduced, which are less bulky. The endograft is then advanced into the aorta and suitably positioned. Note that the best view of the distal arch and descending thoracic aorta is usually in the left anterior oblique position at an angle of approximately 40 to 50 degrees. The device is then deployed, and the proximal and distal ends are expanded by using a balloon catheter (“ballooned”), which optimizes the seal between the device and the aortic wall at this landing zone. An aortogram is then taken to rule out any endoleak, and protamine is administered. Although it is not uncommon to cover the left subclavian artery with the endograft to lengthen the proximal landing zone,101 findings suggest that the risk of spinal cord complications is heightened when the subclavian artery is covered and not revascularized, presumably because of a loss of collateral circulation to the spinal cord.102 To prevent this complication, a carotid-to-subclavian bypass can be easily constructed to maintain vertebral artery blood flow and minimize neurologic injury (Fig. 22-15).103,104 In addition, new generations of stent grafts are being designed with side branches that can be placed within the left subclavian artery. This feature is particularly attractive if the proximal neck is short or if the patient has a patent left internal thoracic artery–to–left anterior descending coronary artery bypass. Because a significant number of patients have coexisting coronary artery disease, care must be taken to avoid left subclavian artery occlusion in patients with previous coronary surgery unless a carotid-to-subclavian bypass has been performed. Elephant Trunk Completion In select patients, elephant trunk com- pletion repairs may be done endovascularly (Fig. 22-8C), rather than by an open approach through a thoracotomy.105 Recall that an elephant trunk is used when an aortic aneurysm extends from the distal arch to the descending thoracic aorta. An endograft can be deployed at the time of elephant trunk construction or during a separate, subsequent procedure.84,106 When the stent is deployed in a retrograde manner in such a second-stage procedure, the procedure is facilitated by placing radiopaque markers at the end of the elephant trunk during the first-stage procedure. This allows the distal end of the trunk to be identified via fluoroscopy. A guidewire can then be manipulated into the trunk and advanced into the ascending aorta to stabilize it during stent deployment. Note that advancing a wire in ­retrograde fashion from the femoral artery into the e­ lephant trunk can be challenging. Occasionally, the wire must be advanced in an antegrade fashion from a brachial artery. Variations of this approach include the frozen elephant trunk, but this technique is most commonly used in patients with extensive aortic dissection (see Acute Dissection discussed later). Thoracoabdominal Aortic Aneurysms Although endovascular tho- racoabdominal aortic aneurysm repair remains experimental, it has been shown to be feasible in a few specialized centers. Endovascular thoracoabdominal aortic aneurysm repairs are quite complex, because at least one of the visceral arteries is incorporated into the repair. The number of visceral branches that need to be addressed varies with the extent of aortic coverage.107 The types of stent grafts used include fenestrated grafts, reinforced fenestrated grafts, branched or cuffed grafts, modular combinations of grafts, and multilayer stents.108 Graft fenestrations and branch vessels are typically aligned by using inflatable angioplasty balloons. Procedure time is not insignificant, nor is the amount of contrast medium required to obtain the highly detailed images needed to plan these procedures. In addition, some of the stent grafts used in endovascular thoracoabdominal aortic aneurysm repair are custom-made in advance and thus may take several weeks to obtain; therefore, their use is limited to cases of elective repair.84 In efforts to hasten repair and utilize off-the-shelf devices, parallel graft approaches, which use a combination of large- and small-diameter stents, have been reported.109 And, although some centers now propose distal coverage of the celiac axis110 for extent I thoracoabdominal aortic aneurysm repairs, this potentially risky approach is not widely used. It should be noted that, like open thoracoabdominal aortic aneurysm repair, endovascular repair carries risks of paraplegia, renal failure, stroke, and death, despite the apparent benefits of its being a less invasive procedure. Notably, reports from centers experienced in endovascular thoracoabdominal aortic repair primarily describe limited extent IV repairs.54 For the near future, endovascular thoracoabdominal aortic aneurysm repair should be considered investigational. Hybrid Repair As discussed previously, hybrid aortic repairs are extremely heterogeneous. For extensive distal aortic repairs, approaches such as the hybrid elephant trunk (described ­previously) are not feasible because the aneurysm extends beyond the visceral arteries. However, extensive hybrid thoracoabdominal aortic aneurysm repair111,112 may be a life-saving option in patients at high surgical risk, such as those who have limited physiologic reserve, are of advanced age, or have significant comorbidities. Hybrid procedures use open surgical techniques to reroute blood supply to the visceral arteries so that their aortic origins can be covered by stent grafts without causing visceral ischemia (see Fig. 22-16). Endovascular methods are then used (either as part of the same procedure or at a later stage) to repair the aortic aneurysm, often with simple tube stent grafts; such devices are more readily available than the customized, modular stent grafts deployed in strictly endovascular repairs. Overall, results for hybrid thoracoabdominal aortic aneurysm repair have been somewhat disappointing.113 However, a few centers report acceptable outcomes in high-risk patients, particularly when a staged hybrid approach is used.114 Postoperative Considerations Open Procedures Aortic anastomoses are often extremely fragile during the early postoperative period. Even brief episodes of postoperative hypertension can disrupt suture lines and precipitate severe bleeding or pseudoaneurysm formation. Therefore, during the initial 24 to 48 hours, meticulous blood pressure control is maintained to protect the integrity of the anastomoses. Generally, we liberally use IV vasoactive agents to keep the mean arterial blood pressure between 80 and 90 mmHg. In patients with extremely friable aortic tissue, such as those with Marfan syndrome, we lower the target range to between 70 and 80 mmHg. It is a delicate balancing act, because one must be mindful of spinal cord perfusion and avoid periods of relative hypotension while maintaining these low pressures. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 805 C B Vertebral artery Subclavian artery Vagus nerve Phrenic nerve Common carotid artery Sternocleidomastoid muscle (divided) Internal thoracic artery Anterior scalene muscle (divided) Figure 22-15. Illustration of a hybrid repair of the proximal descending thoracic aorta. A. The preoperative representation of the aneurysm shows that establishing a 2-cm proximal landing zone for a stent graft will require covering the origin of the left subclavian artery. B. Through a supraclavicular approach, a bypass from the left common carotid artery to the left subclavian artery is performed to reroute circulation and create a landing zone for the stent graft. After the bypass is completed, the left subclavian artery is ligated proximal to the graft. C. In the completed zone 2 hybrid repair, the aneurysm has been excluded successfully by a stent graft that covers the origin of the left subclavian artery, and blood flow to the left vertebral artery and arm is preserved by the bypass graft. (Reproduced with permission from Bozinovski et al,103 Figs. 9, 10, and 11. Copyright The Society of Thoracic Surgeons.) Endovascular Procedures As experience with descending thoracic aortic stent grafts continues to accumulate, so too do reports of both early and late complications.55,115,116 Many of these c­ omplications are directly related to manipulation of the delivery system within the iliac arteries and aorta.117 Patients with small, calcified, tortuous iliofemoral arteries are at particularly high risk for life-threatening iliac artery rupture. Although aortic rupture appears to be rare during thoracic stent graft procedures, acute iatrogenic retrograde dissection into the a­ ortic arch and ascending aorta is a relatively common and life-threatening VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 22 Thoracic Aneurysms and Aortic Dissection A 806 Table 22-4 Classification of and common treatment strategies for endoleak Type I • Incomplete seal between stent graft and aorta at the proximal landing site (Type Ia), the distal landing site (Type Ib), or branch module, fenestration, or plug (Type Ic) • Early reintervention to improve seal or conversion to open surgery UNIT II Part Type II • Retrograde perfusion of sac from excluded collateral arteries • Surveillance; as-needed occlusion with percutaneous or other interventions SPECIFIC CONSIDERATIONS Type III • Incomplete seal between overlapping stent graft or module (Type IIIa), or tear in graft fabric (Type IIIb) • Early reintervention to cover gap or tear or conversion to open surgery Type IV • Perfusion of sac due to porosity of material • Surveillance; as-needed reintervention to reline stent graft Type V • Expansion of sac with no identifiable source • Surveillance; as-needed reintervention to reline stent graft Figure 22-16. Illustration of a hybrid approach—which combines open and endovascular techniques—for repair of an extensive aortic aneurysm. Debranching the arch and thoracoabdominal segments allows the use of a series of endovascular stent grafts to exclude the entire aneurysm. complication that requires emergency repair of the ascending aorta and aortic arch via sternotomy and cardiopulmonary bypass. There are many reports of this complication, and it appears most common in off-label applications55 such as hybrid arch approaches84 and the treatment of descending thoracic aortic dissection.118 Retrograde proximal dissection converts a localized descending thoracic aortic aneurysm into an acute problem involving the entire thoracic aorta. Of note, retrograde aortic dissection may also occur several months after initial repair.119 Another significant complication of descending thoracic aortic stent grafting is endoleak. An endoleak occurs when there is a persistent flow of blood (visible on radiologic ­imaging) into the aneurysm sac, and it may occur during the initial proce- dure or develop over time. Although endoleaks are a relatively ­common complication,120 they are not benign, because they lead to continual pressurization of the sac, which can cause expansion or even rupture. These complications are categorized (Table 22-4) according to the site of the leak.100 Although all endoleaks may progress such that they can be considered life-threatening, type I and type III endoleaks generally necessitate early and aggressive intervention. Recently published reporting guidelines aid standardized reporting.100 Other complications include stent graft misdeployment, device migration, endograft kinking, and stent-graft infection, including fistula. Although not all complications related to stent grafts are fatal, endovascular repairs should be performed by expert teams qualified to address the variety of problems that may arise; some patients may need to have these devices removed and replaced with polyester grafts.55,115,116 Complications of endovascular repair are relatively common, so regularly scheduled radiologic imaging surveillance is of the utmost importance. AORTIC DISSECTION Pathology and Classification Aortic dissection, the most common catastrophic event involving the aorta, is a progressive separation of the aortic wall layers that usually occurs after a tear forms in the intima and inner media. As the separation of the layers of the media propagates, at least two channels form (Fig. 22-17): the original lumen, which remains lined by the intima and which is called the true lumen, and the newly formed channel within the layers of the media, which is called the false lumen. The dissecting membrane separates the true and false lumens. Additional tears in the dissecting membrane that allow communication between VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 807 Aortic dissection Intramural hematoma Penetrating aortic ulcer Figure 22-17. Illustration of longitudinal sections of the aortic wall and lumen. Blood flows freely downstream in normal aortic tissue. In classic aortic dissection, blood entering the media through a tear creates a false channel in the wall. Intramural hematomas arise when hemorrhage from the vasa vasorum causes blood to collect within the media; the intima is intact. Penetrating aortic ulcers are deep atherosclerotic lesions that burrow into the aortic wall and allow blood to enter the media. In each of these conditions, the outer aortic wall is severely weakened and prone to rupture. the two channels are called reentry sites. Although the separation of layers primarily progresses distally along the length of the aorta, it can also proceed in a proximal direction; this process often is referred to as proximal extension or retrograde dissection. The extensive disruption of the aortic wall has severe anatomic consequences (Fig. 22-18). First, the outer wall of the false lumen is extremely thin, inflamed, and fragile, which makes it prone to expansion or rupture in the face of ongoing hemodynamic stress. Second, the expanding false lumen can compress the true lumen and cause malperfusion syndrome by interfering with blood flow in the aorta or any of its branch vessels, including the coronary, carotid, intercostal, visceral, renal, and iliac arteries. Finally, when the separation of layers occurs within the aortic root, the aortic valve commissures can become unhinged, which results in acute valvular regurgitation. The clinical consequences of each of these sequelae are addressed in detail in the section on clinical manifestations. Dissection vs. Aneurysm. The relationship between dissection and aneurysmal disease requires clarification. Dissection and aneurysm are separate entities, although they often coexist and are mutual risk factors. In most cases, dissection occurs in patients without aneurysms. The subsequent progressive dilatation of the weakened outer aortic wall results in an aneurysm. On the other hand, in patients with degenerative aneurysms, the ongoing deterioration of the aortic wall can lead to a superimposed dissection. The overused term dissecting aneurysm should be reserved for this specific situation. Classification. For management purposes, aortic dissections are classified according to their location and chronicity. Improvements in imaging have increasingly revealed variants of aortic dissection that probably represent different forms along the ­spectrum of this condition. Location To guide treatment, dissections are categorized according to their anatomic location and extent. The two traditional classification schemes that remain in common use are the DeBakey and the Stanford classification systems (Fig. 22-19).121,122 In their current forms, both of these schemes describe the segments of aorta that are involved in the dissection, rather than the site of the initial intimal tear. The main drawback of the Stanford classification system is that it does not distinguish between patients with isolated ascending aortic dissection and patients with dissection involving the entire aorta. Both types of patients would be classified as having type A dissections, despite the fact that their treatment, follow-up, and prognosis are substantially different. Additional classification schemas include that by Borst and associates,123 in which the ascending and descending aorta are considered independently; the recent modification of the DeBakey classification by Tsagakis et al,124 which extends type II dissection into the aortic arch; and the Penn modification of the Stanford classification,125,126 which expands the classification to include the presence of tissue and global malperfusion. These modifications may help to better streamline the primary surgical intervention; patients with isolated proximal aortic dissection usually undergo emergent operation, as do patients with both proximal and distal aortic dissection. Patients with isolated distal aortic dissection are typically treated medically, unless complications requiring surgery develop. Additionally, these changes are reflective of a shift in some aortic centers from the more traditional approach that is primarily focused on emergent surgical repair of the ascending aorta toward one that, in select patients, additionally treats distal dissection entry points with off-label endovascular therapy.127 Chronicity Aortic dissection also is categorized according to the time elapsed since the initial tear. Dissection is considered VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Normal aorta 808 UNIT II Part SPECIFIC CONSIDERATIONS Figure 22-18. Illustration of the potential anatomic consequences of aortic dissection, with a mapped diagram of affected regions (inset). A. Ascending aortic rupture and cardiac tamponade. B. Disruption of coronary blood flow. C. Injury to the aortic valve causing regurgitation. D, E, and F. Compromised blood flow to branch vessels, causing ischemic complications. (Images adapted from Creager MA, Dzau VS, Loscalzo J, eds. Vascular Medicine. Philadelphia: WB Saunders; 2006. Copyright © Saunders/ Elsevier, 2006. Fig. 35-1.) acute within the first 14 days after the initial tear; after 14 days, the dissection is considered chronic. Although arbitrary, the distinction between acute and chronic dissections has important implications, not only for decision-making about perioperative management strategies and operative techniques, but also for evaluating surgical results. Figure 22-20 provides an algorithm for the management of acute aortic dissection. In light of the importance of acuity, Borst and associates123 have proposed a third phase—termed subacute—to describe the transition between the acute and chronic phases. The subacute period encompasses days 15 through 60 after the initial tear. Although this is past the traditional 14-day acute phase, patients with subacute dissection continue to have extremely fragile aortic tissue, which may complicate operative treatment and increase the risks associated with surgery. Variants As noted earlier, advancements in noninvasive imaging of the aorta have revealed variants of aortic dissection (see Fig. 22-17). The recently introduced term acute aortic ­syndrome encompasses classic aortic dissection and its variants. Other aortic syndromes, which were once thought to be rare, include intramural hematoma (IMH) and penetrating aortic ulcer (PAU). Although the issue is somewhat controversial, the current consensus is that, in most cases, these variants of dissection should be treated identically to classic dissection. An IMH is a collection of blood within the aortic wall, without an intimal tear, that is believed to be due to rupture of the vasa vasorum within the media. The accumulation of blood can result in a secondary intimal tear that ultimately leads to a dissection.128 Because IMH and aortic dissection represent a continuum, it is possible that IMH is seen less frequently than aortic dissection because IMH rapidly progresses to true dissection. The prevalence of IMH among patients with acute aortic syndromes is approximately 6%, and 16% progress to full dissection.129 An IMH can be classified according to its location (i.e., ascending or descending) and should be treated analogously to classic dissection.130 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 809 A PAU is essentially a disrupted atherosclerotic plaque that projects into the aortic wall and is associated with surrounding hematoma. Eventually, the ulcer can penetrate the aortic wall, which leads to dissection or rupture. The rate of disease progression is higher than that of IMH alone.131 Causes and Clinical History Aortic dissection is a lethal condition with a reported incidence of 3.5 per 100,000 in the United States.132 Without appropriate modern medical or surgical treatment, most patients (approximately 90%) die within 3 months of dissection, mostly from rupture.133,134 Although several risk factors for aortic dissection have been identified, the specific causes remain unknown. Ultimately, any condition that weakens the aortic wall increases the risk of aortic dissection. Common general cardiovascular risk factors, such as smoking, hypertension, atherosclerosis, and hypercholesterolemia, are associated with aortic dissection. Patients with connective tissue disorders, aortitis, bicuspid aortic valve, or preexisting medial degenerative disease are at risk for dissection, especially if they already have a thoracic aortic aneurysm.21 Aortic injury during cardiac catheterization, surgery, or endovascular aortic repair is a common cause of iatrogenic dissection. Other conditions that are associated with aortic dissection include cocaine and amphetamine abuse,135 as well as severe emotional stress or extreme physical exertion such as during weightlifting.136 Advances in the understanding of the molecular mechanisms behind abdominal aortic aneurysms have prompted similar investigations of thoracic aortic dissection.137-139 Clinical Manifestations The onset of dissection often is associated with severe chest or back pain, classically described as “tearing,” that migrates d­ istally as the dissection progresses along the length of the aorta. The location of the pain often indicates which aortic segments are involved. Pain in the anterior chest suggests involvement of the ascending aorta, whereas pain in the back and abdomen generally indicates involvement of the descending and thoracoabdominal aorta. Additional clinical sequelae of acute aortic dissection vary substantially and are best considered in terms of the dissection’s potential anatomic manifestations at each level of the aorta (see Fig. 22-18 and Table 22-5). Thus, potential complications of dissection of the aorta (and involved secondary arteries) may include cardiac ischemia (coronary artery) or tamponade, stroke (brachiocephalic arteries), paraplegia or paraparesis (intercostal arteries), mesenteric ischemia (superior mesenteric artery), kidney failure (renal arteries), and limb ischemia or loss of motor function (brachial or femoral arteries). Ascending aortic dissection can directly injure the aortic valve, causing regurgitation. The severity of the regurgitation varies with the degree of commissural disruption, which ranges from partial separation of only one commissure, producing mild valvular regurgitation, to full separation of all three commissures and complete prolapse of the valve into the left ventricle, producing severe acute heart failure. Patients with acute aortic valve regurgitation may report worsening dyspnea. Ascending dissections also can extend into the coronary arteries or shear the coronary ostia off of the true lumen, causing acute coronary occlusion; when this occurs, it most often involves the right coronary artery. The sudden disruption of coronary blood flow can cause a myocardial infarction. This presentation of acute myocardial ischemia can mask the presence of aortic dissection, which results in delayed diagnosis and treatment.140 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Figure 22-19. Illustration of the classification schemes for aortic dissection based on which portions of the aorta are involved. Dissection can be confined to the ascending aorta (left) or descending aorta (middle), or it can involve the entire aorta (right). (Reproduced with permission from Creager MA, Dzau VS, Loscalzo J, eds. Vascular Medicine. Philadelphia: WB Saunders; 2006. Copyright © Saunders/ Elsevier, 2006, Fig. 35-2). 810 Management of acute aortic dissection Suspected acute dissection Anti-impulse therapy (beta blockers), blood pressure control UNIT II Part Hemodynamically stable? Yes No Contrast-enhanced CT scan SPECIFIC CONSIDERATIONS Transfer to operating room, intubation, diagnostic TEE Aortic dissection? Ascending aortic dissection (Stanford A or DeBakey I or II)? No Yes Secondary diagnostic study (MRA, TEE, or aortography) No Yes Emergency operation Aortic dissection? No Yes Further diagnostic work-up Ascending aortic dissection (Stanford A or DeBakey I or II)? Yes Transfer to intensive care for further stabilization and diagnostic work-up No Emergency operation Yes Emergency endovascular (fenestration, stent) or open intervention No Transfer to intensive care unit for blood pressure control, anti-impulse therapy Complicated descending aortic dissection (malperfusion, rupture)? Figure 22-20. Algorithm used to facilitate decisions regarding treatment of acute aortic dissection. CT = computed tomography; MRA = magnetic resonance angiography; TEE = transesophageal echocardiography. The thin and inflamed outer wall of a dissected ascending aorta often produces a serosanguineous pericardial effusion that can accumulate and cause tamponade. Suggestive signs include jugular venous distention, muffled heart tones, pulsus paradoxus, and low-voltage electrocardiogram (ECG) tracings. Free rupture into the pericardial space produces rapid tamponade and is generally fatal. As the dissection progresses, any branch vessel from the aorta can become involved, which results in compromised blood flow and ischemic complications (i.e., malperfusion). Therefore, depending on which arteries are involved, the dissection can produce acute stroke, paraplegia, hepatic failure, bowel infarction, renal failure, or a threatened ischemic limb. Diagnostic Evaluation Because of the variations in severity and the wide variety of potential clinical manifestations, the diagnosis of acute aortic dissection can be challenging.141-143 Only 3 out of every 100,000 patients who present to an emergency department with acute chest, back, or abdominal pain are eventually diagnosed with aortic dissection. Not surprisingly, diagnostic delays are common; delays beyond 24 hours after hospitalization occur in up to 39% of cases. Unfortunately, delays in diagnosis lead to delays in treatment, which can have disastrous consequences. The European Society of Cardiology Task Force on Aortic Dissection stated, “The main challenge in managing acute aortic dissection is to suspect and thus diagnose the disease as early VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Table 22-5 Anatomic complications of aortic dissection and their associated symptoms and signs Symptoms and Signs Aortic valve insufficiency Dyspnea Murmur Pulmonary rales Shock Coronary malperfusion Chest pain with characteristics of angina Nausea/vomiting Shock Ischemic changes on electrocardiogram Elevated cardiac enzymes Pericardial tamponade Dyspnea Jugular venous distension Pulsus paradoxus Muffled cardiac tones Shock Low-voltage electrocardiogram Subclavian or iliofemoral artery malperfusion Cold, painful extremity Extremity sensory and motor deficits Peripheral pulse deficit Carotid artery malperfusion Syncope Focal neurologic deficit (transient or persistent) Carotid pulse deficit Coma Spinal malperfusion Paraplegia Incontinence Mesenteric malperfusion Nausea/vomiting Abdominal pain Renal malperfusion Oliguria or anuria Hematuria as possible.”141 A recent study by the International Registry of Acute Aortic Dissection examined the reasons for delayed diagnosis and found that diagnosis lagged in women, as well as in patients with atypical symptoms, such as fever or mild pain (rather than severe pain).140 A high index of suspicion is critical, particularly in younger, atypical patients, who may have connective tissue disorders or other, less common risk factors. Most patients with acute aortic dissection (80%–90%) experience severe pain in the chest, back, or abdomen.141-143 The pain usually occurs suddenly, has a sharp or tearing quality, and often migrates distally as the dissection progresses along the aorta. For classification purposes (acute vs. subacute vs. chronic), the onset of pain is generally considered to represent the beginning of the dissection process. Most of the other common symptoms either are nonspecific or are caused by the secondary manifestations of dissection. A discrepancy between the extremities in pulse, blood pressure, or both is the classic physical finding in patients with aortic dissection. It often occurs because of changes in flow in VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 811 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Anatomic Manifestation the true and false lumens, and it does not necessarily indicate extension into an extremity branch vessel. Involvement of the aortic arch often creates differences between the right and left arms, whereas descending aortic dissection often causes differences between the upper and lower extremities. Like symptoms, most of the physical signs after dissection are related to the secondary manifestations and therefore vary considerably (Table 22-5). For example, signs of stroke or a threatened ischemic limb may dominate the physical findings in patients with carotid or iliac malperfusion, respectively. Unfortunately, laboratory studies are of little help in diagnosing acute aortic dissection. There has been continued interest in using D-dimer level to aid in making this diagnosis.144 Several reports indicate that D-dimer is an extremely sensitive indicator of acute aortic dissection; elevated levels are found in approximately 97% of affected patients.145 Tests that are commonly used to detect acute coronary events—including ECG and tests for serum markers of myocardial injury—deserve special consideration and need to be interpreted carefully. Normal ECGs and serum marker levels in patients with acute chest pain should raise suspicion about the possibility of aortic dissection. It is important to remember that ECG changes and elevated serum marker levels associated with myocardial infarction do not exclude the diagnosis of aortic dissection, because dissection can cause coronary malperfusion. Of note, abnormal ECGs have recently been shown to delay the diagnosis of aortic dissection, and the possibility of aortic dissection should not be prematurely ruled out.140,146 Similarly, although CXRs may show a widened mediastinum or abnormal aortic contour, up to 16% of patients with dissection have a normal-appearing CXR.142 The value of the CXR for detecting aortic dissection is limited, with a sensitivity of 67% and a specificity of 86%.147 Once the diagnosis of dissection is considered, the thoracic aorta should be imaged with CT, MRA, or echocardiography. The accuracy of these noninvasive imaging tests has all but eliminated the need for diagnostic aortography in most patients with suspected aortic dissection. Currently, the diagnosis of aortic dissection is usually established with contrast-enhanced CT, which has a sensitivity of 98% and a specificity of 87%, and, acquires images swiftly.148 The classic d­ iagnostic feature is a double-lumen aorta (Fig. 22-21). In addition, CT scans provide essential information about the segments of the aorta involved; the acuity of the dissection; aortic dilatation, including the presence of preexisting degenerative aneurysms; and the development of threatening sequelae, including pericardial effusion, early aortic rupture, and branch vessel compromise. Although MRA also provides excellent imaging (with both a sensitivity and specificity of 98%), the MR suite is not well suited for critically ill patients. In patients who cannot undergo contrastenhanced CT or MRA, transthoracic echocardiography can be used to establish the diagnosis. Transesophageal echocardiography (TEE) is excellent for detecting dissection, aneurysm, and IMH in the ascending aorta. In appropriate hands, TEE has a demonstrated sensitivity and specificity as high as 98% and 95%, respectively.149 Furthermore, TEE offers important information about ventricular function and aortic valve competency. Finally, TEE is the diagnostic modality of choice for hemodynamically unstable patients in whom the diagnosis of ascending dissection is suspected; ideally, these patients should be taken to the operating room, where the TEE can be performed and, if the TEE is confirmatory, surgery can be started immediately. 812 UNIT II Part SPECIFIC CONSIDERATIONS Figure 22-21. Computed tomographic scans showing that the aorta has been separated into two channels—the true (T) and false (F) lumens— in two patients with different phases of aortic dissection. A. An acute DeBakey type I aortic dissection. The dissecting membrane appears wavy (arrows) in the early phase of dissection. Here, the true lumen of the proximal aorta can be seen to be extensively compressed. This may lead to malperfusion of the heart. B. A chronic DeBakey type III aortic dissection. In the chronic phase, the membrane appears straighter and less mobile (arrow) because it has stabilized over time. (Used with permission of Baylor College of Medicine.) In selected patients with ascending aortic dissection (i.e., those who have evidence of preexisting coronary artery disease), coronary angiography can be considered before surgery. Specific relative indications in these patients include a history of angina or myocardial infarction, a recent myocardial perfusion study with abnormal results, previous coronary artery bypass or angioplasty, and acute ischemic changes on ECG. Contraindications include hemodynamic instability, aortic rupture, and pericardial effusion.150 In our practice, patients with acute aortic dissections rarely undergo coronary angiography. However, all patients presenting for elective repair of chronic ascending dissections have diagnostic coronary angiograms taken. Of note, when malperfusion of the renal, visceral, or lower extremity arteries develops, the patient is usually treated in an angiography suite or hybrid operating room.127 Although the dissection usually is diagnosed on CT scan, these patients also undergo aortography, during which the mechanism of the malperfusion is ascertained and, if possible, corrected. Hence, catheter-based aortography may be obsolete as a diagnostic test for dissection, but it remains beneficial for patients with malperfusion. Treatment Initial Assessment and Management. Regardless of the location of the dissection, the initial treatment is the same for all patients with suspected or confirmed acute aortic dissection (see Fig. 22-20). Furthermore, because of the potential for rupture before the diagnosis is confirmed, aggressive pharmacologic management is started once there is clinical suspicion of dissection, and this treatment is continued during the diagnostic evaluation. The goals of pharmacologic treatment are to stabilize the dissection and prevent rupture. Patients are monitored closely in an intensive care unit. Indwelling radial arterial catheters are used to monitor blood pressure and optimize titration of antihypertensive agents. In cases of limb malperfusion, blood pressures in the affected limb can underrepresent the central aortic pressure; therefore, blood pressure is measured in the arm with the better pulse. Central venous catheters ensure reliable IV access for delivering vasoactive medications. Pulmonary artery catheters are reserved for patients with severe cardiopulmonary dysfunction. In addition to confirming the diagnosis of dissection and defining its acuity and extent, the initial evaluation focuses on determining whether any of several life-threatening complications are present. Particular attention is paid to changes in neurologic status, peripheral pulses, and urine output. Serial laboratory studies—including arterial blood gas concentrations, complete blood cell count, prothrombin and partial thromboplastin times, and serum levels of electrolytes, creatinine, blood urea nitrogen, and liver enzymes—are useful for detecting organ ischemia and optimizing management. The initial management strategy, commonly described as anti-impulse therapy or blood pressure control, focuses on reducing aortic wall stress, the force of left ventricular ejection, chronotropy, and the rate of change in blood pressure (dP/ dT). Reductions in dP/dT are achieved by lowering both cardiac contractility and blood pressure. The drugs initially used to accomplish these goals include IV beta-adrenergic blockers, direct vasodilators, calcium channel blockers, and angiotensinconverting enzyme inhibitors. These agents are used to achieve a heart rate between 60 and 80 bpm, a systolic blood pressure between 100 and 110 mmHg, and a mean arterial blood pressure between 60 and 75 mmHg. These hemodynamic targets are maintained as long as urine output remains adequate and neurologic function is not impaired. Achieving adequate pain control with IV opiates, such as morphine and fentanyl, is important for maintaining acceptable blood pressure control. Beta antagonists are administered to all patients with acute aortic dissections unless there are strong contraindications, such as severe heart failure, bradyarrhythmia, high-grade a­ trioventricular VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Treatment of Ascending Aortic Dissection Acute Dissection Because of the risk of aortic rupture, acute ascending aortic dissection is usually considered an absolute indication for emergency surgical repair. However, specific patient groups may benefit from nonoperative management or delayed operation.151 Delayed repair should be considered for patients who (a) present with severe acute stroke or 8 mesenteric ischemia, (b) are elderly and have substantial comorbidity, (c) are in stable condition and may benefit from transfer to specialized centers, or (d) have undergone a cardiac operation in the remote past. Regarding the last group, it is important that the previous operation not be too recent; dissections that occur during the first 3 weeks after cardiac surgery pose a high risk of rupture and tamponade, and such dissections warrant early operation.152 In the absence of the circumstances listed earlier, most patients with acute ascending aortic dissection undergo emergent graft replacement of the ascending aorta. Operative repair is similar to that for aneurysm of the transverse aortic arch (described previously) because hypothermic circulatory arrest is commonly used regardless of the extent of repair. Immediately before the operation begins, intraoperative TEE is commonly performed to further assess baseline myocardial and valvular function and, if necessary, to confirm the diagnosis. The operation is performed via a median sternotomy with cardiopulmonary bypass and hypothermic circulatory arrest (Fig. 22-22). In preparation for circulatory arrest, cannulas are placed in the right axillary artery (to provide arterial inflow) and in the right atrium (to provide venous drainage).77 After an appropriate level of cooling has been achieved (usually between 22°C and 24°C), cardiopulmonary bypass is stopped, and the ascending aorta is opened. The innominate artery is then occluded with a clamp or snare, and flow from the axillary artery cannula is used to provide ACP. A separate perfusion catheter can be placed in the left common carotid artery to ensure perfusion of the left side of the brain. This strategy of performing the distal anastomosis during a brief period of circulatory arrest, often termed open distal anastomosis, obviates the need to place a clamp across the fragile aorta, avoiding further aortic damage. Also, it allows the surgeon to carefully inspect the aortic arch for intimal tears. Traditionally, the entire arch is replaced only if a primary intimal tear is located in the arch or if the arch is aneurysmal; most ­commonly, repair is limited to replacement of the entire ascending aorta or to a beveled “hemiarch” repair.153 Conservative repair has been shown to increase the likelihood of early survival.154 The distal aortic cuff is prepared by tacking the inner and outer walls together and using surgical adhesive to obliterate the false lumen and strengthen the tissue. A polyester tube graft is sutured to the distal aortic cuff. The anastomosis between the graft and the aorta is fashioned so that blood flow will be directed into the true lumen; this often alleviates any distal malperfusion problems that were present preoperatively. After the distal anastomosis is reinforced with additional adhesive, the graft is de-aired and clamped, full cardiopulmonary bypass is resumed, rewarming is initiated, and the proximal portion of the repair is started. In the absence of annuloaortic ectasia or connective tissue disorders—which generally necessitate aortic root replacement—aortic valve regurgitation can be corrected by resuspending the commissures onto the outer aortic wall.155 The proximal aortic cuff is prepared with tacking sutures and surgical adhesive before the proximal aortic anastomosis is performed. In the majority of patients who undergo surgical repair of acute ascending dissection, the dissection persists distal to the site of the operative repair; the residually dissected aorta, which generally includes at least a portion of the transverse aortic arch as well as a large portion of the distal aorta, is susceptible to dilatation over time. Extensive dilatation of the arch or distal aorta develops in 25% to 40% of survivors156,157 and often necessitates further aortic repair. Additionally, long-term survival after acute proximal aortic dissection is generally poor, and rupture of the dilated distal aorta is a common cause of late death in these patients.154,156-158 The challenges that survivors of acute proximal aortic dissection commonly face over time have led to the development of alternate acute dissection strategies such as total arch replacement159 and hybrid arch strategies to extend proximal aortic repair into the distal aorta. The goal of hybrid arch approaches in acute dissection is to thrombose the residual false lumen by compressing it with the radial force that is exerted by a stentgraft placed in the true lumen, thereby facilitating remodeling and preventing late aneurysm formation.160 However, in such repairs, the compressed false lumen may continue to be perfused in a retrograde fashion. In Europe, Japan, and elsewhere, one-piece hybrid prostheses are now available that incorporate a polyester graft for the proximal repair and a stent-graft component for the descending aorta. These devices are deployed in an antegrade fashion after the arch has been resected; this procedure is termed a “frozen elephant trunk” repair.161 In the United States, such devices are unavailable, so this repair is commonly done by concomitantly deploying a commercially available stent-graft in an antegrade fashion after fully or partly162 replacing the ascending aorta and aortic arch. In some variations of this off-label approach, the stent-graft is directly sutured to the distal aspect of the proximal open repair, whereas in others, there may be a gap of native tissue between the open and endovascular repair. Although this technique appears to be extensively used outside the United States, and with early and midterm success,160,163-165 only a few U.S. reports describe its use.162,166,167 Emerging reports describe an enhanced risk of spinal cord ischemia, a risk that is not usually associated with open arch repair. This is probably due to the extensive coverage of the intercostal vessels by the stent-graft. Uncertainties in the frozen elephant trunk procedure need to be addressed before it becomes a standard recommendation for this subset of patients.168 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 813 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection conduction block, or bronchospastic disease. Esmolol can be useful in patients with bronchospastic disease because it is a cardioselective, ultrafast-acting agent with a short half-life. Labetalol, which causes both nonselective beta blockade and postsynaptic alpha1-blockade, reduces systemic vascular resistance without impairing cardiac output. Doses of beta antagonists are titrated to achieve a heart rate of 60 to 80 bpm. In patients who cannot receive beta antagonists, calcium channel blockers such as diltiazem are an effective alternative. Nitroprusside, a direct vasodilator, can be administered once beta blockade is adequate. When used alone, however, nitroprusside can cause reflex increases in heart rate and contractility, elevated dP/dT, and progression of aortic dissection. Enalapril and other angiotensin-converting enzyme inhibitors are useful in patients with renal malperfusion. These drugs inhibit renin release, which may improve renal blood flow. 814 UNIT II Part SPECIFIC CONSIDERATIONS Figure 22-22. Illustration of proximal aortic repair for acute ascending aortic dissection. A. This repair requires a median sternotomy and cardiopulmonary bypass. The ascending aorta is opened during hypothermic circulatory arrest, while antegrade cerebral perfusion is delivered via an axillary artery graft (see Fig. 22-8). B. The dissecting membrane is removed to expose the true lumen. C. Surgical adhesive is used to obliterate the false lumen and strengthen the aorta for the distal anastomosis. A 30-mL balloon catheter is placed in the true lumen to compress the distal false lumen; this helps keep the adhesive (which strengthens the repair) within the proximal false lumen and prevents distal embolization of the adhesive through re-entry sites. A moist gauze sponge is placed in the true lumen to prevent the adhesive from running into the brachiocephalic vessels. D. An open distal anastomosis prevents clamp injury of the arch tissue and allows inspection of the arch lumen. A balloon perfusion catheter in the left common carotid artery ensures antegrade perfusion of the left cerebral circulation. If the origin of the dissection (i.e., intimal tear or disruption) does not extensively involve the greater curvature of the aortic arch, and if there is no evidence of a preexisting arch aneurysm, a beveled, hemi-arch repair is carried out, preserving most of the greater curvature of the arch. The aorta is transected, beginning at the greater curvature immediately proximal to the origin of the innominate artery and extending distally toward the lesser curvature to the level of the left subclavian artery. Consequently, most of the transverse aortic arch, except for the dorsal segment containing the brachiocephalic arteries, is removed. An appropriately sized, sealed (with collagen or gelatin) Dacron tube graft is selected, and the beveled distal anastomosis is made with continuous 3-0 or 4-0 monofilament suture. E. After the anastomosis is covered with additional adhesive and cardiopulmonary bypass is resumed, the aortic valve is assessed. Disrupted commissures are resuspended with pledgeted mattress sutures to restore valvular competence. F. The aorta is generally transected at the sinotubular junction, and adhesive is used to obliterate the false lumen within the proximal aortic stump. A moist gauze sponge is placed within the true lumen to prevent the adhesive from injuring the aortic valve leaflets or entering the coronary artery ostia. G. After the adhesive has set, the proximal anastomosis is carried out at the sinotubular junction, incorporating the distal margin of the commissures. (Reproduced with permission from Creager MA, Dzau VS, Loscalzo J, eds. Vascular Medicine. Philadelphia: WB Saunders; 2006. Copyright © Saunders/Elsevier, 2006, Fig. 35-3A–G.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Treatment of Descending Aortic Dissection Nonoperative Management Nonoperative, pharmacologic management of acute descending aortic dissection results in lower morbidity and mortality rates than traditional surgical treatment does.142 The most common causes of death during nonoperative treatment are aortic rupture and end-organ malperfusion. Therefore, patients are continually reassessed for new complications. At least two serial CT scans—usually obtained on day 2 or 3 and on day 8 or 9 of treatment—are compared with the initial scan to rule out significant aortic expansion. Once the patient’s condition has been stabilized, pharmacologic management is gradually shifted from IV to oral medications. Oral therapy, which usually includes a beta antagonist, is initiated when systolic pressure is consistently between 100 and 110 mmHg and the neurologic, renal, and cardiovascular systems are stable. Many patients can be discharged after their blood pressure is well controlled with oral agents and after serial CT scans confirm the absence of aortic expansion. Long-term pharmacologic therapy is important for patients with chronic aortic dissection. Beta blockers remain the drugs of choice.169 In a 20-year follow-up study, DeBakey and colleagues170 found that inadequate blood pressure control was associated with late aneurysm formation. Aneurysms developed in only 17% of patients with “good” blood pressure control, compared with 45% of patients with “poor” control. Aggressive imaging follow-up is recommended for all patients with chronic aortic dissection.171 Both contrast-enhanced CT and MRA scans provide excellent aortic imaging and facilitate serial comparisons to detect progressive aortic expansion. The first surveillance scan is obtained approximately 6 weeks after the onset of dissection. Subsequent scans are obtained at least every 3 months for the first year, every 6 months for the second year, and annually thereafter. Scans are obtained more frequently in highrisk patients, such as those with Marfan syndrome, and in those in whom significant aortic expansion is detected. For patients who have undergone graft repair of descending aortic dissection, annual CT or MRA scans are also obtained to detect false aneurysm formation or dilatation of unrepaired segments of aorta. Early detection of worrisome changes allows timely, elective intervention before rupture or other complications develop; rupture of the distal aorta is relatively common in patients with chronic aortic dissection and often results in death.158 Indications for Surgery In the acute phase, surgery has been traditionally reserved for patients who experience complications.172 In general terms, such intervention is intended to prevent or repair ruptures and relieve life-threatening ischemic manifestations. During the acute phase of a dissection, the specific indications for operative intervention include aortic rupture, increasing periaortic or pleural fluid volume, rapidly expanding aortic diameter, uncontrolled hypertension, and persistent pain despite adequate medical therapy. Aortic rupture may be contained by nearby tissues (such as a localized periaortic hematoma detected on imaging studies) or it may be free and uncontained (presenting as a hemothorax, hemoperitoneum, or massive retroperitoneal hematoma accompanied by shock). Acute dissection superimposed on a preexisting aneurysm is considered a lifethreatening condition and is therefore another indication for operation. Finally, patients who have a history of noncompliance with medical therapy may ultimately benefit more from surgical treatment if they are otherwise reasonable operative candidates. Acute malperfusion syndromes also warrant intervention. In the recent past, visceral and renal malperfusion were considered indications for operation. Percutaneous interventions, however, have largely replaced open surgery for treatment of these complications. When the endovascular approach is unavailable or unsuccessful, surgical options can be used. In the chronic phase, the indications for operative intervention for aortic dissections are similar to those for degenerative thoracic aortic aneurysms, although a slightly lower threshold of repair is now recommended. Guidelines for thoracic aortic disease40 recommend elective operation in otherwise healthy patients when the affected segment has reached a diameter of 5.5 cm, especially in patients with connective tissue disorders. Rapid aortic enlargement (>1 cm per year) and other factors that increase the likelihood of aortic rupture may also be considered. Endovascular Treatment Malperfusion Syndrome Endovascular therapy is routinely used in patients with descending aortic dissection complicated by visceral malperfusion.173 Abdominal malperfusion syndrome often is fatal; prompt identification of visceral ischemia and expedited treatment to restore hepatic, gastrointestinal, and renal perfusion are imperative for a positive outcome. As described in a later section, several open surgical techniques can be used to re-establish blood flow to compromised organs. However, in acute cases, open surgery is associated with poor outcomes. Therefore, endovascular intervention is the preferred initial approach in such cases. In one endovascular technique known as endovascular fenestration, a balloon is used to create a tear in the dissection flap, which allows blood to flow in both the true and false lumens. This technique can be used when a visceral branch is being supplied by an underperfused true or false lumen. Placement of a stent graft in the true lumen of the aorta can resolve a “dynamic” malperfusion. Occasionally, a small stent must be placed directly in the lumen of a visceral or renal artery because the dissection has propagated into the branch, resulting in “static” malperfusion at the origin. Iliofemoral malperfusion causing limb-threatening leg ischemia also can be treated via an endovascular approach. However, direct surgical revascularization—usually by placing a femoral-to-femoral arterial bypass graft—is a better option whenever the endovascular procedure cannot be performed expeditiously. Acute Dissection Although surgery has been traditionally recommended for patients with complicated acute descending aortic dissection, many centers have shifted toward using endovascular stent grafts as the preferred approach in these cases,174 even though this is an off-label application of stent grafts. Evidence suggests that emergent endovascular repair in patients with true VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 815 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Chronic Dissection Occasionally, patients with ascending aortic dissection present for repair in the chronic phase. In most respects, the operation is similar to that for acute dissection repair. One notable difference is that the tissue is stronger in chronic dissection than in acute dissection, which makes suturing safer. In addition, the false lumen is not obliterated at the distal anastomosis; instead, the dissecting membrane is fenestrated into the arch to ensure perfusion of both lumens and to prevent postoperative malperfusion complications. Unlike operations for acute dissection, operations for chronic dissection are often aggressive repairs that extend into the arch and root, because the tissues are much less fragile. 816 UNIT II Part SPECIFIC CONSIDERATIONS lumen collapse and complications such rupture or dynamic malperfusion may be lifesaving in these difficult-to-treat patients. However, these patients remain at risk of further complication or future reintervention. Although endovascular repair in patients with connective tissue disorder is generally not recommended, this technique may be used as a bridge to later definitive repair in such life-threatening circumstances. Less convincing is the evidence in support of using endovascular stent grafts to treat uncomplicated acute descending dissection. The goal of this treatment strategy is to use the stent graft to cover the intimal tear, seal the entry site of the dissection, and eventually cause thrombosis of the false lumen to aid in aortic remodeling and reduce late aortic expansion. However, whether this approach is more effective than conventional nonoperative management remains controversial. Moreover, inadvertent retrograde perfusion or pressurization of the endovascularly repaired aortic section is still a risk; therefore, at this time, the use of endografts in patients with uncomplicated, classic dissection remains investigational.175,176 Such procedures take place in a hybrid operating room, where access to the true lumen is gained through the femoral arteries. An aortogram is taken, and the intimal tear is identified. Note that the diameter of the true lumen is measured on both the aortogram and a preoperative contrast-enhanced CT scan. A stent graft approximately 10% wider in diameter than the true lumen is selected for these cases. Unlike stents deployed to treat most descending thoracic aortic aneurysms, stents deployed to treat descending aortic dissections must not be ballooned, because ballooning can cause a new intimal tear, retrograde dissection into the ascending aorta, or even aortic rupture. Chronic Dissection Endovascular treatment of chronic descending aortic dissection is also controversial and remains under investigation.174,177 These dissections are particularly challenging because the relative rigidity of the dissecting membrane and the presence of multiple re-entry sites make it difficult to exclude the false lumen. Furthermore, interfering with false lumen perfusion may cause ischemic complications, such as bowel infarction or renal failure. Until the safety and effectiveness of endovascular repair for this condition have been demonstrated, patients with chronic descending aortic dissection should be treated with conventional nonoperative management until indications for open surgical repair develop. Penetrating Aortic Ulcer Unlike patients with classic descending aortic dissection, those with PAUs appear to be very well suited for endovascular intervention. Covering the focal ulceration with a stent graft has been shown to be an effective treatment.178 In a recent study by Patel and colleagues,179 endovascular repair of PAU was associated with better early outcomes than open repair. However, when PAU was associated with adjacent hematoma within the aortic wall, rates of subsequent reintervention were increased. Open Repair Acute Dissection In patients with acute aortic dissection, sur- gical repair of the descending thoracic or thoracoabdominal aorta is traditionally associated with high morbidity and mortality.142 Therefore, the primary goals of surgery are to prevent fatal rupture and to restore branch vessel perfusion.172 A limited graft repair of the life-threatening aortic lesion achieves these goals while minimizing risks. Because the most common site of rupture in descending aortic dissection is in the ­proximal third of the descending thoracic aorta, the upper half of the descending thoracic aorta is usually repaired. The d­ istal half also may be replaced if it exceeds 4 cm in diameter. Graft replacement of the entire thoracoabdominal aorta is not attempted in such cases unless a large coexisting aneurysm mandates this radical approach. Similarly, the repair is not extended into the aortic arch unless the arch is aneurysmal, even if the primary tear is located there. Patients with chronic dissection who require emergency repair because of acute pain or rupture also undergo limited graft replacement of the symptomatic segment. Because repairing acute dissections entails an increased risk of paraplegia, adjuncts that provide spinal cord protection, such as cerebrospinal fluid drainage and left heart bypass, are used liberally during such repairs,180 even if the repair is confined to the upper descending thoracic aorta. Proximal control usually is obtained between the left common carotid and left subclavian arteries; any mediastinal hematoma near the proximal descending thoracic aorta is avoided until proximal control is established. After the aorta is opened, the dissecting membrane is excised from the section undergoing graft replacement. The proximal and distal anastomoses use all layers of the aortic wall, thereby excluding the false lumen in the suture lines and directing all blood flow into the true lumen. Although the relative lack of mural thrombus ensures the presence of multiple patent intercostal arteries, extreme tissue fragility may preclude their ­reattachment. Malperfusion Syndrome Lower-extremity ischemia is commonly addressed with surgical extra-anatomic revascularization techniques, such as femoral-to-femoral bypass grafting. In patients with abdominal organ ischemia, flow to the compromised bed must be re-established swiftly. When an endovascular approach is unavailable or unsuccessful, open surgery is necessary. Although they are considered second-line therapies, multiple techniques are available, including graft replacement of the aorta (with flow redirected into the true lumen), open aortic fenestration, and visceral or renal artery bypass. Chronic Dissection A more aggressive replacement usually is performed during elective aortic repairs in patients with chronic dissection. In many regards, the operative approach used in these patients is identical to that used for descending thoracic and thoracoabdominal aortic aneurysms, as described in the first half of this chapter (Fig. 22-23). One key difference is the need to excise as much dissecting membrane as possible to clearly identify the true and false lumens and to locate all important branch vessels. When the dissection extends into the visceral or renal arteries, the membrane can be fenestrated, or the false lumen can be obliterated with sutures or intraluminal stents. Asymmetric expansion of the false lumen can create wide separation of the renal arteries. This problem is addressed by reattaching the mobilized left renal artery to a separate opening in the graft or by performing a left renal artery bypass with a side graft. Wedges of dissecting membrane also are excised from the aorta adjacent to the proximal and distal anastomoses, which allows blood to flow through both true and false lumens. When placing the proximal clamp is not technically feasible, hypothermic circulatory arrest can be used to facilitate the proximal portion of the repair. OUTCOMES Improvements in anesthesia, surgical techniques, and perioperative care have led to substantial improvements in outcome after thoracic aortic aneurysm repair. When performed in specialized centers, these operations are associated with excellent survival VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ rates and acceptable morbidity rates. The interpretation of outcomes data is complicated by site-specific variables, such as the number of years reported and whether data are taken from single-practice centers or from pooled, multicenter, or national registries, and by patient-specific variables, such as type of enrollment, urgency and extent of repair, concomitant procedures performed, and the presence of preexisting risk factors such as advanced age, previous cardiovascular repair, disease of any system or organ, or connective tissue disorder. Repair of Proximal Aortic Aneurysms Risks associated with the open repair of the proximal aorta vary by extent of repair and are greatest for repairs involving total arch replacement. All varieties of aortic root replacement have shown acceptable early mortality rates and few complications. Two groups with 20 and 27 years’ experience with composite valve graft replacement reported early mortality rates of 5.6% and 1.9%, respectively; the more recent repairs had better outcomes.181,182 Early mortality rates for stentless p­ orcine CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Left heart bypass circuit Cold renal perfusion system A B False lumen 817 D C E Figure 22-23. Illustration of distal aortic repair of a chronic dissection. A. Thoracoabdominal incision. B. Extent II thoracoabdominal aortic aneurysm resulting from chronic aortic dissection. The patient has previously undergone composite valve graft replacement of the aortic root and ascending aorta. After left heart bypass is initiated, the proximal portion of the aneurysm is isolated by placing clamps on the left subclavian artery, between the left common carotid and left subclavian arteries, and across the middle descending thoracic aorta. C. The isolated segment of aorta is opened by using electrocautery. D. The dissecting membrane is excised, and bleeding intercostal arteries are oversewn. The aorta is prepared for proximal anastomosis by transecting it distal to the proximal clamp and separating this portion from the esophagus (not shown). E. The proximal anastomosis between the aorta and an appropriately sized Dacron graft is completed with continuous polypropylene suture. F. After left heart bypass has been stopped and the distal aortic cannula has been removed, the proximal clamp is repositioned onto the graft, the other two clamps are removed, and the remainder of the aneurysm is opened. G. The rest of the dissecting membrane is excised, and the openings to the celiac, superior mesenteric, and renal arteries are identified. H. Selective visceral perfusion with oxygenated blood from the bypass circuit is delivered through balloon perfusion catheters placed in the celiac and superior mesenteric arterial ostia. Cold crystalloid is delivered to the renal arteries. The critical intercostal arteries are reattached to an opening cut in the graft. I. To minimize spinal cord ischemia, the proximal clamp is repositioned distal to the intercostal reattachment site. A second oval opening is fashioned in the graft adjacent to the visceral vessels. Selective perfusion of the visceral arteries continues during their reattachment to the graft. A separate anastomosis is often required to reattach the left renal artery. J. After the balloon perfusion catheters are removed and the visceral anastomosis is completed, the clamp is again moved distally, restoring blood flow to the celiac, renal, and superior mesenteric arteries. The final anastomosis is created between the graft and the distal aorta. (Reproduced with permission from Creager MA, Dzau VS, Loscalzo J, eds. Vascular Medicine. Philadelphia: WB Saunders; 2006. Copyright © Saunders/Elsevier, 2006, Fig. 35-8A–J.) VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 818 UNIT II Part SPECIFIC CONSIDERATIONS Figure 22-23. (Continued) tissue root replacements are also low, ranging from 3.6% to 6.0%.183-187 Early mortality rates for contemporary valve-sparing approaches to aortic root replacement are quite low (1%–2%) in experienced centers.66,188,189 Late survival rates after valve-sparing root procedures range from 97% to 99% at 5 years66,188,189 and approach 94% at 10 years.66 Repairs incorporating the ascending aorta and aortic arch have acceptable outcomes; risk increases with patient-specific factors such as severe atherosclerosis190 or as larger sections of the aortic arch are incorporated into the repair.191,192 A revised surgical strategy—such as the use of hypothermic circulatory arrest—is often needed to avoid clamping atherosclerotic sections in the “porcelain” aorta. In Zingone and colleagues’ series190 of 64 patients who underwent replacement of atherosclerotic ascending aorta, hypothermic circulatory arrest was used in 61 patients (95%). Even though these patients had substantial comorbidity and 83% underwent concomitant cardiac repairs, acceptable rates of early mortality (11%) and stroke (6%) were obtained. Other studies indicate that the enhanced risk of neurocognitive disturbances in ascending repairs using circulatory arrest are not offset by lower rates of early mortality.193,194 Regarding extended proximal repair, reported early mortality rates after traditional stage 1 elephant trunk repairs (primarily using island reattachment strategies) range from 2.3% to 13.9%.195-199 Contemporary mortality rates for extensive proximal aortic repair have improved as new strategies and modified adjuncts have been adopted. For example, by adopting contemporary approaches, we have reduced early mortality for stage 1 elephant trunk repairs from 12% to 2% in our patients.73,196 Similarly, in a report by Kazui and colleagues200 covering 20 years of experience and 472 consecutive patients who underwent aortic arch repair with selective ACP, operative mortality was 16.0% for early repairs and 4.1% for more recent repairs. Other contemporary reports of the use of techniques such as moderate hypothermia and Y-graft approaches201-204 indicate similarly improved outcomes; early mortality ranges from 1% to 7%, stroke rates range from 1% to 6%, and no cases of paraplegia are reported. Although paraplegia has traditionally been an unusual and infrequent complication of aortic arch repair, it has been reported as a complication of “long” elephant trunk approaches205 and frozen elephant trunk approaches.206 Because of the heterogeneity of hybrid arch approaches and the tendency to use these approaches in high-risk patients, results of hybrid arch repair are difficult to interpret. A metaanalysis conducted by Koullias and Wheatley82 of data from VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 15 studies with 463 patients found an average 30-day mortality rate of 8.3%; stroke, 4.4%; paraplegia, 3.9%; and endoleak, 9.2%. Of note, relatively few repairs (30%) were performed “off-pump,” and the majority of repairs used cardiopulmonary bypass or hypothermic circulatory arrest. Additionally, several reports of small series (ranging from 33 to 66 patients) have documented a substantial risk of acute retrograde aortic dissection during hybrid arch repairs; rates range from 3.0% to 7.5%, and these patients face significant mortality risk (ranging from 33% to 100%) should this occur.85,207-209 The International Registry of Acute Aortic Dissection (IRAD) provides the most comprehensive data on contemporary outcomes in patients with acute aortic dissection. This registry was established in 1996 and has accumulated data from >3000 patients treated for acute aortic dissection at 30 centers in 11 countries. A recent IRAD analysis of data from 776 patients who underwent surgical repair of acute ascending aortic dissection revealed an in-hospital mortality rate of 23.8%.210 The investigators identified several preoperative predictors of early mortality, including age >70 years, previous cardiac surgery, hypotension or shock at presentation, abrupt onset of symptoms, migrating pain, cardiac tamponade, preoperative renal failure, pulse deficit, and evidence of myocardial ischemia or infarction on ECG.210,211 The German Registry for Acute Aortic Dissection (GERAADA) has collected data on more than 2500 patients from 52 centers since 2006. In a report of 1436 patients with acute proximal dissection that was surgically repaired using hypothermic circulatory arrest with or without unilateral and bilateral ACP, the early mortality rates ranged from 13.9% to 19.4%; the 628 patients with unilateral ACP had the lowest rate of early death.212 Repair of Distal Aortic Aneurysms Endovascular Repair of Descending Thoracic Aortic Aneurysms. In the earliest series of endovascular repairs of descending thoracic aortic aneurysms, mortality and morbidity were difficult to assess. Most of the reported series were small and included a large proportion of high-risk patients with substantial comorbidity. For example, in the Stanford experience with “first-generation” stent grafts in 103 patients with descending thoracic aortic aneurysms, the operative mortality rate was 9%, the stroke rate was 7%, the paraplegia/paraparesis rate was 3%, and actuarial survival was only 73 ± 5% at 2 years. However, 62 patients (60%) were not considered candidates for thoracotomy and open surgical repair; as expected, this group experienced the majority of the morbidity and mortality.213 In a follow-up series, the Stanford group reported survival rates of 74% at 1 year and 31% at 5 years after stent grafting in patients who were deemed not to be surgical candidates; in contrast, survival rates were 93% at 1 year and 78% at 5 years (P<0.001) after stent grafting in patients who were deemed reasonable candidates for conventional open repair.214 This study also found a 30% incidence of late aortic complications, which stresses the necessity for appropriate follow-up. Evidence from pivotal, nonrandomized trials that compared patients who underwent endograft exclusion with historical or concurrent patients who underwent open repair215-217 shows that the stent graft groups had significantly less morbidity and early mortality than the open repair groups, although in two of the trials, a nonsignificant between-group difference Open Repair of Descending Thoracic and Thoracoabdominal Aortic Aneurysms. Contemporary results of open repairs of descending thoracic aortic aneurysms, including those performed in select patients with chronic dissection, indicate that early mortality rates range from 4.1% to 8.0%, renal failure rates range from to 4.2% to 7.5%, and paraplegia rates range from 2.3% to 5.7%; stroke rates are generally lower, ranging from 1.8% to 2.1%.223-225 In our series, although the risk of paraplegia increased with the extent of repair, the risk of mortality was greatest for those undergoing repair of the proximal two thirds of the descending aorta.223 As expected, stroke rates after distal aortic repairs were highest when the clamp site was near the left subclavian artery. Several studies have compared endovascular and surgical approaches to descending thoracic aortic repair. Some studies found no significant differences in rates of early death, stroke, and paraplegia,217,226,227 whereas others found that surgical patients had higher rates of early mortality (27%)228 and paraplegia (14%).215 However, a recent study of Medicare patients showed that the early survival advantage associated with stent grafts is soon lost in the majority of patients.229 Contemporary series of open thoracoabdominal aortic repairs show acceptable survival. Reported outcome rates range from 5% to 12% for early mortality, 3.8% to 9.5% for paraplegia, 1.7% to 5.2% for stroke, and 6% to 12% for renal complications.230-234 Many of these series summarize 10 to 20 years of surgical experience,231-234 although some present a shorter but more contemporary experience.230 Even for complex thoracoabdominal aortic repairs, such as stage 2 elephant trunk repairs, several centers report acceptable early mortality rates ranging from 0% to 10%.195-199 Worse outcomes are also d­ ocumented, as in a statewide, nonfederal analysis of data from 1010 patients whose early mortality rate was 25%. Of note, 40% of these patients VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 819 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection Treatment of Acute Ascending Aortic Dissection was observed in the rate of stroke.215,217 Available 5-year comparative data show that the two groups differed significantly in their aneurysm-related mortality rates (2.8% for endovascular patients and 11.7% for open repair patients) but not in their rates of all-cause mortality (which were 32% and 31%, respectively).218 Additional pivotal trial 5-year outcomes219 indicate the growing disparity between aneurysm-related (96.1%) and all-cause survival (58.5%) in patients with endovascular repair, leading some to comment on the possible futility of repair in many patients.174 Although the feasibility of endovascular treatment of chronic descending thoracic aortic dissection has been shown in small series,148,220 the efficacy of such repairs has not been established. The eagerly anticipated initial outcomes of the INSTEAD trial (INvestigation of STEnt grafts in patients with type B Aortic Dissection), which involves 136 patients with uncomplicated chronic descending aortic dissection, show no survival benefit of stent grafting over standard medical antihypertensive therapy in the first 2 years after randomization.221 However, it appears that the extended study may find a survival advantage at 5 years.174 Likewise, the ADSORB (A Prospective Randomized Trial in Acute Uncomplicated Type B Dissections) trial222 is currently underway, and once complete, it may help elucidate whether endovascular repair in patients with uncomplicated descending dissection provides an advantage over standard medical antihypertensive therapy as pertains to its study endpoints—thrombosis of the false lumen, aortic enlargement, and aortic rupture. Thus, at present, the use of stent grafts to treat chronic descending aortic dissection should be considered experimental. 820 were treated at centers averaging only one thoracoabdominal aortic aneurysm repair per year.235 Cowan and colleagues,236 who examined the influence of familiarity with the procedure on rates of mortality and morbidity after thoracoabdominal aortic aneurysm repair, reported that patients treated at low-volume centers fared less well. Replacing the entire thoracoabdominal aorta (i.e., performing an extent II repair) carries the highest risk of death, bleeding, renal failure, and paraplegia.92,231,232 Early survival has been estimated at 79% at 2 years,237 and midterm survival has been estimated at 63% at 5 years.234 UNIT II Part Treatment of Acute Descending Aortic Dissection Nonoperative Management. The in-hospital mortality rate is SPECIFIC CONSIDERATIONS nearly 10% for patients with acute descending aortic dissection who receive nonoperative treatment142; however, when IRAD stratified patients according to clinical presentation, the mortality rate for patients with uncomplicated dissection was less than 4%, whereas the mortality rate for patients with complicated dissection was more than 20%.142,238 The primary causes of death during nonoperative management are rupture, malperfusion, and cardiac failure. Risk factors associated with treatment failure— defined as death or need for surgery—include an enlarged aorta, persistent hypertension despite maximal treatment, oliguria, and peripheral ischemia. Among patients who receive nonoperative treatment for descending aortic dissection and who survive the acute period, approximately 90% remain alive 1 year later, and approximately 76% are alive 3 years later.239 Endovascular Treatment. For malperfusion of the visceral or renal arteries, an endovascular approach is ideal. The Stanford group reported a 93% technical success rate for endovascular reperfusion of an ischemic bed.240 Their experience with the use of first-generation stents to treat acute complicated descending dissections was also encouraging: Complete thrombosis of the false lumen occurred in 79% of patients. The early mortality rate was 16%, comparable to that associated with open techniques.241 A meta-analysis of observational studies of endovascular stenting, which included 248 patients with acute descending aortic dissection, found a 30-day mortality rate of 9.8%.242 Compared with early mortality rates obtained from IRAD data,142 this rate is substantially lower than the rate associated with open surgical treatment but is similar to the rate achieved with nonoperative management. However, patients with complicated acute descending dissection remain susceptible to late events; at 1 year, survival is approximately 70%, and reintervention is needed in about 10% of survivors.243 Open Repair. We recently reported our contemporary experience with 32 patients with acute complicated descending aortic dissection, including 7 patients (22%) with aortic rupture. Complexities included dangerously large aneurysms in the majority of patients (69%), which implied either rapid expansion or an aneurysm superimposed on the dissection. Malperfusion was present in one patient; this patient had an open fenestration procedure. A substantial number of patients (n = 7, 22%) had connective tissue disorders. The operative mortality rate was 6% overall.244 There were 3 cases of permanent spinal cord complications (10%), 1 stroke (3%), and 2 cases of permanent renal failure (6%). In recent multicenter studies by IRAD, investigators found a 29% in-hospital mortality rate among 70 patients with acute dissection who underwent open surgical replacement of the descending thoracic aorta238 and a 22% in-hospital mor- tality rate among 18 patients who underwent open fenestration procedures. Another study found that, of patients who survived surgical treatment of acute descending aortic dissection, approximately 96% were alive at 1 year and approximately 83% were alive at 3 years after the procedure,239 which is substantially better than 1-year survival after endovascular repair in acute complicated distal dissection.239,243 CONCLUSIONS Aortic aneurysm may present as localized or extensive disease. The availability and development of adjuncts and endovascular techniques have supported the constant evolution of surgical strategies to tackle these complex problems. Repair strategies range from isolated, totally endovascular aortic repair for descending thoracic aneurysms to extensive total aortic and staged replacements with a combination of both open and endovascular techniques. Regardless of the difficulty of accurately assessing the risks associated with aortic repair, surgical repair of the thoracoabdominal aorta clearly remains the most challenging aortic repair in terms of mortality and morbidity. Accordingly, replacing the entire thoracoabdominal aorta (i.e., performing an extent II repair) carries the highest risk of death, renal failure, and paraplegia.89,221,226 ACKNOWLEDGMENTS The authors wish to thank Susan Y. Green, MPH, and Stephen N. Palmer, PhD, ELS, for editorial assistance; Scott A. Weldon, MA, CMI, and Carol P. Larson, CMI, for creating the illustrations; and Kapil Sharma, MD, for his substantial contributions to the chapter published in the 9th edition of the textbook, on which this updated chapter was based. 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Increased collagen deposition and elevated expression of connective tissue growth factor in human thoracic aortic dissection. Circulation. 2006;114(1 Suppl):I200-205. 139. Shen YH, Zhang L, Ren P, et al. AKT2 confers protection against aortic aneurysms and dissections. Circ Res. 2013;112(4):618-632. 140. Harris KM, Strauss CE, Eagle KA, et al. Correlates of delayed recognition and treatment of acute type A aortic dissection: the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2011;124(18):1911-1918. 141. Erbel R, Alfonso F, Boileau C, et al. Diagnosis and management of aortic dissection. Eur Heart J. 2001;22(18):1642-1681. 142. Hagan PG, Nienaber CA, Isselbacher EM, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283(7):897-903. 143. Klompas M. Does this patient have an acute thoracic aortic dissection? JAMA. 2002;287(17):2262-2272. 144. Shimony A, Filion KB, Mottillo S, Dourian T, Eisenberg MJ. Meta-analysis of usefulness of D-dimer to diagnose acute aortic dissection. Am J Cardiol. 2011;107(8):1227-1234. 145. Sodeck G, Domanovits H, Schillinger M, et al. D-dimer in ruling out acute aortic dissection: a systematic review and prospective cohort study. Eur Heart J. 2007;28(24):3067-3075. 146. Rapezzi C, Longhi S, Graziosi M, et al. Risk factors for diagnostic delay in acute aortic dissection. Am J Cardiol. 2008; 102(10):1399-1406. 147. von Kodolitsch Y, Nienaber CA, Dieckmann C, et al. Chest radiography for the diagnosis of acute aortic syndrome. Am J Med. 2004;116(2):73-77. 148. Nienaber CA, von Kodolitsch Y, Nicolas V, et al. The diagnosis of thoracic aortic dissection by noninvasive imaging procedures. N Engl J Med. 1993;328(1):1-9. 149. Keren A, Kim CB, Hu BS, et al. Accuracy of biplane and multiplane transesophageal echocardiography in diagnosis of typical acute aortic dissection and intramural hematoma. J Am Coll Cardiol. 1996;28(3):627-636. 150. Miller JS, LeMaire SA, Coselli JS. Evaluating aortic dissection: when is coronary angiography indicated? Heart. 2000;83(6):615-616. 151. Scholl FG, Coady MA, Davies R, et al. Interval or permanent nonoperative management of acute type A aortic dissection. Arch Surg. 1999;134(4):402-405. 152. Gillinov AM, Lytle BW, Kaplon RJ, et al. Dissection of the ascending aorta after previous cardiac surgery: differences in presentation and management. J Thorac Cardiovasc Surg. 1999;117(2):252-260. 153. Kirsch M, Soustelle C, Houel R, Hillion ML, Loisance D. Risk factor analysis for proximal and distal reoperations after surgery for acute type A aortic dissection. J Thorac Cardiovasc Surg. 2002;123(2):318-325. 154. Crawford ES, Kirklin JW, Naftel DC, et al. Surgery for acute dissection of ascending aorta. Should the arch be included? J Thorac Cardiovasc Surg. 1992;104(1):46-59. 155. Westaby S, Saito S, Katsumata T. Acute type A dissection: conservative methods provide consistently low mortality. Ann Thorac Surg. 2002;73(3):707-713. 156. Geirsson A, Bavaria JE, Swarr D, et al. Fate of the residual distal and proximal aorta after acute type A dissection repair using a contemporary surgical reconstruction algorithm. Ann Thorac Surg. 2007;84(6):1955-1964. 157. Malvindi PG, van Putte BP, Sonker U, et al. Reoperation after acute type A aortic dissection repair: a series of 104 patients. Ann Thorac Surg. 2013;95(3):922-927. 158. Glower DD, Speier RH, White WD, et al. Management and long-term outcome of aortic dissection. Ann Surg. 1991; 214(1):31-41. 159. Kazui T, Washiyama N, Muhammad BA, et al. Extended total arch replacement for acute type A aortic dissection: experience with seventy patients. J Thorac Cardiovasc Surg. 2000;119(3):558-565. 160. Hoffman A, Damberg AL, Schalte G, et al. Thoracic stent graft sizing for frozen elephant trunk repair in acute type A dissection. J Thorac Cardiovasc Surg. 2013;145(4):964-969. 161. Karck M, Chavan A, Khaladj N, et al. 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Eur J Cardiothorac Surg. 2010;37(6): 1338-1345. 166. Lima B, Roselli EE, Soltesz EG, et al. Modified and “reverse” frozen elephant trunk repairs for extensive disease and complications after stent grafting. Ann Thorac Surg. 2012;93(1):103109; discussion 109. 167. Roselli EE, Soltesz EG, Mastracci T, Svensson LG, Lytle BW. Antegrade delivery of stent grafts to treat complex thoracic aortic disease. Ann Thorac Surg. 2010;90(2): 539-546. 168. Kouchoukos NT. Frozen elephant trunk technique for extensive chronic thoracic aortic dissection: is it the final answer? Ann Thorac Surg. 2011;92(5):1557-1558. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 188. Badiu CC, Eichinger W, Bleiziffer S, et al. Should root replacement with aortic valve-sparing be offered to patients with bicuspid valves or severe aortic regurgitation? Eur J Cardiothorac Surg. 2010;38(5):515-522. 189. David TE, Maganti M, Armstrong S. Aortic root aneurysm: principles of repair and long-term follow-up. J Thorac Cardiovasc Surg. 2010;140(6 Suppl):S14-S19; discussion S45-S51. 190. Zingone B, Gatti G, Spina A, et al. Current role and ­outcomes of ascending aortic replacement for severe nonaneurysmal aortic atherosclerosis. Ann Thorac Surg. 2010;89(2): 429-434. 191. Achneck HE, Rizzo JA, Tranquilli M, Elefteriades JA. Safety of thoracic aortic surgery in the present era. Ann Thorac Surg. 2007;84(4):1180-1185. 192. Estrera AL, Miller CC III, Madisetty J, et al. Ascending and transverse aortic arch repair: the impact of glomerular filtration rate on mortality. Ann Surg. 2008;247(3):524-529. 193. Fleck TM, Czerny M, Hutschala D, et al. The incidence of transient neurologic dysfunction after ascending aortic replacement with circulatory arrest. Ann Thorac Surg. 2003;76(4):1198-1202. 194. Immer FF, Barmettler H, Berdat PA, et al. Effects of deep hypothermic circulatory arrest on outcome after resection of ascending aortic aneurysm. Ann Thorac Surg. 2002;74(2):422-425. 195. Heinemann MK, Buehner B, Jurmann MJ, Borst HG. Use of the “elephant trunk technique” in aortic surgery. Ann Thorac Surg. 1995;60(1):2-6. 196. LeMaire SA, Carter SA, Coselli JS. The elephant trunk technique for staged repair of complex aneurysms of the entire thoracic aorta. Ann Thorac Surg. 2006;81(5):1561-1569. 197. Safi HJ, Miller CC III, Estrera AL, et al. Staged repair of extensive aortic aneurysms: long-term experience with the elephant trunk technique. Ann Surg. 2004;240(4):677-684. 198. Sundt TM, Moon MR, DeOliviera N, et al. Contemporary results of total aortic arch replacement. J Card Surg. 2004; 19(3):235-239. 199. Svensson LG, Kim KH, Blackstone EH, et al. Elephant trunk procedure: newer indications and uses. Ann Thorac Surg. 2004;78(1):109-116. 200. Kazui T, Yamashita K, Washiyama N, et al. Aortic arch replacement using selective cerebral perfusion. Ann Thorac Surg. 2007;83(2):S796-S798; discussion S824-S831. 201. Bischoff MS, Brenner RM, Scheumann J, et al. Long-term outcome after aortic arch replacement with a trifurcated graft. J Thorac Cardiovasc Surg. 2010;140(6 Suppl):S71-76; discussion S86-S91. 202. Iba Y, Minatoya K, Matsuda H, et al. Contemporary open aortic arch repair with selective cerebral perfusion in the era of endovascular aortic repair. J Thorac Cardiovasc Surg. 2013; 145(3 Suppl):S72-S77. 203. Thomas M, Li Z, Cook DJ, Greason KL, Sundt TM. Contemporary results of open aortic arch surgery. J Thorac Cardiovasc Surg. 2012;144(4):838-844. 204. Urbanski PP, Lenos A, Bougioukakis P, et al. Mild-tomoderate hypothermia in aortic arch surgery using circulatory arrest: a change of paradigm? Eur J Cardiothorac Surg. 2012;41(1):185-191. 205. Kondoh H, Taniguchi K, Funatsu T, et al. Total arch replacement with long elephant trunk anastomosed at the base of the innominate artery: a single-centre longitudinal experience. Eur J Cardiothorac Surg. 2012;42(5):840-848; discussion 848. 206. Flores J, Kunihara T, Shiiya N, et al. Extensive deployment of the stented elephant trunk is associated with an increased risk of spinal cord injury. J Thorac Cardiovasc Surg. 2006;131(2):336-342. 207. Antoniou GA, Mireskandari M, Bicknell CD, et al. Hybrid repair of the aortic arch in patients with extensive aortic ­disease. Eur J Vasc Endovasc Surg. 2010;40(6):715-721. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 825 CHAPTER 22 Thoracic Aneurysms and Aortic Dissection 169. Genoni M, Paul M, Jenni R, et al. Chronic beta-blocker therapy improves outcome and reduces treatment costs in chronic type B aortic dissection. Eur J Cardiothorac Surg. 2001;19(5):606-610. 170. DeBakey ME, McCollum CH, Crawford ES, et al. Dissection and dissecting aneurysms of the aorta: twenty-year follow-up of five hundred twenty-seven patients treated surgically. Surgery. 1982;92(6):1118-1134. 171. Fann JI, Smith JA, Miller DC, et al. Surgical management of aortic dissection during a 30-year period. Circulation. 1995;92(9 Suppl):II113-II121. 172. Elefteriades JA, Hartleroad J, Gusberg RJ, et al. Long-term experience with descending aortic dissection: the complication-­ specific approach. Ann Thorac Surg. 1992;53(1):11-20. 173. Barnes DM, Williams DM, Dasika NL, et al. A single-center experience treating renal malperfusion after aortic dissection with central aortic fenestration and renal artery stenting. J Vasc Surg. 2008;47(5):903-910. 174. Miller DC. Through the looking glass: The first 20 years of thoracic aortic stent-grafting. J Thorac Cardiovasc Surg. 2013;145(3 Suppl):S142-S148. 175. Hughes GC, Andersen ND, McCann RL. Management of acute type B aortic dissection. J Thorac Cardiovasc Surg. 2013;145(3 Suppl):S202-S207. 176. Kusagawa H, Shimono T, Ishida M, et al. Changes in false lumen after transluminal stent-graft placement in aortic ­dissections: six years’ experience. Circulation. 2005;111(22): 2951-2957. 177. Nienaber CA, Rousseau H, Eggebrecht H, et al. Randomized comparison of strategies for type B aortic dissection: the INvestigation of STEnt Grafts in Aortic Dissection (INSTEAD) trial. Circulation. 2009;120(25):2519-2528. 178. Demers P, Miller DC, Mitchell RS, et al. Stent-graft repair of penetrating atherosclerotic ulcers in the descending thoracic aorta: mid-term results. Ann Thorac Surg. 2004;77(1):81-86. 179. Patel HJ, Sood V, Williams DM, et al. Late outcomes with repair of penetrating thoracic aortic ulcers: the merits of an endovascular approach. Ann Thorac Surg. 2012;94(2): 516-522; discussion 522-523. 180. Coselli JS, LeMaire SA, de Figueiredo LP, Kirby RP. Paraplegia after thoracoabdominal aortic aneurysm repair: is dissection a risk factor? Ann Thorac Surg. 1997;63(1):28-35. 181. Aomi S, Nakajima M, Nonoyama M, et al. Aortic root replacement using composite valve graft in patients with aortic valve disease and aneurysm of the ascending aorta: twenty years’ experience of late results. Artif Organs. 2002;26(5):467-473. 182. Kindo M, Billaud P, Gerelli S, et al. Twenty-seven-year experience with composite valve graft replacement of the aortic root. J Heart Valve Dis. 2007;16(4):370-377. 183. David TE, Mohr FW, Bavaria JE, et al. Initial experience with the Toronto Root bioprosthesis. J Heart Valve Dis. 2004;13(2):248-251. 184. Gleason TG, David TE, Coselli JS, Hammon JW Jr., Bavaria JE. St. Jude Medical Toronto biologic aortic root prosthesis: early FDA phase II IDE study results. Ann Thorac Surg. 2004;78(3):786-793. 185. Kincaid EH, Cordell AR, Hammon JW, Adair SM, Kon ND. Coronary insufficiency after stentless aortic root replacement: risk factors and solutions. Ann Thorac Surg. 2007;83(3): 964-968. 186. Kon ND, Cordell AR, Adair SM, Dobbins JE, Kitzman DW. Aortic root replacement with the freestyle stentless porcine aortic root bioprosthesis. Ann Thorac Surg. 1999;67(6):1609-1615. 187. Melina G, De Robertis F, Gaer JA, et al. Mid-term pattern of survival, hemodynamic performance and rate of complications after Medtronic Freestyle versus homograft full aortic root replacement: results from a prospective randomized trial. J Heart Valve Dis. 2004;13(6):972-975. 826 UNIT II Part SPECIFIC CONSIDERATIONS 208. Geisbusch P, Kotelis D, Muller-Eschner M, Hyhlik-Durr A, Bockler D. Complications after aortic arch hybrid repair. J Vasc Surg. 2011;53(4):935-941. 209. Czerny M, Weigang E, Sodeck G, et al. Targeting landing zone 0 by total arch rerouting and TEVAR: midterm results of a transcontinental registry. Ann Thorac Surg. 2012;94(1): 84-89. 210. Trimarchi S, Eagle KA, Nienaber CA, et al. Role of age in acute type A aortic dissection outcome: report from the International Registry of Acute Aortic Dissection (IRAD). J Thorac Cardiovasc Surg. 2010;140(4):784-789. 211. Rampoldi V, Trimarchi S, Eagle KA, et al. Simple risk models to predict surgical mortality in acute type A aortic dissection: the International Registry of Acute Aortic Dissection score. Ann Thorac Surg. 2007;83(1):55-61. 212. Kruger T, Weigang E, Hoffmann I, et al. Cerebral protection during surgery for acute aortic dissection type A: results of the German Registry for Acute Aortic Dissection Type A (GERAADA). Circulation. 2011;124(4):434-443. 213. Dake MD, Miller DC, Mitchell RS, et al. The “first generation” of endovascular stent-grafts for patients with aneurysms of the descending thoracic aorta. J Thorac Cardiovasc Surg. 1998;116(5):689-703. 214. Demers P, Miller DC, Mitchell RS, et al. Midterm results of endovascular repair of descending thoracic aortic aneurysms with first-generation stent grafts. J Thorac Cardiovasc Surg. 2004;127(3):664-673. 215. Bavaria JE, Appoo JJ, Makaroun MS, et al. Endovascular stent grafting versus open surgical repair of descending thoracic aortic aneurysms in low-risk patients: a multicenter comparative trial. J Thorac Cardiovasc Surg. 2007;133(2):369-377. 216. Fairman RM, Criado F, Farber M, et al. Pivotal results of the Medtronic Vascular Talent Thoracic Stent Graft System: the VALOR trial. J Vasc Surg. 2008;48(3):546-554. 217. Matsumura JS, Cambria RP, Dake MD, et al. International controlled clinical trial of thoracic endovascular aneurysm repair with the Zenith TX2 endovascular graft: 1-year results. J Vasc Surg. 2008;47(2):247-257. 218. Makaroun MS, Dillavou ED, Wheatley GH, Cambria RP. Five-year results of endovascular treatment with the Gore TAG device compared with open repair of thoracic aortic aneurysms. J Vasc Surg. 2008;47(5):912-918. 219. Foley PJ, Criado FJ, Farber MA, et al. Results with the Talent thoracic stent graft in the VALOR trial. J Vasc Surg. 2012;56(5):1214-1221 1221.e1. 220. Czerny M, Zimpfer D, Rodler S, et al. Endovascular stentgraft placement of aneurysms involving the descending aorta originating from chronic type B dissections. Ann Thorac Surg. 2007;83(5):1635-1639. 221. Nienaber CA. Results from the INSTEAD trial. Paper presented at: Sixth Annual International Symposium on Advances in Understanding Aortic Diseases; Sept 30-Oct 1, 2005; ­Berlin, Germany. 222. Brunkwall J, Lammer J, Verhoeven E, Taylor P. ADSORB: a study on the efficacy of endovascular grafting in uncomplicated acute dissection of the descending aorta. Eur J Vasc Endovasc Surg. 2012;44(1):31-36. 223. Coselli JS, LeMaire SA, Conklin LD, Adams GJ. Left heart bypass during descending thoracic aortic aneurysm repair does not reduce the incidence of paraplegia. Ann Thorac Surg. 2004;77(4):1298-1303. 224. Chiesa R, Tshomba Y, Civilini E, et al. Open repair of descending thoracic aneurysms. HSR Proc Intensive Care Cardiovasc Anesth. 2010;2(3):177-190. 225. Estrera AL, Miller CC, III, Chen EP, et al. Descending thoracic aortic aneurysm repair: 12-year experience using distal aortic perfusion and cerebrospinal fluid drainage. Ann Thorac Surg. 2005;80(4):1290-1296. 226. Dick F, Hinder D, Immer FF, et al. Outcome and quality of life after surgical and endovascular treatment of descending aortic lesions. Ann Thorac Surg. 2008;85(5):1605-1612. 227. Stone DH, Brewster DC, Kwolek CJ, et al. Stent-graft versus open-surgical repair of the thoracic aorta: mid-term results. J Vasc Surg. 2006;44(6):1188-1197. 228. Brandt M, Hussel K, Walluscheck KP, et al. Stent-graft repair versus open surgery for the descending aorta: a case-control study. J Endovasc Ther. 2004;11(5):535-538. 229. Goodney PP, Travis L, Lucas FL, et al. Survival after open versus endovascular thoracic aortic aneurysm repair in an observational study of the Medicare population. Circulation. 2011;124(24):2661-2669. 230. LeMaire SA, Price MD, Green SY, Zarda S, Coselli JS. Results of open thoracoabdominal aortic aneurysm repair. Ann Cardiothorac Surg. 2012;1(3):286-292. 231. Chiesa R, Melissano G, Civilini E, et al. Ten years experience of thoracic and thoracoabdominal aortic aneurysm surgical repair: lessons learned. Ann Vasc Surg. 2004;18(5): 514-520. 232. Coselli JS, Bozinovski J, LeMaire SA. Open surgical repair of 2286 thoracoabdominal aortic aneurysms. Ann Thorac Surg. 2007;83(2):S862-S864. 233. Conrad MF, Crawford RS, Davison JK, Cambria RP. Thoracoabdominal aneurysm repair: a 20-year perspective. Ann Thorac Surg. 2007;83(2):S856-S861. 234. Schepens MA, Kelder JC, Morshuis WJ, et al. Long-term ­follow-up after thoracoabdominal aortic aneurysm repair. Ann Thorac Surg. 2007;83(2):S851-S855. 235. Rigberg DA, McGory ML, Zingmond DS, et al. Thirty-day mortality statistics underestimate the risk of repair of thoracoabdominal aortic aneurysms: a statewide experience. J Vasc Surg. 2006;43(2):217-222. 236. Cowan JA Jr., Dimick JB, Henke PK, et al. Surgical treatment of intact thoracoabdominal aortic aneurysms in the United States: hospital and surgeon volume-related outcomes. J Vasc Surg. 2003;37(6):1169-1174. 237. Wong DR, Parenti JL, Green SY, et al. Open repair of thoracoabdominal aortic aneurysm in the modern surgical era: contemporary outcomes in 509 patients. J Am Coll Surg. 2011; 212(4):569-579; discussion 579-581. 238. Trimarchi S, Tolenaar JL, Tsai TT, et al. Influence of clinical presentation on the outcome of acute B aortic dissection: evidences from IRAD. J Cardiovasc Surg (Torino). 2012;53(2):161-168. 239. Tsai TT, Fattori R, Trimarchi S, et al. Long-term survival in patients presenting with type B acute aortic dissection: insights from the International Registry of Acute Aortic Dissection. Circulation. 2006;114(21):2226-2231. 240. Slonim SM, Miller DC, Mitchell RS, et al. Percutaneous balloon fenestration and stenting for life-threatening ischemic complications in patients with acute aortic dissection. J Thorac Cardiovasc Surg. 1999;117(6):1118-1126. 241. Dake MD, Kato N, Mitchell RS, et al. Endovascular stentgraft placement for the treatment of acute aortic dissection. N Engl J Med. 1999;340(20):1546-1552. 242. Eggebrecht H, Nienaber CA, Neuhauser M, et al. Endovascular stent-graft placement in aortic dissection: a meta-analysis. Eur Heart J. 2006;27(4):489-498. 243. White RA, Miller DC, Criado FJ, et al. Report on the results of thoracic endovascular aortic repair for acute, complicated, type B aortic dissection at 30 days and 1 year from a multidisciplinary subcommittee of the Society for Vascular Surgery Outcomes Committee. J Vasc Surg. 2011;53(4):1082-1090. 244. Coselli JS, LeMaire SA. Acute type B dissections: open surgical options. In: Eskandari MK, Pearce WH, Yao JST, eds. Current Vascular Surgery 2012. Shelton: People’s Medical Publishing House-USA; 2013:351-362. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 23 chapter General Approach to the Vascular Patient 828 The Vascular History / 828 The Vascular Physical Examination / 829 Noninvasive Diagnostic Evaluation of the Vascular Patient / 829 Radiologic Evaluation of the Vascular Patient / 830 Preoperative Cardiac Evaluation / 833 Basic Principles of Endovascular Therapy 834 Needles and Access / 834 Guidewires / 835 Hemostatic Sheaths / 835 Catheters / 835 Angioplasty Balloons / 835 Stents / 836 Stent Grafts / 836 Carotid Artery Disease 837 Epidemiology and Etiology of Carotid Occlusive Disease / 837 Clinical Manifestations of Cerebral Ischemia / 838 Diagnostic Evaluation / 839 Treatment of Carotid Occlusive Disease / 841 Carotid Endarterectomy versus Angioplasty and Stenting / 842 Surgical Techniques of Carotid Endarterectomy / 843 Techniques of Carotid Angioplasty and Stenting / 845 Nonatherosclerotic Disease of the Carotid Artery / 847 Abdominal Aortic Aneurysm Arterial Disease Peter H. Lin, Mun Jye Poi, Jesus Matos, Panagiotis Kougias, Carlos Bechara, and Changyi Chen Mesenteric Artery Disease Anatomy and Pathophysiology / 860 Types of Mesenteric Artery Occlusive Disease / 860 Clinical Manifestations / 861 Diagnostic Evaluation / 861 Surgical Repair / 863 Endovascular Treatment / 864 Clinical Results of Interventions for Mesenteric Ischemia / 865 Renal Artery Disease 850 866 Etiology / 866 Clinical Manifestations / 867 Diagnostic Evaluation / 867 Treatment Indications / 869 Surgical Reconstruction / 869 Clinical Results of Surgical Repair / 870 Endovascular Treatment / 870 Clinical Results of Endovascular Interventions / 871 Aortoiliac Occlusive Disease Causes and Risk Factors / 850 Natural History of Aortic Aneurysm / 850 Clinical Manifestations / 851 Relevant Anatomy / 851 Diagnostic Evaluation / 852 Surgical Repair of Abdominal Aortic Aneurysm / 852 Endovascular Repair of Abdominal Aortic Aneurysm / 853 Results from Clinical Studies Comparing Endovascular versus Open Repair / 857 Classification and Management of Endoleak / 858 859 872 Diagnostic Evaluation / 872 Differential Diagnosis / 872 Collateral Arterial Network / 873 Disease Classification / 873 General Treatment Considerations / 875 Surgical Reconstruction of Aortoiliac Occlusive Disease / 876 Complications of Surgical Aortoiliac Reconstruction / 878 Endovascular Treatment for Aortic Disease / 879 Endovascular Treatment for Iliac Artery Disease / 879 Complications of Endovascular Aortoiliac Interventions / 880 Clinical Results Comparing Surgical and Endovascular Treatment of Aortoiliac Disease / 880 Lower Extremity Arterial Occlusive Disease 881 Epidemiology / 882 Diagnostic Evaluation / 882 Differential Diagnosis / 882 Lower Extremity Occlusive Disease Classification / 883 Etiology of Acute Limb Ischemia / 885 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Clinical Manifestations of Acute Limb Ischemia / 886 Treatment Considerations for Acute Limb Ischemia / 887 Endovascular Treatment / 887 Surgical Treatment / 887 Complications Related to Treatment for Acute Limb Ischemia / 888 Clinical Manifestations of Chronic Limb Ischemia / 889 Treatment Considerations for Chronic Limb Ischemia / 890 Endovascular Treatment / 891 Complications of Endovascular Interventions / 896 Surgical Treatment for Chronic Limb Ischemia due to Femoropopliteal Disease / 897 Complications of Surgical Reconstruction / 898 Choice of Conduit for Infrainguinal Bypass Grafting / 898 Clinical Results of Surgical and Endovascular Interventions for Femoropopliteal Occlusive Disease / 899 Nonatherosclerotic Disorders of Blood Vessels Giant Cell Arteritis (Temporal Arteritis) / 901 Takayasu’s Arteritis / 901 Ehlers-Danlos Syndrome / 901 Marfan’s Syndrome / 902 Pseudoxanthoma Elasticum / 902 Kawasaki’s Disease / 902 Inflammatory Arteritis and Vasculitis / 902 Behçet’s Disease / 903 Polyarteritis Nodosa / 903 Radiation-Induced Arteritis / 903 Raynaud’s Syndrome / 904 Fibromuscular Dysplasia / 904 Nonatherosclerotic Disease Affecting the Popliteal Artery Disease / 905 Buerger’s Disease (Thromboangiitis Obliterans) / 906 900 Key Points 1 2 Carotid intervention as a preventive strategy should be performed in patients with 50% or greater symptomatic internal carotid artery stenosis and those with 80% or greater asymptomatic internal carotid artery stenosis. Carotid intervention for asymptomatic stenosis between 60% and 79% remains controversial and is a function of an operator’s stroke rate. The choice of intervention—carotid endarterectomy versus carotid stenting—remains controversial; currently, carotid endarterectomy appears to be associated with lower stroke rate, whereas carotid stenting is more suitable under certain anatomic or physiologic conditions. Abdominal aortic aneurysms should be repaired when the risk of rupture, determined mainly by aneurysm size, exceeds the risk of death due to perioperative complications or concurrent illness. Endovascular repair is associated with less perioperative morbidity and mortality compared to open reconstruction and is preferred for high-risk patients who meet specific anatomic criteria. GENERAL APPROACH TO THE VASCULAR PATIENT 828 4 5 Symptomatic mesenteric ischemia should be treated to improve quality of life and prevent bowel infarction. Operative treatment—bypass—is superior to endovascular intervention, although changes in wire and stent technology have improved the results of mesenteric stenting in recent series. Aortoiliac occlusive disease can be treated with either endovascular means or open reconstruction, depending on patient risk stratification, occlusion characteristics, and symptomatology. Claudication is a marker of extensive atherosclerosis and is mainly managed with risk factor modification and pharmacotherapy. Only 5% of patients with claudication will need intervention because of disabling extremity pain. The 5-year mortality of a patient with claudication approaches 30%. Patients with rest pain or tissue loss need expeditious evaluation and vascular reconstruction to ameliorate the severe extremity pain and prevent limb loss. Table 23-1 Since the vascular system involves every organ system in our body, the symptoms of vascular disease are as varied as those encountered in any medical specialty. Lack of adequate blood supply to target organs typically presents with pain; for example, calf pain with lower extremity claudication, postprandial abdominal pain from mesenteric ischemia, and arm pain with axillo-subclavian arterial occlusion. In contrast, stroke and transient ischemic attack (TIA) are the presenting symptoms from middle cerebral embolization as a consequence of a stenosed internal carotid artery. The pain syndrome of arterial disease is usually divided clinically into acute and chronic types, with all shades of severity between the two extremes. Sudden onset of pain can indicate complete occlusion of a critical vessel, leading to more severe pain and critical ischemia in the target organ, resulting in lower limb gangrene or intestinal infarction. Chronic pain results from a slower, more progressive atherosclerotic occlusion, which can be totally or partially compensated by developing collateral vessels. Acute on chronic is another pain pattern in which a patient most likely has an underlying arterial stenosis that suddenly occludes; for example, the patient with a history of calf claudication who now presents with sudden, severe acute limb-threatening ischemia. The clinician should always try to understand and relate the clinical manifestations to the underlying pathologic process. The Vascular History 3 Appropriate history should be focused based on the presenting symptoms related to the vascular system (Table 23-1). Of particular importance in the previous medical history is noting prior vascular interventions (endovascular or open surgical), and all vascular patients should have inquiry made about their prior cardiac history and current cardiac symptoms. Approximately 30% of vascular patients will be diabetic. A history of prior and current smoking status should be noted. Pertinent elements in vascular history • History of stroke or transient ischemic attack • History of coronary artery disease, including previous myocardial infarction and angina • History of peripheral arterial disease • History of diabetes • History of hypertension • History of tobacco use • History of hyperlipidemia The patient with carotid disease in most cases is completely asymptomatic, having been referred based on the finding of a cervical bruit or duplex finding of stenosis. Symptoms of carotid territory TIAs include transient monocular blindness (amaurosis), contralateral weakness or numbness, and dysphasia. Symptoms persisting longer than 24 hours constitute a stroke. In contrast, the patient with chronic mesenteric ischemia is likely to present with postprandial abdominal pain and weight loss. The patient fears eating because of the pain, avoids food, and loses weight. It is very unlikely that a patient with abdominal pain who has not lost weight has chronic mesenteric ischemia. The patient with lower extremity pain on ambulation has intermittent claudication that occurs in certain muscle groups; for example, calf pain upon exercise usually reflects superficial femoral artery disease, while pain in the buttocks reflects iliac disease. In most cases, the pain manifests in one muscle group below the level of the affected artery, occurs only with exercise, and is relieved with rest only to recur at the same location, hence the term “window gazer’s disease.” Rest pain (a manifestation of severe underlying occlusive disease) is constant and occurs in the foot (not the muscle groups), typically at the metatarsophalangeal junction, and is relieved by dependency. Often the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ patient is prompted to sleep with their foot hanging off one side of the bed to increase the hydrostatic pressure. The Vascular Physical Examination Grading scales for peripheral pulses Traditional Scale Basic Scale 4+ Normal 2+ Normal 3+ Slightly reduced 1+ Diminished 2+ Markedly reduced 0 Absent 1+ Barely palpable The in situ lower extremity graft runs in the subcutaneous fat and can be palpated along most of its length. A change in pulse quality, aneurysmal enlargement, or a new bruit should be carefully noted. Axillofemoral grafts, femoral-to-femoral grafts, and arteriovenous access grafts can usually be easily palpated as well. Noninvasive Diagnostic Evaluation of the Vascular Patient Ankle-Brachial Index. There is increasing interest in the use of the ankle-brachial index (ABI) to evaluate patients at risk for cardiovascular events. An ABI less than 0.9 correlates with increased risk of myocardial infarction and indicates significant, although perhaps asymptomatic, underlying peripheral vascular disease. The ABI is determined in the following ways. Blood pressure is measured in both upper extremities using the highest systolic blood pressure as the denominator for the ABI. The ankle pressure is determined by placing a blood pressure cuff above the ankle and measuring the return to flow of the posterior tibial and dorsalis pedis arteries using a pencil Doppler probe over each artery. The ratio of the systolic pressure in each vessel divided by the highest arm systolic pressure can be used to express the ABI in both the posterior tibial and dorsalis pedis arteries (Fig. 23-1). Normal is more than 1. Patients with claudication typically have an ABI in the 0.5 to 0.7 range, and those with rest pain are in the 0.3 to 0.5 range. Those with gangrene have an ABI of less than 0.3. These ranges can vary depending on the degree of compressibility of the vessel. The test is less reliable in patients with heavily calcified vessels. Due to noncompressibility, some patients, such as diabetics and those with end-stage renal disease, may have ABI ≥1.40 and require additional noninvasive diagnostic testing to evaluate for peripheral artery disease. Alternative tests include toe-brachial pressures, pulse volume recordings, transcutaneous oxygen measurements, or vascular imaging (duplex ultrasound). Segmental Limb Pressures. By placing serial blood pressure cuffs down the lower extremity and then measuring the pressure with a Doppler probe as flow returns to the artery below the cuff, it is possible to determine segmental pressures down the leg. This data can then be used to infer the level of the occlusion. The systolic pressure at each level is expressed as a ratio, with the highest systolic pressure in the upper extremities as the denominator. Normal segmental pressures commonly show high thigh pressures 20 mmHg or greater in comparison to the brachial artery pressures. The low thigh pressure should be equivalent to brachial pressures. Subsequent pressures should fall by no more than 10 mmHg at each level. A pressure gradient of 20 mmHg between two subsequent levels is usually indicative of occlusive disease at that level. The most frequently used VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Specific vascular examination should include abdominal aortic palpation, carotid artery examination, and pulse examination of the lower extremity (femoral, popliteal, posterior tibial, and dorsalis pedis arteries). The abdomen should be palpated for an abdominal aortic aneurysm, detected as an expansile pulse above the level of the umbilicus. It should also be examined for the presence of bruits. Because the aorta typically divides at the level of the umbilicus, an aortic aneurysm is most frequently palpable in the epigastrium. In thin individuals, a normal aortic pulsation is palpable, while in obese patients, even large aortic aneurysms may not be detectable. Suspicion of a clinically enlarged aorta should lead to the performance of an ultrasound scan for a more accurate definition of aortic diameter. The carotids should be auscultated for the presence of bruits, although there is a higher correlation with coronary artery disease than underlying carotid stenosis. A bruit at the angle of the mandible is a significant finding, leading to followup duplex scanning. The differential diagnosis is a transmitted murmur from a sclerotic or stenotic aortic valve. The carotid is palpable deep to the sternocleidomastoid muscle in the neck. Palpation, however, should be gentle and rarely yields clinically useful information. Upper extremity examination is necessary when an arteriovenous graft is to be inserted in patients who have symptoms of arm pain with exercise. Thoracic outlet syndrome (TOS) can result in occlusion or aneurysm formation of the subclavian artery. Distal embolization is a manifestation of TOS; consequently, the fingers should be examined for signs of ischemia and ulceration. The axillary artery enters the limb below the middle of the clavicle, where it can be palpated in thin patients. It is usually easily palpable in the axilla and medial upper arm. The brachial artery is most easily located at the antecubital fossa immediately medial to the biceps tendon. The radial artery is palpable at the wrist anterior to the radius. For lower extremity vascular examination, the femoral pulse is usually palpable midway between the anterior superior iliac spine and the pubic tubercle. The popliteal artery is palpated in the popliteal fossa with the knee flexed to 45° and the foot supported on the examination table to relax the calf muscles. Palpation of the popliteal artery is a bimanual technique. Both thumbs are placed on the tibial tuberosity anteriorly and the fingers are placed into the popliteal fossa between the two heads of the gastrocnemius muscle. The popliteal artery is palpated by compressing it against the posterior aspect of the tibia just below the knee. The posterior tibial pulse is detected by palpation 2 cm posterior to the medial malleolus. The dorsalis pedis is detected 1 cm lateral to the hallucis longus extensor tendon, which dorsiflexes the great toe and is clearly visible on the dorsum of the foot. Pulses can be graded using either the traditional four-point scale or the basic two-point scale system (Table 23-2). The foot should also be carefully examined for pallor on elevation and rubor on dependency, as these findings are indicative of chronic ischemia. Note should also be made of nail changes and loss of hair. Ulceration and other findings specific to disease states are described in relevant sections later in this chapter. After reconstructive vascular surgery, the graft may be available for examination, depending on its type and course. 829 Table 23-2 830 UNIT II PART Pulse Volume Recording. In patients with noncompressible vessels, segmental plethysmography can be used to determine underlying arterial occlusive disease. Cuffs placed at different levels on the leg detect changes in blood volume and produce a pulse volume recording (PVR) when connected to a plethysmograph (Fig. 23-2). To obtain accurate PVR waveforms, the cuff is inflated to 60 to 65 mmHg, so as to detect volume changes without causing arterial occlusion. Pulse volume tracings are suggestive of proximal disease if the upstroke of the pulse is not brisk, the peak of the wave tracing is rounded, and there is disappearance of the dicrotic notch. Although isolated segmental limb pressures and PVR measurements are 85% accurate when compared with angiography in detecting and localizing significant atherosclerotic lesions, when used in combination, accuracy approaches 95%.3 For this reason, it is suggested that these two diagnostic modalities be used in combination when evaluating peripheral artery disease. SPECIFIC CONSIDERATIONS Radiologic Evaluation of the Vascular Patient Ultrasound. Ultrasound examinations are relatively time Right ABI = ratio of Higher of the right ankle systolic pressures (posterior tibial or dorsalis pedis) Higher arm systolic pressure (left or right arm) Left ABI = ratio of Higher of the left ankle systolic pressures (posterior tibial or dorsalis pedis) Higher arm systolic pressure (left or right arm) Figure 23-1. Calculating the ankle-brachial index (ABI). index is the ratio of the ankle pressure to the brachial pressure, the ABI. Normally, the ABI is greater than 1.0, and a value of less than 0.9 indicates some degree of arterial obstruction and has been shown to be correlated with an increased risk of coronary heart disease.1 Limitations of relying on segmental limb pressures include: (a) missing isolated moderate stenoses (usually iliac) that produce little or no pressure gradient at rest; (b) falsely elevated pressures in patients with diabetes and endstage renal disease; and (c) the inability to differentiate between stenosis and occlusion.2 Patients with diabetes and end-stage renal disease have calcified vessels that are difficult to compress, thus rendering this method inaccurate, due to recording of falsely elevated pressure readings. Noncompressible arteries yield ankle systolic pressures ≥250 mmHg and ABIs >1.40. In this situation, absolute toe and ankle pressures can be measured to gauge critical limb ischemia. Ankle pressures less than 50 mmHg or toe pressures less than 30 mmHg are indicative of critical limb ischemia. The toe pressure is normally 30 mmHg less than the ankle pressure, and a toe-brachial index (TBI) <0.70 is abnormal. False-positive results with the TBI are unusual. The main limitation of this technique is that it may be impossible to measure pressures in the first and second toes due to pre-existing ulceration. consuming, require experienced technicians, and may not visualize all arterial segments. Doppler waveform analysis can suggest atherosclerotic occlusive disease if the waveforms in the insonated arteries are biphasic, monophasic, or asymmetrical. B-mode ultrasonography provides black and white, real-time images. B-mode ultrasonography does not evaluate blood flow; thus, it cannot differentiate between fresh thrombus and flowing blood, which have the same echogenicity. Calcification in atherosclerotic plaques will cause acoustic shadowing. B-mode ultrasound probes cannot be sterilized. Use of the B-mode probe intraoperatively requires a sterile covering and gel to maintain an acoustic interface. Experience is needed to obtain and interpret images accurately. Duplex ultrasonography entails performance of B-mode imaging, spectral Doppler scanning, and color-flow duplex scanning. The caveat to performance of duplex ultrasonography is meticulous technique by a certified vascular ultrasound technician, so that the appropriate 60° Doppler angle is maintained during insonation with the ultrasound probe. Alteration of this angle can markedly alter waveform appearance and subsequent interpretation of velocity measurements. Direct imaging of intra-abdominal vessels with duplex ultrasound is less reliable because of the difficulty in visualizing the vessels through overlying bowel. These disadvantages currently limit the applicability of duplex scanning in the evaluation of aortoiliac and infrapopliteal disease. In a recent study, duplex ultrasonography had lower sensitivity in the calculation of infrapopliteal vessel stenosis in comparison to conventional digital subtraction or computed tomography angiography.4 Few surgeons rely solely on duplex ultrasonography for preoperative planning in lower extremity revascularizations; but with experience, lower extremity arteries can be insonated to determine anatomy, and the functional significance of lesions can be determined by calculation of degree of stenosis from velocity ratios. Duplex scanning is unable to evaluate recently implanted polytetrafluoroethylene (PTFE) and polyester (Dacron) grafts because they contain air, which prevents ultrasound penetration. Computed Tomography Angiography. Computed tomography angiography (CTA) is a noninvasive, contrast-dependent method for imaging the arterial system. It depends on intravenous infusion of iodine-based contrast agents. The patient is advanced through a rotating gantry, which images serial transverse VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 831 0.75 0.50 0.25 0.00 0.25 0.75 0.50 0.25 0.00 0.25 0.75 0.50 0.25 0.00 0.25 0.75 0.50 0.25 0.00 0.25 Right Femoral Sup. femoral Popliteal Posterior tibial Dorsalis pedis Doppler waveforms 1 sec/div 99 157 105 150 109 157 PT 98 DT 92 PT 151 DT 111 88 Sup. femoral Popliteal Posterior tibial 114 149 Brachial Indexes 0.66 U. thigh 0.70 L. thigh 0.73 Calf 0.66 Ankle-PT 0.62 Ankle-DP 0.59 Toe Left Femoral 144 1.05 1.01 1.05 1.01 0.74 0.77 Dorsalis pedis 0.75 0.50 0.25 0.00 0.25 1.50 1.00 0.50 0.00 0.50 1.50 1.00 0.50 0.00 0.50 1.50 1.00 0.50 0.00 0.50 0.75 0.50 0.25 0.00 0.25 Figure 23-2. Typical report of peripheral vascular study with arterial segmental pressure measurement plus Doppler evaluation of the lower extremity. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease 0.75 0.50 0.25 0.00 0.25 832 UNIT II PART SPECIFIC CONSIDERATIONS A B Figure 23-3. A multidetector computed tomography angiography with three-dimensional reconstruction of the iliofemoral arterial circulation in two patients with lower leg claudication. A. A 50-year-old male with an occluded right superficial femoral artery (single long arrow) with reconstituted superficial femoral artery at the level of mid-thigh. Arterial calcifications (single short arrows) are present in the bilateral distal superficial femoral arteries. B. A 53-year-old male with occluded right common iliac artery (double arrows). slices. The contrast-filled vessels can be extracted from the slices and rendered in three-dimensional format (Fig. 23-3). The extracted images can also be rotated and viewed from several different directions during postacquisition image processing. This technology has been advanced as a consequence of aortic endografting. CTA provides images for postprocessing that can be used to display the aneurysm in a format that demonstrates thrombus, calcium, lumen, and the outer wall, and allows “fitting” of a proposed endograft into the aneurysm (Fig. 23-4). CTA is increasingly being used to image the carotid bifurcation, and as computing power increases, the speed of image acquisition and resolution will continue to increase. The major limitations of multidetector CTA are use of contrast and presence of artifacts caused by calcification and stents. CTA can overestimate the degree of in-stent stenosis, while heavy calcification can limit the diagnostic accuracy of the method by causing a “blooming artifact.”5 The artifacts can be overcome with alteration in image acquisition technique. There are no randomized trials to document the superiority of multidetector CTA over traditional angiography, but there is emerging evidence to support the claim that multidetector CTA has sensitivity, specificity, and accuracy that rival invasive angiography.5 Magnetic Resonance Angiography. Magnetic resonance angiography (MRA) has the advantage of not requiring iodinated contrast agents to provide vessel opacification (Fig. 23-5). Gadolinium is used as a contrast agent for MRA studies, and because it is generally not nephrotoxic, it can be used in patients with elevated creatinine. MRA is contraindicated in patients with pacemakers, defibrillators, spinal cord stimulators, intracerebral shunts, cochlear implants, and cranial clips. Patients with claustrophobia may require sedation to be able to complete the test. The presence of metallic stents causes artifacts and signal drop-out; however, these can be dealt with using alternations in image acquisition and processing. Nitinol stents produce minimal artifact.6 Compared to other modalities, MRA is relatively slow and expensive. However, due to its noninvasive nature and decreased nephrotoxicity, MRA is being used more frequently for imaging vasculature in various anatomic distributions. Diagnostic Angiography. Diagnostic angiography is considered the gold standard in vascular imaging. In many centers, its use is rapidly decreasing due to the development of noninvasive imaging modalities such as duplex arterial mapping, CTA, and MRA. Nevertheless, contrast angiography still remains in Figure 23-4. Three-dimensional computed tomography angiogram of an abdominal aortic aneurysm that displays various aneurysm components including thrombus, aortic calcification, blood circulation, and aneurysm wall. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 833 CHAPTER 23 Arterial Disease Figure 23-5. Magnetic resonance angiogram of aortic arch and carotid arteries. This study can provide a three-dimensional analysis of vascular structure such as aortic arch branches and carotid and vertebral arteries. widespread use. The essential aspects of angiography are vascular access and catheter placement in the vascular bed that requires examination. The imaging system and the contrast agent are used to opacify the target vessel. Although in the past this function has largely been delegated to the interventional radiology service, an increasing number of surgeons are performing this procedure and following the diagnostic imaging with immediate surgical or endovascular intervention. There are several considerations when relying on angiography for imaging. Approximately 70% of atherosclerotic plaques occur in an eccentric location within the blood vessel; therefore, images can be misleading when trying to evaluate stenoses because angiography is limited to a uniplanar “lumenogram.” With increased use of intravascular stent deployment, it has also been noted that assessment of stent apposition and stent position in relation to surrounding branches may be inaccurate. Furthermore, angiography exposes the patient to the risks of both ionizing radiation and intravascular contrast. Nevertheless, contrast angiography remains the most common invasive method of vascular investigation for both diagnostic and therapeutic intervention. The angiogram usually provides the final information needed to decide whether or not to proceed with operation or endovascular interventions. Digital subtraction angiography (DSA) offers some advantages over conventional cut-film angiography such as excellent visualization despite use of lower volumes of contrast media. In Figure 23-6. Digital subtraction angiography (DSA) provides excellent visualization of intravascular circulation with intraarterial contrast administration. As depicted in this DSA study, multilevel lesions are demonstrated, which include a focal left iliac artery stenosis (large arrow), right superficial femoral occlusion (curved arrows), left superficial femoral stenosis (small arrow), and multiple tibial artery stenoses (arrowheads). particular, when multilevel occlusive lesions limit the amount of contrast reaching distal vessels, supplemental use of digital subtraction angiographic techniques may enhance visualization and definition of anatomy. Intra-arterial DSA uses a portable, axially rotatable imaging device that can obtain views from different angles. DSA also allows for real-time video replay (Fig. 23-6). An entire extremity can be filmed with DSA using repeated injections of small amounts of contrast agent to obtain sequential angiographic images, the so-called pulse-chase technique. Preoperative Cardiac Evaluation The most important and most controversial aspect of preoperative evaluation in patients with atherosclerotic disease requiring surgical intervention is the detection and subsequent management of associated coronary artery disease.7 Several studies VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 834 UNIT II PART SPECIFIC CONSIDERATIONS have documented the existence of significant coronary artery disease in 40% to 50% or more of patients requiring peripheral vascular reconstructive procedures, 10% to 20% of whom may be relatively asymptomatic largely because of their inability to exercise.8 Myocardial infarction is responsible for the majority of both early and late postoperative deaths. Most available screening methods lack sensitivity and specificity to predict postoperative cardiac complications. There have been conflicting reports regarding the utility of preoperative dipyridamolethallium nuclear imaging or dobutamine-echocardiography to stratify vascular patients in terms of perioperative cardiac morbidity and mortality. In nearly half of patients, thallium imaging proves to be unnecessary because cardiac risk can be predicted by clinical information alone.7 Even with coronary angiography, it is difficult to relate anatomic findings to functional significance and, hence, surgical risk. There are no data confirming that percutaneous coronary interventions or surgical revascularization prior to vascular surgical procedures impact mortality or incidence of myocardial infarctions. In fact, coronary angiography is associated with its own inherent risks, and patients undergoing coronary artery bypass grafting or coronary percutaneous transluminal angioplasty (PTA) before needed aortoiliac reconstructions are subjected to the risks and complications of both procedures. The Coronary Artery Revascularization Prophylaxis (CARP) trial showed that coronary revascularization in patients with peripheral vascular disease and significant coronary artery disease, who are considered high risk for perioperative complications, did not reduce overall mortality or perioperative myocardial infarction.9 Additionally, patients who underwent prophylactic coronary revascularization had significant delays prior to undergoing their vascular procedure and increased limb morbidity compared to patients who did not. Studies do support improvement in cardiovascular and overall prognosis with medical optimization of patients. Therefore, use of perioperative β-blockade, as well as use of antiplatelet medication, statins, and angiotensin-converting enzyme inhibitors, is encouraged in vascular patients.10,11 BASIC PRINCIPLES OF ENDOVASCULAR THERAPY Cardiovascular disease remains a major cause of mortality in the developed world since the beginning of the twenty-first century. Although surgical revascularization has played a predominant role in the management of patients with vascular disease, the modern treatment paradigms have evolved significantly with increased emphasis of catheter-based percutaneous interventions over the past two decades. The increasing role of this minimally invasive vascular intervention is fueled by various factors, including rapid advances in imaging technology, reduced morbidity and mortality in endovascular interventions, and faster convalescence following percutaneous therapy when compared to traditional operations. There is little doubt that with continued device development and refined image-guided technology, endovascular intervention will provide improved clinical outcomes and play an even greater role in the treatment of vascular disease. The technique of percutaneous access for both the diagnostic and therapeutic management of vascular disease has resulted in tremendous changes in the practice of several subspecialties, including interventional radiology, invasive cardiology, and vascular surgery. The development of catheter and endoscopic instrumentation allows the vascular surgeon to operate via an intra- or extraluminal route. Endovascular techniques are now able to treat the full spectrum of vascular pathology, including stenoses and occlusions resulting from several etiologies, aneurysmal pathology, and traumatic lesions. Many of these procedures have only recently been developed and, as such, have not been investigated in a manner that would enable an accurate comparison with the more traditional methods of open surgical intervention. Long-term follow-up for these procedures is frequently lacking; however, because of the potential to treat patients with decreased mortality and morbidity, endovascular skills and techniques are being adopted into mainstream vascular surgery. Needles and Access Needles are used to achieve percutaneous vascular access. The size of the needle will be dictated by the diameter of the guidewire used. Most often, an 18-gauge needle is used, as it will accept a 0.035-inch guidewire. A 21-gauge micropuncture needle will accept a 0.018-inch guidewire. The most popular access needle is the Seldinger needle, which can be used for single- and double-wall puncture techniques. Femoral arterial puncture is the most common site for access. The common femoral artery (CFA) is punctured over the medial third of the femoral head, which is landmarked using fluoroscopy. The single-wall puncture technique requires a sharp, beveled needle tip and no central stylet. The anterior wall of the vessel is punctured with the bevel of the needle pointing up, and pulsatile back-bleeding indicates an intraluminal position. This method is most useful for graft punctures, patients with abnormal clotting profiles, or if thrombolytic therapy is anticipated. Once the needle assumes an intraluminal position, verified by pulsatile back-bleeding, the guidewire may be advanced. This is always passed gently and under fluoroscopic guidance to avoid subintimal dissection or plaque disruption. Double-wall puncture techniques are performed with a blunt needle that has a removable inner cannula. The introducer needle punctures both walls of the artery and is withdrawn until bleeding is obtained to confirm intraluminal position prior to advancing a guidewire. There can be troublesome bleeding from the posterior arterial wall puncture; therefore, single puncture techniques are preferred. Retrograde femoral access is the most common arterial access technique (Fig. 23-7). The advantages of this technique include the size and fixed position of the CFA, as well as the relative ease of compression against the femoral head at the end of the procedure. Care should be taken to avoid puncturing the external iliac artery above the inguinal ligament because this can result in retroperitoneal hemorrhage secondary to ineffective compression of the puncture site. Likewise, puncturing too low, at or below the CFA bifurcation, can result in thrombosis or pseudoaneurysm formation of the superficial femoral artery (SFA) or profunda femoris artery (PFA). Antegrade femoral access is more difficult than retrograde femoral access, and there is a greater tendency to puncture the SFA, but it is invaluable when the aortic bifurcation cannot be traversed or when devices are not long enough to reach a lesion from a contralateral femoral access approach. Occasionally, when the distal aorta or bilateral iliac arteries are inaccessible because of the extent of atherosclerotic lesions, scarring, or presence of bypass conduits, the brachial artery must be used to obtain access for diagnostic and therapeutic interventions. The left brachial artery is punctured because this avoids the origin of the carotid artery VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 835 and thus decreases the risk of catheter-related emboli to the brain. The artery is accessed with a micropuncture needle just proximal to the antecubital crease. The use of brachial access is associated with a higher risk of thrombosis and nerve injuries than femoral access. Guidewires Guidewires are used to introduce, position, and exchange catheters. A guidewire generally has a flexible and stiff end. In general, only the flexible end of the guidewire is placed in the vessel. All guidewires are composed of a stiff inner core and an outer tightly coiled spring that allows a catheter to track over the guidewire. There are five essential characteristics of guidewires: size, length, stiffness, coating, and tip configuration. Guidewires come in different maximum transverse diameters, ranging from 0.011 to 0.038 inches. For most aortoiliac procedures, a 0.035-inch wire is most commonly used, whereas the smaller diameter 0.018-inch guidewires are reserved for selective small vessel angiography such as infrageniculate or carotid lesions. In addition to diameter size, guidewires come in varying lengths, usually ranging from 180 to 260 cm in length. Increasing the length of the wire always makes it more difficult to handle and increases the risk of contamination. While performing a procedure, it is important to maintain the guidewire across the lesion until the completion arteriogram has been satisfactorily completed. The stiffness of the guidewire is also an important characteristic. Stiff wires allow for passage of large aortic stent graft devices without kinking. They are also useful when trying to perform sheath or catheter exchanges around a tortuous artery. An example of a stiff guidewire is the Amplatz wire. Hydrophilic coated guidewires, such as the Glidewire, have become invaluable tools for assisting in difficult catheterizations. The coating is primed by bathing the guidewire in saline solution. The slippery nature of this guidewire along with its torque capability significantly facilitate in difficult catheterizations. Figure 23-8. All percutaneous endovascular procedures are performed through an introducer sheath (large arrow), which provides an access conduit from skin to intravascular compartment. The sheath also acts to protect the vessel from injury as guidewires (small arrows) and catheters are introduced. Guidewires also come in various tip configurations. Angled tip wires like the angled Glidewire can be steered to manipulate a catheter across a tight stenosis or to select a specific branch of a vessel. The Rosen wire has a soft curled end, which makes it ideal for renal artery stenting. The soft curl of this wire prevents it from perforating small renal branch vessels. Hemostatic Sheaths The hemostatic sheath is a device through which endovascular procedures are performed. The sheath acts to protect the vessel from injury as wires and catheters are introduced (Fig. 23-8). A one-way valve prevents bleeding through the sheath, and a side-port allows contrast or heparin flushes to be administered during the procedure. Sheaths are sized by their inner diameter. The most commonly used sheaths for percutaneous access have a 5- to 9-French inner diameter, but with open surgical exposure of the CFA, sheaths as large as 26 French can be introduced. Sheaths also vary in length, and long sheaths are available so that interventions remote from the site of arterial access can be performed. Catheters A wide variety of catheters exist that differ primarily in the configuration of the tip. The multiple shapes permit access to vessels of varying dimensions and angulations. Catheters are used to perform angiography and protect the passage of balloons and stents, and can be used to direct the guidewire through tight stenoses or tortuous vessels. Angioplasty Balloons Angioplasty balloons differ primarily in their length and diameter, as well as the length of the catheter shaft. As balloon technology has advanced, lower profiles have been manufactured (i.e., the size that the balloon assumes upon deflation). Balloons are used to perform angioplasty on vascular stenoses, to deploy stents, and to assist with additional expansion after insertion of self-expanding stents (Fig. 23-9). Besides length and diameter, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Figure 23-7. A. Antegrade femoral artery access. The needle is inserted just below the inguinal ligament in the common femoral artery whereby the guidewire is inserted in the ipsilateral superficial femoral artery. B. Brachial artery approach. The needle is inserted in a retrograde fashion in the brachial artery just above the antecubital fossa, whereby the guidewire is next inserted in the brachial artery. 836 UNIT II PART Figure 23-9. A. An artery with luminal narrowing caused by plaque. B. A balloon angioplasty catheter is positioned within the diseased artery, which is inflated to enlarge the intravascular channel. C. The plaque is compressed with widened flow lumen as the result of balloon angioplasty. SPECIFIC CONSIDERATIONS operators need to be familiar with several other balloon characteristics. Noncompliant and low-compliance balloons tend to be inflated to their preset diameter and offer greater dilating force at the site of stenosis. Low-compliance balloons are the mainstay for peripheral intervention. Lower profile balloons are less likely to get caught during passage through stents and are easier to pull out of sheaths. Under fluoroscopic guidance, balloon inflation is performed until the waist of the atherosclerotic lesion disappears and the balloon is at the full profile. The duration of balloon inflation and pressures used for the angioplasty depend on the indication for the intervention and the location and characteristics of the lesion being treated. Frequently, several inflations are required to achieve a full profile of the balloon. Occasionally, a lower profile balloon is needed to predilate the tight stenosis so that the selected balloon catheter can cross the lesion. After inflation, most balloons do not regain their preinflation diameter and assume a larger profile. Trackability, pushability, and crossability of the balloon should all be considered when choosing a particular balloon. Lastly, shoulder length is an important characteristic to consider when selecting a balloon because of the potential to cause injury during performance of PTA in adjacent arterial segments. There is always risk of causing dissection or rupture during PTA; thus a completion angiogram is performed while the wire is still in place. Leaving the wire in place provides access for repeating the procedure, placing a stent or stent graft if warranted. Stents Vascular stents are commonly used after an inadequate angioplasty with dissection or elastic recoil of an arterial stenosis. They serve to buttress collapsible vessels and help prevent atherosclerotic restenosis. Appropriate indications for primary stenting of a lesion without an initial trial of angioplasty alone are evolving in manners that are dependent on the extent and site of the lesion. Stents are manufactured from a variety of metals including stainless steel, tantalum, cobalt-based alloy, and nitinol. Vascular stents are classified into two basic categories: balloon-expandable stents and self-expanding stents. Self-expanding stents (Fig. 23-10) are deployed by retracting a restraining sheath and usually consist of Elgiloy (a cobalt, chromium, nickel alloy) or nitinol (a shape memory alloy composed of nickel and titanium), the latter of which will contract and assume a heat-treated shape above a transition temperature that depends on the composition of the alloy. Self-expanding stents will expand to a final diameter that is determined by stent geometry, hoop strength, and vessel size. The self-expanding stent is mounted on a central shaft and is placed inside an outer sheath. It relies on a mechanical springlike action to achieve expansion. With deployment of these stents, there is some degree of foreshortening that has to be taken into account when choosing the area of deployment. In this way, self-expanding stents are more difficult to place with absolute precision. There are several advantages related to self-expanding stents. Self-expanding stents generally come in longer lengths than balloon-expandable stents and are therefore used to treat long and tortuous lesions. Their ability to continually expand after delivery allows them to accommodate adjacent vessels of different size. This makes these stents ideal for placement in the internal carotid artery. These stents are always oversized by 1 to 2 mm relative to the largest diameter of normal vessel adjacent to the lesion in order to prevent immediate migration. Balloon-expandable stents are usually composed of stainless steel, mounted on an angioplasty balloon, and deployed by balloon inflation (Fig. 23-11). They can be manually placed on a chosen balloon catheter or obtained premounted on a balloon catheter. The capacity of a balloon-expandable stent to shorten in length during deployment depends on both stent geometry and the final diameter to which the balloon is expanded. These stents are more rigid and are associated with a shorter time to complete endothelialization. They are often of limited flexibility and have a higher degree of crush resistance when compared to self-expanding stents. This makes them ideal for short-segment lesions, especially those that involve the ostia such as proximal common iliac or renal artery stenosis. The most exciting area of development in stents is the evolution of drug-eluting stents (DES). These stents are usually composed of nitinol and have various anti-inflammatory drugs bonded to them. Over time, the stents release the drug into the surrounding arterial wall and help prevent restenosis. Numerous randomized controlled trials have proven their benefit in coronary arteries.12 Clinical studies have similarly proved early efficacy of DES in the treatment of peripheral arterial disease.13,14 Stent Grafts The combination of a metal stent covered with fabric gave birth to the first stent grafts. Covered stents have been designed VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CAROTID ARTERY DISEASE Atherosclerotic occlusive plaque is by far the most common pathology seen in the carotid artery bifurcation. Thirty percent to 60% of all ischemic strokes are related to atherosclerotic carotid bifurcation occlusive disease. In the following section, we first focus our discussion on the clinical presentation, diagnosis, and management, including medical therapy, surgical carotid endarterectomy, and stenting, of atherosclerotic carotid occlusive disease. In the second part of the section, we provide a review on other less common nonatherosclerotic diseases involving the extracranial carotid artery, including kink and coil, fibromuscular dysplasia, arterial dissection, aneurysm, radiation arteritis, Takayasu’s arteritis, and carotid body tumor. Figure 23-11. In a balloon-expandable stent, the stent is premounted on a balloon catheter. The balloon stretches the stent members beyond their elastic limit. The stent is deployed by full balloon expansion. This type of stent has a higher degree of crush resistance when compared to self-expanding stents, which is ideal for short-segment calcified ostial lesions. Epidemiology and Etiology of Carotid Occlusive Disease Approximately 700,000 Americans suffer a new or recurrent stroke each year.19 Eighty-five percent of all strokes are ischemic, and 15% are hemorrhagic. Hemorrhagic strokes are caused by head trauma or spontaneous disruption of intracerebral blood VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 837 CHAPTER 23 Arterial Disease Figure 23-10. Self-expanding stents are made of tempered stainless steel or nitinol, an alloy of nickel and titanium, and are restrained when folded inside a delivery catheter. After being released from the restraining catheter, the self-expanding stents will expand to a final diameter that is determined by stent geometry, hoop strength, and vessel size. with either a surrounding PTFE or polyester fabric and have been used predominantly for treatment of traumatic vascular lesions, including arterial disruption and arteriovenous fistulas (Fig. 23-12). However, these devices may well find a growing role in treatment of iliac or femoral arterial occlusive disease as well as popliteal aneurysms. Endovascular aneurysm repair using the concept of stent grafts was initiated by Parodi in 1991.15 Since that time, a large number of endografts have been inserted under the auspice of clinical trials initially and now as Food and Drug Administration (FDA)–approved devices. Current available FDAapproved devices include the following: (a) AneuRx device (Medtronic/AVE, Santa Rosa, CA); (b) Gore Excluder device (WL Gore & Associates, Flagstaff, AZ); (c) Endologix Powerlink device (Endologix Inc., Irvine, CA); (d) Zenith device (Cook Inc., Bloomington, IN); (e) Talent device (Medtronic/ AVE, Santa Rosa, CA); and (f) Endurant device (Medtronic/ AVE, Santa Rosa, CA) for the treatment of abdominal aortic aneurysms. All of these devices require that patients have an infrarenal aneurysm with at least a 15-mm proximal aortic neck below the renal arteries and not greater than 60° of angulation. For those patients with associated common iliac artery aneurysmal disease, endovascular treatment can be achieved by initial coil embolization of the ipsilateral hypogastric artery with extension of the endovascular device into the external iliac artery. Newer generation endografts, including devices such as AFX Endovascular AAA System (Endologix Inc., Irvine, CA), Aorfix Flexible Stent (Lombard Medical Inc., Framingham, MA), and Ovation Prime Stent (TriVascular Inc., Santa Rosa, CA), are designed to overcome previous challenges of difficult anatomy by incorporating more flexible stents and lower profile delivery systems. Clinical trials are under way with devices that will expand indications to aneurysms involving the visceral segment of the abdominal aorta. The FDA has similarly approved several thoracic endograft devices for the treatment of descending thoracic aortic aneurysm. Early studies have demonstrated short-term efficacy of thoracic aortic devices in the treatment of traumatic aortic transections and aortic dissections.16-18 More experience with these devices exists in both Europe and Asia, and trials are under way in the United States with several devices. 838 UNIT II PART Figure 23-12. A stent graft is a metal stent covered with fabric that is commonly used for aneurysm exclusion. SPECIFIC CONSIDERATIONS vessels. Ischemic strokes are due to hypoperfusion from arterial occlusion or, less commonly, to decreased flow resulting from proximal arterial stenosis and poor collateral network. Common causes of ischemic strokes are cardiogenic emboli in 35%, carotid artery disease in 30%, lacunar in 10%, miscellaneous in 10%, and idiopathic in 15%.19 The term cerebrovascular accident is often used interchangeably to refer to an ischemic stroke. A transient ischemic attack (TIA) is defined as a temporary focal cerebral or retinal hypoperfusion state that resolves spontaneously within 24 hours after its onset. However, the majority of TIAs resolve within minutes, and longer lasting neurologic deficits more likely represent a stroke. Recently, the term brain attack has been coined to refer to an acute stroke or TIA, denoting the condition as a medical emergency requiring immediate attention, similar to a heart attack. Stroke due to carotid bifurcation occlusive disease is usually caused by atheroemboli (Fig. 23-13). The carotid bifurcation is an area of low flow velocity and low shear stress. As the blood circulates through the carotid bifurcation, there is separation of flow into the low-resistance internal carotid artery and the high-resistance external carotid artery. Characteristically, atherosclerotic plaque forms in the outer wall opposite to the flow divider (Fig. 23-14). Atherosclerotic plaque formation is complex, beginning with intimal injury, platelet deposition, smooth muscle cell proliferation, and fibroplasia, and leading to subsequent luminal narrowing. With increasing degree of stenosis in the internal carotid artery, flow becomes more turbulent, and the risk of atheroembolization escalates. The severity of stenosis is commonly divided into three categories according to the luminal diameter reduction: mild (<50%), moderate (50%–69%), and severe (70%–99%). Severe carotid stenosis is a strong predictor for stroke.20 In turn, a prior history of neurologic symptoms (TIA or stroke) is an important determinant for recurrent ipsilateral stroke. The risk factors for the development of carotid artery bifurcation disease are similar to those causing atherosclerotic occlusive disease in other vascular beds. Increasing age, male gender, hypertension, tobacco smoking, diabetes mellitus, homocysteinemia, and hyperlipidemia are well-known predisposing factors for the development of atherosclerotic occlusive disease. Clinical Manifestations of Cerebral Ischemia TIA is a focal loss of neurologic function, lasting for less than 24 hours. Crescendo TIAs refer to a syndrome comprising repeated TIAs within a short period of time that is characterized by complete neurologic recovery in between. At a minimum, the term should probably be reserved for those with either daily events or multiple resolving attacks within 24 hours. Hemodynamic TIAs represent focal cerebral events that are aggravated by exercise or hemodynamic stress and typically occur after short bursts of physical activity, postprandially, or after getting out of a hot bath. It is implied that these are due to severe External carotid artery Internal carotid artery Emboli Superior thyroid artery Ulcer Plaque Common carotid artery Figure 23-13. Stroke due to carotid bifurcation occlusive disease is usually caused by atheroemboli arising from the internal carotid artery, which provides the majority of blood flow to the cerebral hemisphere. With increasing degree of stenosis in the carotid artery, flow becomes more turbulent, and the risk of atheroembolization escalates. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 839 High shear region Figure 23-14. A. The carotid bifurcation is an area of low flow velocity and low shear stress. As the blood circulates through the carotid bifurcation, there is separation of flow into the low-resistance internal carotid artery and the high-resistance external carotid artery. B. The carotid atherosclerotic plaque typically forms in the outer wall opposite to the flow divider due in part to the effect of the low shear stress region, which also creates a transient reversal of flow during the cardiac cycle. Sectional view A B extracranial disease and poor intracranial collateral recruitment. Reversible ischemic neurologic deficits refer to ischemic focal neurologic symptoms lasting longer than 24 hours but resolving within 3 weeks. When a neurologic deficit lasts longer than 3 weeks, it is considered a completed stroke. Stroke in evolution refers to progressive worsening of the neurologic deficit, either linearly over a 24-hour period or interspersed with transient periods of stabilization and/or partial clinical improvement. Patients who suffer cerebrovascular accidents typically present with three categories of symptoms including ocular symptoms, sensory/motor deficit, and/or higher cortical dysfunction. The common ocular symptoms associated with extracranial carotid artery occlusive disease include amaurosis fugax and presence of Hollenhorst plaques. Amaurosis fugax, commonly referred to as transient monocular blindness, is a temporary loss of vision in one eye that patients typically describe as a window shutter coming down or grey shedding of the vision. This partial blindness usually lasts for a few minutes and then resolves. Most of these phenomena (>90%) are due to embolic occlusion of the main artery or the upper or lower divisions. Monocular blindness progressing over a 20-minute period suggests a migrainous etiology. Occasionally, the patient will recall no visual symptoms while the optician notes a yellowish plaque within the retinal vessels, which is also known as Hollenhorst plaque. These plaques are frequently derived from cholesterol embolization from the carotid bifurcation and warrant further investigation. Additionally, several ocular symptoms may be caused by microembolization from extracranial carotid diseases including monocular visual loss due to retinal artery or optic nerve ischemia, the ocular ischemia syndrome, and visual field deficits secondary to cortical infarction and ischemia of the optic tracts. Typical motor and/or sensory symptoms associated with cerebrovascular accidents are lateralized or focal neurologic deficits. Ischemic events tend to have an abrupt onset, with the severity of the insult being apparent from the onset and not usually associated with seizures or paresthesia. In contrast, they represent loss or diminution of neurologic function. Furthermore, motor or sensory deficits can be unilateral or bilateral, with the upper and lower limbs being variably affected depending on the site of the cerebral lesion. The combination of a motor and sensory deficit in the same body territory is suggestive of a cortical thromboembolic event as opposed to lacunar lesions secondary to small vessel disease of the penetrating arterioles. However, a small proportion of the latter may present with a sensorimotor stroke secondary to small vessel occlusion within the posterior limb of the internal capsule. Pure sensory and pure motor strokes and those strokes where the weakness affects one limb only or does not involve the face are more typically seen with lacunar as opposed to cortical infarction. A number of higher cortical functions, including speech and language disturbances, can be affected by thromboembolic phenomena from the carotid artery, with the most important clinical example for the dominant hemisphere being dysphasia or aphasia and visuospatial neglect being an example of nondominant hemisphere injury. Diagnostic Evaluation Duplex ultrasonography is the most widely used screening tool to evaluate for atherosclerotic plaque and stenosis of the extracranial carotid artery. It is also commonly used to monitor patients serially for progression of disease or after intervention (carotid endarterectomy or angioplasty). Duplex ultrasound of the carotid artery combines B-mode gray scale imaging and Doppler waveform analysis. Characterization of the carotid plaque on gray scale imaging provides useful information about its composition. However, there are currently no universal recommendations that can be made based solely on the sonographic appearance of the plaque. On the other hand, criteria have been developed and well refined for grading the degree of carotid stenosis based primarily on Doppler-derived velocity waveforms. The external carotid artery has a high-resistance flow pattern with a sharp systolic peak and a small amount of flow in VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Low shear region 840 UNIT II PART SPECIFIC CONSIDERATIONS diastole. In contrast, a normal internal carotid artery will have a low-resistance flow pattern with a broad systolic peak and a large amount of flow during diastole. The flow pattern in the common carotid artery resembles that in the internal carotid artery, as 80% of the flow is directed to the internal carotid artery, with waveforms that have broad systolic peaks and moderate amount of flow during diastole. Conventionally, velocity measurements are recorded in the common, external, carotid bulb, and the proximal, mid, and distal portions of the internal carotid artery. Characteristically, the peak systolic velocity is increased at the site of the vessel stenosis. The end-diastolic velocity is increased with greater degree of stenosis. In addition, stenosis of the internal carotid artery can lead to color shifts with color mosaics indicating a poststenotic turbulence. Dampening of the Doppler velocity waveforms is typically seen in areas distal to severe carotid stenosis where blood flow is reduced. It is well known that occlusion of the ipsilateral internal carotid artery can lead to a “falsely” elevated velocity on the contralateral side due to an increase in compensatory blood flow. In the presence of a high-grade stenosis or occlusion of the internal carotid artery, the ipsilateral common carotid artery displays high flow resistance waveforms, similar to those seen in the external carotid artery. If there is a significant stenosis in the proximal common carotid artery, its waveforms may be dampened with low velocities. The Doppler grading systems of carotid stenosis were initially established by comparison to angiographic findings of disease. Studies have shown variability in the measurements of the duplex properties by different laboratories, as well as heterogeneity in the patient population, study design, and techniques. One the most commonly used classifications was established at the University of Washington School of Medicine in Seattle. Diameter reduction of 50% to 79% is defined by peak systolic velocity greater than 125 cm/s with extensive spectral broadening. For stenosis in the range of 80% to 99%, the peak systolic velocity is greater than 125 cm/s, and peak diastolic velocity is greater than 140 cm/s. The ratio of internal carotid to common carotid artery peak systolic velocity has also been part of various ultrasound diagnostic classifications. A ratio greater than 4 is a great predictor of angiographic stenosis of 70% to 99%. A multispecialty consensus panel has developed a set of criteria for grading carotid stenosis by duplex examination (Table 23-3).21 MRA is increasingly being used to evaluate for atherosclerotic carotid occlusive disease and intracranial circulation. MRA is noninvasive and does not require iodinated contrast agents. MRA uses phase contrast or time-of-flight, with either two-dimensional or three-dimensional data sets for greater accuracy. Three-dimensional contrast-enhanced MRA allows data to be obtained in coronal and sagittal planes with improved image qualities due to shorter study time. In addition, the new MRA techniques allow for better reformation of images in various planes to allow better grading of stenosis. There have been numerous studies comparing the sensitivity and specificity of MRA imaging for carotid disease to duplex and selective contrast angiography.22 Magnetic resonance imaging (MRI) of the brain is essential in the assessment of acute stroke patients. MRI with diffusion-weighted imaging can differentiate areas of acute ischemia, areas still at risk for ischemia (penumbra), and chronic cerebral ischemic changes. However, computed tomography (CT) imaging remains the most expeditious test in the evaluation of acute stroke patients to rule out intracerebral hemorrhage. Recently, multidetector CTA has gained increasing popularity in the evaluation of carotid disease.23 This imaging modality can provide volume rendering, which allows rotation of the object with accurate anatomic structures from all angles (Fig. 23-15). The advantages of CTA over MRA include faster data acquisition time and better spatial resolution. However, grading of carotid stenosis by CTA requires further validation at the time of this writing before it can be widely applied. Historically, DSA has been the gold standard test to evaluate the extra- and intracranial circulation (Fig. 23-16). This is an invasive procedure, typically performed via a transfemoral puncture, and involves selective imaging of the carotid and vertebral arteries using iodinated contrast. The risk of stroke during cerebral angiography is generally reported at approximately 1% and is typically due to atheroembolization related to wire and catheter manipulation in the arch aorta or proximal branch vessels. Over the last few decades, however, the incidence of neurologic complications following angiography has been reduced, due to the use of improved guidewires and catheters, better resolution digital imaging, and increased experience. Local access complications of angiography are infrequent and include development of hematoma, pseudoaneurysm, distal embolization, and acute vessel thrombosis. Currently, selective angiography is particularly used for patients with suspected intracranial Table 23-3 Carotid duplex ultrasound criteria for grading internal carotid artery stenosis Degree of Stenosis (%) ICA PSV (cm/s) ICA/CCA PSV Ratio ICA EDV (cm/s) Plaque Estimate (%)a Normal <125 <2.0 <40 None <50 <125 <2.0 <40 <50 50–69 125–230 2.0–4.0 40–100 ≥50 ≥70 to less than near occlusion >230 >4.0 >100 ≥50 Near occlusion High, low, or not detected Variable Variable Visible Total occlusion Not detected Not applicable Not detected Visible, no lumen Plaque estimate (diameter reduction) with gray scale and color Doppler ultrasound. CCA = common carotid artery; EDV = end-diastolic velocity; ICA = internal carotid artery; PSV = peak systolic velocity. a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 841 B disease and for patients in whom percutaneous revascularization is considered. The techniques of carotid angioplasty and stenting for carotid bifurcation occlusive disease are described in detail later in this chapter. We generally use CTA or MRA to get information about the aortic arch anatomy and presence of concomitant intracranial disease and collateral pathway in planning our strategy for carotid stenting or endarterectomy. Treatment of Carotid Occlusive Disease Conventionally, patients with carotid bifurcation occlusive disease are divided into two broad categories: patients without prior history of ipsilateral stroke or TIA (asymptomatic) and those with prior or current ipsilateral neurologic symptoms (symptomatic). It is estimated that 15% of all strokes are preceded by a TIA. The 90-day risk of a stroke in a patient presenting with a TIA is 3% to 17%.19 According to the Cardiovascular Health Study, a longitudinal population-based study of coronary artery disease and stroke in men and women, the prevalence of TIA in men was 2.7% for ages of 65 and 69 and 3.6% for ages 75 to 79; the prevalence in women was 1.4% and 4.1%, respectively.24 There have been several studies reporting on the effectiveness of stroke prevention with medical treatment and carotid endarterectomy for symptomatic patients with moderate to 1 severe carotid stenosis. Early and chronic aspirin therapy has been shown to reduce stroke recurrence rate in several large clinical trials.25 Symptomatic Carotid Stenosis. Currently, most stroke Figure 23-16. A carotid angiogram reveals an ulcerated carotid plaque (arrow) in the proximal internal carotid artery, which also resulted in a high-grade internal carotid artery stenosis. neurologists prescribe both aspirin and clopidogrel for secondary stroke prevention in patients who have experienced a TIA or stroke.19 In patients with symptomatic carotid stenosis, the degree of stenosis appears to be the most important predictor in determining risk for an ipsilateral stroke. The risk of a recurrent ipsilateral stroke in patients with severe carotid stenosis approaches 40%. Two large multicenter randomized clinical trials, the European Carotid Surgery Trial (ECST) and the North American Symptomatic Carotid Endarterectomy Trial (NASCET), have both shown a significant risk reduction in stroke for patients with symptomatic high-grade stenosis (70%–99%) undergoing carotid endarterectomy when compared to medical therapy alone.26,27 There has been much discussion regarding the different methodology used in the measurement of carotid stenosis and calculation of the life-table data between the two studies, yet they both studies had similar results.28 Findings of these two landmark trials have also been reanalyzed in many subsequent publications. The main conclusions of the trials remain validated and widely acknowledged. Briefly, the NASCET study showed that for high-grade carotid stenosis, the cumulative risk of ipsilateral stroke was 26% in the medically treated group and 9% in the surgically treated group at 2 years. For patients with moderate carotid artery stenosis (50%–69%), the benefit of carotid endarterectomy is less but still favorable when compared to medical treatment alone; the 5-year fatal or nonfatal ipsilateral stroke rate was 16% in the surgically treated group versus 22% in the medically treated group.29 The risk of stroke was similar for the remaining group of symptomatic patients with less than 50% carotid stenosis, whether they had VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease A Figure 23-15. A. Carotid computed tomography angiography is a valuable imaging modality that can provide a three-dimensional image reconstruction with high image resolution. A carotid artery occlusion is noted in the internal carotid artery B. The entire segment of extracranial carotid artery is visualized from the thoracic compartment to the base of skull. 842 UNIT II PART SPECIFIC CONSIDERATIONS endarterectomy or medical treatment alone. The ECST reported similar stroke risk reduction for patients with severe symptomatic carotid stenosis and no benefit in patients with mild stenosis, when carotid endarterectomy was performed versus medical therapy.27 The optimal timing of carotid intervention after acute stroke, however, remains debatable. Earlier studies showed an increased rate of postoperative stroke exacerbation and conversion of a bland to hemorrhagic infarction when carotid endarterectomy was carried out within 5 to 6 weeks after acute stroke. The dismal outcome reported in the early experience was likely related to poor patient selection. The rate of stroke recurrence is not insignificant during the interval period and may be reduced with early intervention for symptomatic carotid stenosis. Contemporary series have demonstrated acceptable low rates of perioperative complications in patients undergoing carotid endarterectomy within 4 weeks after acute stroke.29 In a recent retrospective series, carotid artery stenting when performed early (<2 weeks) after the acute stroke was associated with higher mortality than when delayed (>2 weeks).30 Asymptomatic Carotid Stenosis. Whereas there is universal agreement that carotid revascularization (endarterectomy or stenting) is effective in secondary stroke prevention for patients with symptomatic moderate and severe carotid stenosis, the management of asymptomatic patients remains an important controversy to be resolved. Generally, the detection of carotid stenosis in asymptomatic patients is related to the presence of a cervical bruit or based on screening duplex ultrasound findings. In one of the earlier observational studies, the authors showed that the annual occurrence rate of neurologic symptoms was 4% in a cohort of 167 patients with asymptomatic cervical bruits followed prospectively by serial carotid duplex scan.31 The mean annual rate of carotid stenosis progression to a greater than 50% stenosis was 8%. The presence of or progression to a greater than 80% stenosis correlated highly with either the development of a total occlusion of the internal carotid artery or new symptoms. The major risk factors associated with disease progression were cigarette smoking, diabetes mellitus, and age. This study supported the contention that it is prudent to follow a conservative course in the management of asymptomatic patients presenting with a cervical bruit. One of the first randomized clinical trials on the treatment of asymptomatic carotid artery stenosis was the Asymptomatic Carotid Atherosclerosis Study (ACAS), which evaluated the benefits of medical management with antiplatelet therapy versus carotid endarterectomy.32 Over a 5-year period, the risk of ipsilateral stroke in individuals with a carotid artery stenosis greater than 60% was 5.1% in the surgical arm. On the other hand, the risk of ipsilateral stroke in patients treated with medical management was 11%. Carotid endarterectomy produced a relative risk reduction of 53% over medical management alone. The results of a larger randomized trial from Europe, the Asymptomatic Carotid Surgery Trial (ACST), recently confirmed similar beneficial stroke risk reduction for patients with asymptomatic, greater than 70% carotid stenosis undergoing endarterectomy versus medical therapy.33 An important point derived from this latter trial was that even with improved medical therapy, including the addition of statin drugs and clopidogrel, medical therapy was still inferior to endarterectomy in the primary stroke prevention for patients with high-grade carotid artery stenosis. It is generally agreed that asymptomatic patients with severe carotid stenosis (80%–99%) are at significantly increased risk for stroke and stand to benefit from either surgical or endovascular revascularization. However, revascularization for asymptomatic patients with a less severe degree of stenosis (60%–79%) remains controversial. Carotid Endarterectomy versus Angioplasty and Stenting Currently, the argument is no longer whether medical therapy alone is inferior to surgical endarterectomy in stroke prevention for severe carotid stenosis. Rather, the debate now revolves around whether carotid angioplasty and stenting produce the same benefits demonstrated by carotid endarterectomy. Since carotid artery stenting was approved by the FDA for clinical application in 2004, this percutaneous procedure has become a treatment alternative in patients who are deemed “high risk” for endarterectomy (Table 23-4). In contrast to many endovascular peripheral arterial interventions, percutaneous carotid stenting represents a much more challenging procedure, because it requires complex catheter-based skills using the 0.014-inch guidewire system and distal protection device. Moreover, current carotid stent devices predominantly use the monorail guidewire system, which requires more technical agility compared with the over-the-wire catheter system that is routinely used in peripheral interventions. This percutaneous intervention often Table 23-4 Conditions qualifying patients as high surgical risk for carotid endarterectomy Anatomic Factors Physiologic Factors • High carotid bifurcation (above C2 vertebral body) • Age ≥80 years • Left ventricular ejection fraction ≤30% • • • • • New York Heart Association class III/IV congestive heart failure • Unstable angina: Canadian Cardiovascular Society class III/IV angina pectoris • Recent myocardial infarction Low common carotid artery (below clavicle) Contralateral carotid occlusion Restenosis of ipsilateral prior carotid endarterectomy Previous neck irradiation • Prior radical neck dissection • Contralateral laryngeal nerve palsy • Presence of tracheostomy • C  linically significant cardiac disease (congestive heart failure, abnormal stress test, or need for coronary revascularization) • Severe chronic obstructive pulmonary disease • End-stage renal disease on dialysis VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Surgical Techniques of Carotid Endarterectomy Although carotid endarterectomy is one of the earliest vascular operations ever described and its techniques have been perfected in the last two decades, surgeons continue to debate many aspects of this procedure. For instance, there is no universal agreement with regard to the best anesthetic of choice, the best intraoperative cerebral monitoring, whether to “routinely” shunt, open versus eversion endarterectomy, and patch versus primary closure. Various anesthetic options are available for patient undergoing carotid endarterectomy including general, local, and regional anesthesia. Typically the anesthesia of choice depends on the preference of the surgeon, anesthesiologist, and patient. However, depending on the anesthetic given, the surgeon must decide whether intraoperative cerebral monitoring is necessary or intra-arterial carotid shunting will be used. In general, if the patient is awake, then his or her abilities to respond to commands during carotid clamp period determine the adequacy of collateral flow to the ipsilateral hemisphere. On the other hand, intraoperative electroencephalogram (EEG) or transcranial power Doppler (TCD) has been used to monitor for adequacy of cerebral perfusion during the clamp period for patients undergoing surgery under general anesthesia. Focal ipsilateral decreases in amplitudes and slowing of EEG waves are indicative of cerebral ischemia. Similarly, a decrease to less than 50% of baseline velocity in the ipsilateral middle cerebral artery is a sign of cerebral ischemia. For patients with poor collateral flow exhibiting signs of cerebral ischemia, intra-arterial carotid shunting with removal of the clamp will restore cerebral flow for the remaining part of the surgery. Stump pressures have been used to determine the need for intra-arterial carotid shunting. Some surgeons prefer to shunt all patients on a routine basis and do not use intraoperative cerebral monitoring. The patient’s neck is slightly hyperextended and turned to the contralateral side, with a roll placed between the shoulder blades. An oblique incision is made along the anterior border of the sternocleidomastoid muscle centered on top of the carotid bifurcation (Fig. 23-17). The platysma is divided completely. Typically tributaries of the anterior jugular vein are ligated and Figure 23-17. To perform carotid endarterectomy, the patient’s neck is slightly hyperextended and turned to the contralateral side. An oblique incision is made along the anterior border of the sternocleidomastoid muscle centered on top of the carotid bifurcation. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 843 CHAPTER 23 Arterial Disease requires balloon angioplasty and stent placement through a long carotid guiding sheath via a groin approach. Poor technical skills can result in devastating treatment complications such as stroke, which can occur in part due to plaque embolization during the balloon angioplasty and stenting of the carotid artery. Because of these various procedural components that require high technical proficiency, many early clinical investigations of carotid artery stenting, which included physicians with little or no carotid stenting experience, resulted in alarmingly poor clinical outcomes. A recent Cochrane review noted that, before 2006, a total of 1269 patients had been studied in five randomized controlled trials comparing percutaneous carotid intervention and surgical carotid reconstruction.34 Taken together, these trials revealed that carotid artery stenting had a greater procedural risk of stroke and death when compared to carotid endarterectomy (odds ratio, 1.33; 95% confidence interval, 0.86 to 2.04). Additionally, a greater incidence of carotid restenosis was noted in the stenting group than the endarterectomy cohorts. However, the constant improvement of endovascular devices, procedural techniques, and adjunctive pharmacologic therapy will likely improve the treatment success of percutaneous carotid intervention. Critical appraisals of several prospective randomized trials comparing the efficacy of carotid stenting versus endarterectomy are available for review.35 Two recently published randomized controlled trial, the Carotid Revascularization Endarterectomy Versus Stent Trial (CREST) and the International Carotid Stenting Study (ICSS) have reported somewhat differing results.36 CREST compared the efficacy of carotid endarterectomy and carotid stenting in both symptomatic and asymptomatic patients.37 Primary end points included 30-day periprocedural composite death, stroke, myocardial infarction, or any ipsilateral stroke up to 4 years. CREST investigators reported no difference between stenting (5.2%) and endarterectomy (4.5%) in terms of primary end point. When each variable was independently analyzed, there was a higher rate of stroke in the stenting group at 30 days (4.1% vs. 2.3%) and a higher rate of myocardial infarction in the endarterectomy group (2.3% vs. 1.1%). The ICSS was a multicenter, international, randomized controlled trial comparing carotid stenting versus endarterectomy in patients with symptomatic carotid stenosis.38 The risk of stroke, death, and myocardial infarction in the stenting group (8.5%) was significantly higher than in the surgical arm (5.2%). The finding that carotid endarterectomy is safer than carotid stenting is also supported by the results of an MRI substudy, which showed significantly more new lesions by diffusion-weighted imaging in the carotid stenting than the carotid endarterectomy patients. All available randomized studies have provided some answers and raised some questions. Some ongoing clinical trials will undoubtedly provide more insights on the efficacy of carotid stenting in the near future. Currently, the Society for Vascular Surgeons recommends carotid endarterectomy as firstline treatment for most symptomatic patients with stenosis of 50% to 99% and asymptomatic patients with stenosis of 60% to 99%.39 The perioperative risk of stroke and death in asymptomatic patients must be below 3% to ensure benefit for the patient. Carotid artery stenting should be reserved for symptomatic patients with stenosis of 50% to 99% at high risk for carotid endarterectomy for anatomic or medical reasons. Carotid artery stenting is not recommended for asymptomatic patients at this time. Asymptomatic patients at high risk for intervention or with a life expectancy of less than 3 years should be considered for medical management as the first-line therapy. 844 UNIT II PART SPECIFIC CONSIDERATIONS divided. The dissection is carried medial to the sternocleidomastoid. The superior belly of the omohyoid muscle is usually encountered just anterior to the common carotid artery. This muscle can be divided. The carotid fascia is incised, and the common carotid artery is exposed. The common carotid artery is mobilized cephalad toward the bifurcation. The dissection of the carotid bifurcation can cause reactive bradycardia related to stimulation of the carotid body. This reflex can be blunted with injection of lidocaine 1% into the carotid body or reversed with administration of intravenous atropine. A useful landmark in the dissection of the carotid bifurcation is the common facial vein. This vein can be ligated and divided. Frequently the 12th cranial nerve (hypoglossal nerve) traverses the carotid bifurcation just behind the common facial vein. The external carotid artery is mobilized just enough to get a clamp across. Often, a branch of the external carotid artery crossing to the sternocleidomastoid can be divided to allow further cephalad mobilization of the internal carotid artery. For high bifurcation, division of the posterior belly of the digastric muscle is helpful in establishing distal exposure of the internal carotid artery. Intravenous heparin sulfate (1 mg/kg) is routinely administered just prior to carotid clamping. The internal carotid artery is clamped first using a soft noncrushing vascular clamp to prevent distal embolization. The external and common carotid arteries are clamped subsequently. A longitudinal arteriotomy is made in the distal common carotid artery and extended into the bulb and past the occlusive plaque into the normal part of the internal carotid artery. Endarterectomy is carried out to remove the occlusive plaque (Fig. 23-18). If necessary, a temporary shunt can be inserted from the common carotid artery to the internal carotid artery to maintain continuous antegrade cerebral blood flow (Fig. 23-19). Typically, a plane is teased Figure 23-18. A. During carotid endarterectomy, vascular clamps are applied in the common carotid, external carotid, and internal carotid arteries. Carotid plaque is elevated from the carotid lumen. B. Carotid plaque is removed, and the arteriotomy is closed either primarily or with a patch angioplasty. Figure 23-19. A temporary carotid shunt is inserted from the common carotid artery (long arrow) to the internal carotid artery (short arrow) during carotid endarterectomy to provide continuous antegrade cerebral blood flow. out from the vessel wall, and the entire plaque is elevated and removed. The distal transition line in the internal carotid artery where the plaque had been removed must be examined carefully and should be smooth. Tacking sutures are placed when an intimal flap remains in this transition to ensure no obstruction to flow (Fig. 23-20). The occlusive plaque is usually removed from the origin of the external carotid artery using the eversion technique. The endarterectomized surface is then irrigated and any debris removed. A patch (autogenous saphenous vein, synthetic such as polyester, PTFE, or biologic material) is sewn to close the arteriotomy (Fig. 23-21). Whether patch closure is necessary in all patients and which patch is the best remain controversial. However, most surgeons agree that patch closure is indicated particularly for the small vessel (<7 mm). The eversion technique has also been advocated for removing the plaque from the internal carotid artery. In the eversion technique, the internal carotid artery is transected at the bulb, the edges of the divided vessel are everted, and the occluding plaque is “peeled” Figure 23-20. The distal transition line (left side of the picture) in the internal carotid artery where the plaque had been removed must be examined carefully and should be smooth. Tacking sutures (arrows) are placed when an intimal flap remains in this transition to ensure no obstruction to flow. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 845 B Figure 23-21. A. An autologous or synthetic patch can be used to close the carotid arteriotomy incision, which maintains the luminal patency. B. A completion closure of carotid endarterectomy incision using a synthetic patch. off the vessel wall. The purported advantages of the eversion technique are no need for patch closure and a clear visualization of the distal transition area. Reported series have not shown a clear superiority of one technique over the others.40 Surgeons will likely continue to use the technique of their choice. Just prior to completion of the anastomosis to close the arteriotomy, we thoroughly flush the vessels of any potential debris. When the arteriotomy is closed, flow is restored to the external carotid artery first and to the internal carotid artery second. Intravenous protamine sulfate can be given to reverse the effect of heparin anticoagulation following carotid endarterectomy. The wound is closed in layers. After surgery, the patient’s neurologic condition is asserted in the operating room prior to transfer to the recovery area. Complications of Carotid Endarterectomy. Most patients tolerate carotid endarterectomy very well and typically are discharged home within 24 hours after surgery. Complications after endarterectomy are infrequent but can be potentially lifethreatening or disabling. Acute ipsilateral stroke is a dreaded complication following carotid endarterectomy. Cerebral ischemia can be due to either intraoperative or postoperative events. Embolizations from the occlusive plaque or prolonged cerebral ischemia are potential causes of intraoperative stroke. The most common cause of postoperative stroke is due to embolization. Less frequently, acute carotid artery occlusion can cause acute postoperative stroke. This is usually due to carotid artery thrombosis related to closure of the arteriotomy, an occluding intimal flap, or distal carotid dissection. When patients experience acute symptoms of neurologic ischemia after endarterectomy, immediate intervention may be indicated. Carotid duplex scan can be done expeditiously to assess patency of the extracranial internal carotid artery. Re-exploration is mandated for acute carotid artery occlusion. Cerebral angiography can be useful if intracranial revascularization is considered. Local complications related to surgery include excessive bleeding and cranial nerve palsies. Postoperative hematoma in the neck after carotid endarterectomy can lead to devastating airway compromise. Any expanding hematoma should be evacuated and active bleeding stopped. Securing an airway is critical and can be extremely difficult in patients with large postoperative neck hematoma. The reported incidence of postoperative cranial nerve palsies after carotid endarterectomy varies from 1% to 30%.41 Well-recognized injuries involve the marginal mandibular, vagus, hypoglossal, superior laryngeal, and recurrent laryngeal nerves. Often these are traction injuries but can also be due to severance of the respective nerves. Techniques of Carotid Angioplasty and Stenting Percutaneous carotid artery stenting has become an accepted alternative treatment in the management of patients with carotid bifurcation disease (Fig. 23-22). The perceived advantages of percutaneous carotid revascularization are related to the minimal invasiveness of the procedure compared to surgery. There are anatomic conditions based on angiographic evaluation in which carotid artery stenting should be avoided due to increased procedure-related risks (Table 23-5). In preparation for carotid stenting, the patient should be given oral clopidogrel 3 days prior to the intervention if the patient was not already taking the drug. The procedure is done in either the operating room with angiographic capabilities or in a dedicated angiography room. The patient is placed in the supine position. The patient’s blood pressure and cardiac rhythm are closely monitored. To gain access to the carotid artery, a retrograde transfemoral approach is most commonly used as the access site for carotid intervention. Using the Seldinger technique, we insert a diagnostic 5- or 6-French sheath in the CFA. A diagnostic arch aortogram is obtained. The carotid artery to be treated is then selected using a 5-French diagnostic catheter, and contrast is injected to show the carotid anatomy. It is important to assess the contralateral carotid artery, vertebrobasilar, and intracranial circulation if these are not known based on the preoperative noninvasive studies. Once the decision is made to proceed with carotid artery stenting, with the tip of the diagnostic catheter still in the common carotid artery, a 0.035-inch, 260-cm long stiff guidewire is placed in the ipsilateral external carotid artery. Anticoagulation with intravenous bivalirudin bolus (0.75 mg/kg) followed by an infusion rate of 2.5 mg/kg/h for the remainder of the procedure is routinely administered. Next the diagnostic catheter is withdrawn and a 90-cm, 6-French guiding sheath is advanced into the common carotid artery over the stiff glide wire. It is critical not to advance the sheath beyond the occlusive plaque in the carotid bulb. The stiff wire is then removed, and preparation is made to deploy the distal embolic protection device (EPD). Several distal EPDs are available (Table 23-6). The EPD device is carefully deployed beyond the target lesion. With regard to the carotid stents, there are several stents that have received approval from the FDA and are commercially available for carotid revascularization (Table 23-7). All current carotid stents use the rapid-exchange monorail 0.014-inch platform. The size selection is typically based on the size of common carotid artery. Predilatation using a 4-mm balloon may be necessary to allow passage of the stent delivery catheter. Once VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease A 846 UNIT II PART SPECIFIC CONSIDERATIONS A Figure 23-22. A. Carotid angiogram demonstrating a high-grade stenosis of the left internal carotid artery. B. Completion angiogram demonstrating a satisfactory result following a carotid stent placement. B the stent is deployed across the occlusive plaque, postdilatation is usually performed using a ≤5.5-mm balloon. It is noteworthy that balloon dilation of the carotid bulb may lead to immediate bradycardia due to stimulation of the glossopharyngeal nerve. The EPD is then retrieved and the procedure is completed with removal of the sheath from the femoral artery. The puncture site is closed using available closure device or with manual compression. Throughout the procedure, the patient’s neurologic function is closely monitored. The bivalirudin infusion is stopped and the patient is kept on clopidogrel (75 mg daily) for at least 1 month and aspirin indefinitely. Complications of Carotid Stenting. Although there have been no randomized trials comparing carotid stenting with and without EPD, the availability of EPDs appears to have reduced the risk of distal embolization and stroke. The results of the various clinical trials and registries of carotid stenting have been reported and compared. It is well known that distal embolization as detected by TCD is much more frequent with carotid stenting even with EPD, when compared with carotid endarterectomy. However, the clinical significance of the distal embolization detected by TCD is not clear because most are asymptomatic. Acute carotid stent thrombosis is rare. The incidence of in-stent carotid restenosis is not well known but is estimated at 10% to 30%. Duplex surveillance shows elevated peak systolic velocities within the stent after carotid stenting not infrequently. However, velocity criteria are being formulated to determine the severity of in-stent restenosis after carotid stenting by ultrasound duplex.42 It appears that systolic velocities exceeding 300 to 400 cm/s would represent >70% to 80% restenosis. Bradycardia and hypotension occur in up to 20% of patients undergoing carotid stenting.43 Systemic administration of atropine is usually effective in reversing the bradycardia. Other technical complications Table 23-6 Commonly used embolic protection devices (EPDs) Pore Size (mm) Mechanism Name of EPD Table 23-5 Distal balloon occlusion PercuSurge Guard Wire, NA Export catheter (Medtronic) Unfavorable carotid angiographic appearance in which carotid stenting should be avoided Distal filter • • • • • • • Angioguard (Cordis) Accunet (Abbott) Emboshield (Abbott) FilterWire (Boston Scientific) SpiderRx (EV3) 100 150 140 110 <100 Flow reversala Parodi Neuro Protection (Gore) NA Extensive carotid calcification Polypoid or globular carotid lesions Severe tortuosity of the common carotid artery Long-segment stenoses (>2 cm in length) Carotid artery occlusion Severe intraluminal thrombus (angiographic defects) Extensive middle cerebral artery atherosclerosis Clinical trial (EMPIRE) in United States. NA = not applicable. a VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 847 Table 23-7 Currently approved carotid stents in the United States Manufacturer Cell Design Tapered Stent Delivery System Size (French) Acculink Abbott Open Yes 6 Exact Abbott Closed Yes 6 NexStent Boston Scientific Closed Self-tapering 5 Protégé RX EV3 Open Yes 6 Precise RX Cordis Open No 6 Exponent Medtronic Open No 6 of carotid stenting are infrequent and include carotid artery dissection and access site complications, such as groin hematoma, femoral artery pseudoaneurysm, distal embolization, and acute femoral artery thrombosis. Nonatherosclerotic Disease of the Carotid Artery Carotid Coil and Kink. A carotid coil consists of an excessive elongation of the internal carotid artery producing tortuosity of the vessel (Fig. 23-23). Embryologically, the carotid artery is Figure 23-23. Excessive elongation of the carotid artery can result in carotid kinking (arrow), which can compromise cerebral blood flow and lead to cerebral ischemia. derived from the third aortic arch and dorsal aortic root and is uncoiled as the heart and great vessels descend into the mediastinum. In children, carotid coils appear to be congenital in origin. In contrast, elongation and kinking of the carotid artery in adults are associated with the loss of elasticity and an abrupt angulation of the vessel. Kinking is more common in women than men. Cerebral ischemic symptoms caused by kinks of the carotid artery are similar to those from atherosclerotic carotid lesions but are more likely due to due to cerebral hypoperfusion than embolic episodes. Classically, sudden head rotation, flexion, or extension can accentuate the kink and provoke ischemic symptoms. Most carotid kinks and coils are found incidentally on carotid duplex scan. However, interpretation of the Doppler frequency shifts and spectral analysis in tortuous carotid arteries can be difficult because of the uncertain angle of insonation. Cerebral angiography, with multiple views taken in neck flexion, extension, and rotation, is useful in the determination of the clinical significance of kinks and coils. Fibromuscular Dysplasia. Fibromuscular dysplasia (FMD) usually involves medium-sized arteries that are long and have few branches (Fig. 23-24). Women in the fourth or fifth decade of life are more commonly affected than men. Hormonal effects on the vessel wall are thought to play a role in the pathogenesis of FMD. FMD of the carotid artery is commonly bilateral, and in about 20% of patients, the vertebral artery is also involved.44 An intracranial saccular aneurysm of the carotid siphon or middle cerebral artery can be identified in up to 50% of the patients with FMD. Four histologic types of FMD have been described in the literature. The most common type is medial fibroplasia, which may present as a focal stenosis or multiple lesions with intervening aneurysmal outpouchings. The disease involves the media with the smooth muscle being replaced by fibrous connective tissue. Commonly, mural dilations and microaneurysms can be seen with this type of FMD. Medial hyperplasia is a rare type of FMD, with the media demonstrating excessive amounts of smooth muscle. Intimal fibroplasia accounts for 5% of all cases and occurs equally in both sexes. The media and adventitia remain normal, and there is accumulation of subendothelial mesenchymal cells with a loose matrix of connective tissue causing a focal stenosis in adults. Finally, premedial dysplasia represents a type of FMD with elastic tissue accumulating between the media and adventitia. FMD can also involve the renal and external iliac arteries. It is estimated that approximately 40% of patients with FMD present with a TIA due to embolization of platelet aggregates.44 DSA demonstrates the VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Name of Stent 848 UNIT II PART Figure 23-25. Carotid ultrasound reveals a patient with a carotid artery dissection in which carotid flow is separated in the true flow lumen (long arrow) from the false lumen (short arrow). SPECIFIC CONSIDERATIONS Figure 23-24. A carotid fibromuscular dysplasia with typical characteristics of multiple stenoses with intervening aneurysmal outpouching dilatations. The disease involves the media, with the smooth muscle being replaced by fibrous connective tissue. characteristic “string of beads” pattern, which represents alternating segments of stenosis and dilatation. The string of beads can also be shown noninvasively by CTA or MRA. FMD should be suspected when an increased velocity is detected across a stenotic segment without associated atherosclerotic changes on carotid duplex ultrasound. Antiplatelet medication is the generally accepted therapy for asymptomatic lesions. Endovascular treatment is recommended for patients with documented lateralizing symptoms. Surgical correction is rarely indicated. Carotid Artery Dissection. Dissection of the carotid artery accounts for approximately 20% of strokes in patients younger than 45 years of age. The etiology and pathogenesis of spontaneous carotid artery dissection remain incompletely understood. Arterial dissection involves hemorrhage within the media, which can extend into the subadventitial and subintimal layers. When the dissection extends into the subadventitial space, there is an increased risk of aneurysm formation. Subintimal dissections can lead to intramural clot or thrombosis. Traumatic dissection is typically a result of hyperextension of the neck during blunt trauma, neck manipulation, strangulation, or penetrating injuries to the neck. Even in supposedly spontaneous cases, a history of preceding unrecognized minor neck trauma is not uncommon. Connective disorders, such as Ehlers-Danlos syndrome, Marfan’s syndrome, α1-antitrypsin deficiency, or FMD, may predispose to carotid artery dissection. Iatrogenic dissections can also occur due to catheter manipulation or balloon angioplasty. Typical clinical features of carotid artery dissection include unilateral neck pain, headache, and ipsilateral Horner’s syndrome in up to 50% of patients, followed by manifestations of the cerebral or ocular ischemia and cranial nerve palsies. Neurologic deficits can result either because of hemodynamic failure (caused by luminal stenosis) or by an artery-to-artery thromboembolism. The ischemia may cause TIAs or infarctions, or both. Catheter angiography has been the method of choice to diagnose arterial dissections, but with the advent of duplex ultrasonography, MRI/MRA, and CTA, most dissections can now be diagnosed using noninvasive imaging modalities (Fig. 23-25). The dissection typically starts in the internal carotid artery distal to the bulb. Uncommonly, the dissection can start in the common carotid artery or is an extension of a more proximal aortic dissection. Medical therapy has been the accepted primary treatment of symptomatic of carotid artery dissection. Anticoagulation (heparin and warfarin) and antiplatelet therapy have been commonly used, although there have not been any randomized studies to evaluate their effectiveness. The prognosis depends on the severity of neurologic deficit but is generally good in extracranial dissections. The recurrence rate is low. Therapeutic interventions have been reserved for recurrent TIAs or strokes or failure of medical treatment. Endovascular options include intra-arterial stenting, coiling of associated pseudoaneurysms, or, more recently, deployment of covered stents. Carotid Artery Aneurysms. Carotid artery aneurysms are rare, encountered in less than 1% of all carotid operations (Fig. 23-26). The true carotid artery aneurysm is generally due to atherosclerosis or medial degeneration. The carotid bulb is involved in most carotid aneurysms, and bilaterality is present in 12% of the patients. Patients typically present with a pulsatile neck mass. The available data suggest that, untreated, these aneurysms lead to neurologic symptoms from embolization. Thrombosis and rupture of the carotid aneurysm are rare. Pseudoaneurysms of the carotid artery can result from injury or infection. Mycotic aneurysms often involved syphilis in the past, but are now more commonly associated with peritonsillar abscesses caused by Staphylococcus aureus infection. FMD and spontaneous dissection of the carotid artery can lead to the formation of true aneurysms or pseudoaneurysms. Whereas conventional surgery has been the primary mode of treatment in the past, carotid aneurysms are currently being treated more commonly using endovascular approaches.45 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 849 B C Figure 23-26. A. An anteroposterior angiogram of the neck revealing a carotid artery aneurysm. B. A lateral projection of the carotid artery aneurysm. C. Following endovascular placement, the carotid artery aneurysm is successfully excluded. Carotid Body Tumor. The carotid body originates from the third branchial arch and from neuro-ectodermal derived neural crest lineage. The normal carotid body is located in the adventitia or periadventitial tissue at the bifurcation of the common carotid artery (Fig. 23-27). The gland is innervated by the glossopharyngeal nerve. Its blood supply is derived predominantly from the external carotid artery but can also come from the vertebral artery. Carotid body tumor is a rare lesion of the neuroendocrine system. Other glands of neural crest origin are seen in the neck, parapharyngeal spaces, mediastinum, retroperitoneum, A and adrenal medulla. Tumors involving these structures have been referred to as paraganglioma, glomus tumor, or chemodectoma. Approximately 5% to 7% of carotid body tumors are malignant. Although chronic hypoxemia has been invoked as a stimulus for hyperplasia of carotid body, approximately 35% of carotid body tumors are hereditary. The risk of malignancy is greatest in young patients with familial tumors. Symptoms related to the endocrine products of the carotid body tumor are rare. Patients usually present between the fifth and seventh decades of life with an asymptomatic lateral neck B VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 23-27. A. A carotid body tumor (arrow) located adjacent to the carotid bulb. B. Following periadventitial dissection, the carotid body tumor is removed. CHAPTER 23 Arterial Disease A 850 UNIT II PART mass. The diagnosis of carotid body tumor requires confirmation on imaging studies. Carotid duplex scan can localize the tumor to the carotid bifurcation, but CT or MRI is usually required to further delineate the relationship of the tumor to the adjacent structures. Classically, a carotid body tumor will widen the carotid bifurcation. The Shamblin classification describes the tumor extent: I, tumor is less than 5 cm and relatively free of vessel involvement; II, tumor is intimately involved but does not encase the vessel wall; and III, tumor is intramural and encases the carotid vessels and adjacent nerves.46 With goodresolution CT and MRI, arteriography is usually not required. However, arteriography can provide an assessment of the vessel invasion and intracranial circulation and allows for preoperative embolization of the feeder vessels, which has been reported to reduce intraoperative blood loss. Surgical resection is the recommended treatment for suspected carotid body tumor. SPECIFIC CONSIDERATIONS Carotid Trauma. Blunt or penetrating trauma to the neck can cause injury to the carotid artery. Notwithstanding the massive bleeding from carotid artery transection, injury to the carotid artery can result in carotid dissection, thrombosis, or pseudoaneurysm formation. Carotid duplex ultrasound can be useful to locate the site of injury in the cervical segment of the carotid artery. Spiral CTA has become the modality of choice to detect extracranial carotid artery injury. Confirmation of carotid injury by contrast cerebral angiography remains the gold standard diagnostic test. Injuries to the cervical segment of the common and internal carotid arteries can be repaired surgically. Acute carotid artery thrombosis is usually treated medically with anticoagulation if the patient is asymptomatic. Revascularization should be considered for patients presenting with ongoing cerebral ischemia related to carotid artery thrombosis. Traumatic carotid artery dissection can cause cerebral ischemia due to thromboembolization, decreased flow, or thrombosis. Commonly, the dissection involves the distal portion of the cervical and petrous segment of the internal carotid artery. Medical management with antiplatelet or anticoagulation therapy is usually adequate for uncomplicated traumatic carotid dissection. In patients with pseudoaneurysms of the carotid artery that are located in a segment that is out of surgical reach, the use of selective coil embolization of the pseudoaneurysm or exclusion of the pseudoaneurysm by a covered stent graft has been reported. Bare metal stent has been used with success in the treatment of traumatic carotid artery dissection. ABDOMINAL AORTIC ANEURYSM Despite more than 50,000 patients undergoing elective repair of abdominal aortic aneurysm (AAA) each year in the United States, approximately 15,000 patients die annually as a result of ruptured aneurysm, making it the 10th leading cause of death in men in this country.47 The incidence appears to be increasing, and this is due in part to improvements in diagnostic imaging and, more importantly, a growing elderly population. With early diagnosis and timely intervention, aneurysm rupture–related death is largely preventable. Conventional treatment of an AAA involves replacing the aneurysmal segment of the aorta with a prosthetic graft, with the operation performed through a large abdominal incision. Techniques for this open abdominal surgery have been refined, adapted, and extensively studied by vascular surgeons over the past four decades. Despite a well-documented low perioperative mortality rate of 2% to 3% in large academic institutions, the thought of undergoing an open abdominal aortic operation often provokes a sense of anxiety in many patients due in part to the postoperative pain associated with the large abdominal incision as well as the long recovery time needed before the patient can return to normal physical activity. The most common location of aortic aneurysms is the infrarenal aorta. Endovascular stent graft placement represents a revolutionary and minimally invasive treatment for infrarenal AAAs that only requires 1 to 2 days of hospitalization, and the patient can return to normal physical activity within 1 week. The concept of using an endoluminal device in the management of vascular disease was first proposed by Dotter and colleagues, who successfully treated a patient with iliac occlusion using transluminal angioplasty in 1964.48 Nearly two decades later, Parodi and colleagues reported the first successful endovascular repair of AAA using a stent graft device.15 Since then, a variety of stent graft technologies have been developed to treat AAA. The rapid innovation of this new treatment modality has undoubtedly captured the attention of patients with aortic aneurysms as well as physicians who practice endovascular therapy. Physicians in general should be knowledgeable regarding available treatment options of AAA in order to provide adequate evaluation and education to patients and their families. The purpose of this section is to outline the treatment options for AAAs, including conventional repair and endovascular approach. Advantages and potential complications of these treatments will also be addressed. Causes and Risk Factors The pathogenesis of aneurysmal disease of the aorta is complex and multifactorial. A degenerative process in the aortic wall is the most common cause of AAA development.49 Matrix metalloproteinases (MMP), proteolytic enzymes, are found abundantly in the wall of AAA. Atherosclerotic disease, age, male sex, smoking history, family history, hypertension, coronary artery disease, and chronic obstructive pulmonary disease are associated with the development of AAA.50,51 Diabetes and black race have negative association with AAA.50 Other less common causes include inflammation, infection, and connective tissue disease. Inflammatory AAA accounts for 5% to 10% of all AAAs.52 In contrast to atherosclerotic AAA, the inflammatory variant is characterized pathologically by marked thickening of the aneurysm wall, fibrosis of the adjacent retroperitoneum, and rigid adherence of the adjacent structures to the anterior aneurysm wall.53 Male sex and smoking are even stronger risk factors in inflammatory AAA.54 Smoking cessation is the first step of medical therapy, followed by surgical repair. Infectious or mycotic AAA is rare but is associated with high mortality.55 Patients with connective tissue disorders such as Marfan’s syndrome and Ehlers-Danlos syndrome tend to have more extensive and larger aneurysms at a younger age.56 Natural History of Aortic Aneurysm The natural history of an AAA is to expand and rupture. AAA exhibits a “staccato” pattern of growth, where periods of relative quiescence may alternate with expansion. Therefore, although an individual pattern of growth cannot be predicted, average aggregate growth is approximately 3 to 4 mm/year. There is some evidence to suggest that larger aneurysms may expand faster than smaller aneurysms, but there is significant overlap between the ranges of growth rates at each strata of size. Rupture risk appears to be directly related to aneurysm size as predicted by Laplace’s Law. Although more sophisticated VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 851 Table 23-8 Annualized risk of rupture of abdominal aortic aneurysm (AAA) based on size Diameter of Aorta (cm) Estimated Annual Risk of Rupture (%) Estimated 5-Year Risk of Rupture (%)a Normal aorta 2–3 0 0 (unless AAA develops) Small AAA 4–5 1 5–10 Moderate AAA 5–6 2–5 30–40 Large AAA 6–7 3–10 >50 Very large AAA >7 >10 Approaching 100 The estimated 5-year risk is more than five times the estimated annual risk because over that 5 years, the AAA, if left untreated, will continue to grow in size. a methods of assessing rupture risk based on finite element analysis of wall stress are under active investigation, maximum transverse diameter remains the standard method of risk assessment for aneurysm rupture. In the past, AAA rupture risk has been overestimated. More recently, two landmark studies have served to better define the natural history of AAA.57,58 Based on best available evidence, the annualized risk of rupture is given in Table 23-8. The rupture risk is quite low below 5.5 cm and 2 begins to rise exponentially thereafter. This size can serve as an appropriate threshold for recommending elective repair provided one’s surgical mortality is below 5%. For each size strata, however, women appear to be at higher risk for rupture than men, and a lower threshold of 4.5 to 5.0 cm may be reasonable in good-risk patients. Although data are less compelling, a pattern of rapid expansion of >0.5 cm within 6 months can be considered a relative indication for elective repair. Aneurysms that fall below these indications may safely be followed with CT or ultrasound at 6-month intervals, with long-term outcomes equivalent to earlier surgical repair. Interestingly, in the Aneurysm Detection and Management (ADAM) study, 80% of all AAAs that were followed in this manner eventually came to repair within 5 years.58 Unless symptomatic or ruptured, AAA repair is a prophylactic repair. The rationale for recommending repair is predicated on the assumption that the risk of aneurysm rupture exceeds the combined risk of death from all other causes such as cardiopulmonary disease and cancer. On the other hand, our limitation in predicting timing and cause of death is underscored by the observation that over 25% of patients who were deemed unfit for surgical repair because of their comorbidities died from rupture of their aneurysms within 5 years. unstable with a history of acute back pain and/or syncope and a known unrepaired AAA or a pulsatile abdominal mass should be immediately taken to the operating room with a presumed diagnosis of a ruptured AAA. Overall mortality of AAA rupture is 71% to 77%, which includes all out-of-hospital and in-hospital deaths, as compared with 2% to 6% for elective open surgical repair.59 Nearly half of all patients with ruptured AAA will die before reaching the hospital. For the remainder, surgical mortality is 45% to 50% and has not substantially changed in the last 30 years. Relevant Anatomy An AAA is defined as a pathologic focal dilation of the aorta that is greater than 30 mm or 1.5 times the adjacent diameter of the normal aorta (Fig. 23-28). Male aortas tend to be larger Clinical Manifestations Most AAAs are asymptomatic and are usually found incidentally during workup for chronic back pain or kidney stones. Physical examination is neither sensitive nor specific except in thin patients. Large aneurysms may be missed in the obese, while normal aortic pulsations may be mistaken for an aneurysm in thin individuals. Rarely patients present with back pain and/or abdominal pain with a tender pulsatile mass. Patients with these symptoms must be treated as a rupture until proven otherwise. If the patient is hemodynamically stable and the aneurysm is intact on a CT scan, the patient is admitted for blood pressure control with intravenous antihypertensive agents and undergoes repair usually within 12 to 24 hours or at least during the same hospitalization. In contrast, patients who are hemodynamically Figure 23-28. An operative view of an infrarenal aortic aneurysm. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Description 852 UNIT II PART SPECIFIC CONSIDERATIONS than female aortas, and there is generalized growth of the aortic diameter with each decade of life. Ninety percent of AAAs are infrarenal in location and have a fusiform morphology. There is a higher predilection for juxtarenal and suprarenal AAAs in women compared with men. Concomitant common iliac and/or hypogastric artery aneurysms can be found in 20% to 25% of patients. Although the etiology of most aortic aneurysms is atherosclerotic, clinically significant peripheral occlusive disease is unusual and present in less than 10% of all cases. Although extravascular anatomy is important for open surgical repair of AAA, intravascular anatomy and aortoiliac morphology are important for endovascular repair. Pertinent anatomic dimensions include the diameter of the proximal nondilated infrarenal aortic neck, which can range from 18 to 30 mm; common iliac artery, which can range from 8 to 16 mm; and external iliac arteries, which can range from 6 to 10 mm. Morphologically, the aortic neck can manifest complex angulation above and below the renal arteries due to combination of elongation and anterolateral displacement by the posterior bulge of the aneurysmal aorta. Furthermore, the shape of the proximal neck is rarely tubular, but often is conical, reverse conical, or barrel-shaped. Distally, the iliac arteries can have severe tortuosity with multiple compound turns. Although significant from hemodynamic standpoint, severe iliac calcifications combined with extreme tortuosity can pose a formidable challenge during endovascular repair. Diagnostic Evaluation Preoperative evaluation should include routine history and physical exam with particular attention to (a) any symptoms referable to the aneurysm, which may impact the timing of repair; (b) history of pelvic surgery or radiation, in the event retroperitoneal exposure is required or interruption of hypogastric circulation is planned; (c) claudication suggestive of significant iliac occlusive disease; (d) lower extremity bypass or other femoral reconstructive procedures; and (e) chronic renal insufficiency or contrast allergy. Cross-sectional imaging is required for definitive evaluation of AAA. Although ultrasound is safe, widely available, relatively accurate, and inexpensive and thus the screening modality of choice, CT scan remains the gold standard for determination of anatomic eligibility for endovascular repair. Size of AAA may differ up to 1 cm between CT and ultrasound, and during longitudinal follow-up, comparisons should be made between identical modalities. With modern multirow detector scanners, a timed-bolus intravenous contrast-enhanced, 2.5- to 3.0-mm slice spiral CT of the chest, abdomen, and pelvis can be performed in less than 30 seconds with a single breath hold. Extremely high-resolution images are obtained with submillimeter spatial resolution (Fig. 23-29). Proper window level and width (brightness and contrast) are important for discrimination among aortic wall, calcific plaque, thrombus, and lumen. The only major drawback to CT is the risk of contrast nephropathy in diabetics and in patients with renal insufficiency. The spiral technique further affords the ability for threedimensional reconstruction. Three-dimensional reconstructions can yield important morphologic information that is critical to endovascular therapy. Using third-party software, these images can be viewed and manipulated on one’s desktop computer, and so-called “center-line” (transverse slices perpendicular to the central flow lumen of the aorta) diameter and length measurements obtained. Conventional angiography has a minimal role Figure 23-29. High resolution of image displaying an aortic aneurysm (arrow) can be achieved with multidetector computed tomography angiography. in the current management of AAA. Angiography is invasive with an increased risk of complications. Indications for angiography are isolated to concomitant iliac occlusive disease (present in <10% of patients with AAA) and unusual renovascular anatomy. Surgical Repair of Abdominal Aortic Aneurysm General anesthesia is necessary when performing a conventional open AAA repair. While a retroperitoneal incision is a wellaccepted surgical approach, a midline transabdominal incision remains the more common approach for open aortic aneurysm operation. Since the abdominal incision can lead to significant pain and discomfort, an epidural catheter can be placed prior to the operation for postoperative analgesic infusion to provide pain control. Once the abdominal cavity is opened, the small intestines and transverse colon are retracted to expose the retroperitoneum overlying the AAA. The retroperitoneum is next divided, followed by isolation of both proximal and distal segments of the AAA. Intravenous heparin (100 IU/kg) is given followed by clamping of the proximal and distal segments of the aneurysm. The aneurysm sac is open next, and a prosthetic graft is used to reconstruct the aorta. If the aneurysm only involves the abdominal aorta, a tube graft can be used to replace the aorta (Fig. 23-30). If the aneurysm extends distally to the iliac arteries, a prosthetic bifurcated graft is used for either an aorto-bi-iliac or aorto-bi-femoral bypass reconstruction (Fig. 23-31). The overlying aneurysm sac and the retroperitoneum are closed to cover the prosthetic bypass graft to minimize potential bowel contact to the graft. Small and large intestines are returned to the abdominal cavity followed by the closure of the abdominal fascia and skin. Advantages and Risks of Open Abdominal Aortic Aneurysm Repair. The main advantage of a conventional open repair is that the AAA is permanently eliminated because it is entirely replaced by a prosthetic aortic graft. The risk of aneurysm VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 853 CHAPTER 23 Arterial Disease A B Figure 23-30. A. Schematic depiction of an aortic tube graft used to repair an aortic aneurysm. B. Intraoperative image of an aortic tube graft reconstruction. recurrence or delayed rupture no longer exists. As a result, longterm imaging surveillance is not needed with these patients. In contrast, the long-term efficacy of endovascular repair remains unclear. Consequently, long-term imaging surveillance is critical to ensure that the aortic aneurysm remains properly sealed by the stent graft. Other potential advantages of open repair include direct assessment of the circulatory integrity of the colon. If signs of colonic ischemia become evident after aortic bypass grafting, a concomitant mesenteric artery bypass can be performed to revascularize the colonic circulation. In addition, open repair permits the surgeons to explore for other abdominal pathologies, such as gastrointestinal tumors, liver mass, or cholelithiasis. As for the risks associated with open repair, cardiac complications, in the form of either myocardial infarction or arrhythmias, remain the most common morbidity, with an incidence between 2% and 6%.60 Another significant complication is renal failure or transient renal insufficiency as a result of perioperative hypotension, atheromatous embolization, inadvertent injury to the ureter, preoperative contrast-induced nephropathy, or suprarenal aortic clamping. Although the incidence of renal failure is less than 2% in elective aneurysm repair, it can occur in more than 20% of patients after repair of a ruptured AAA.60 Ischemic colitis is a devastating potential complication after open repair. The likelihood of such a complication is highest in those who had a prior colon resection and undergo repair of a ruptured AAA, due to the loss of collateral blood supply to the rectosigmoid colon. It is estimated that 5% of patients who undergo elective aneurysm repair will develop partial-thickness ischemic colitis but without significant clinical sequelae.61 However, if the partial-thickness ischemia progresses to full-thickness gangrene and peritonitis, mortality can be as high as 90%.61 The incidence of prosthetic graft infection ranges between 1% and 4% after open repair.61 It is more common in those who undergo repair of a ruptured AAA. If the prosthetic graft is not fully covered by the aneurysm sac or retroperitoneum, intestinal adhesion with subsequent bowel erosion may occur, resulting in an aortoenteric fistula. The predominant sign of such a complication is massive hematemesis, and it typically occurs years after the operation. Despite these potential complications, however, the majority of patients who undergo successful elective open repair have an uneventful recovery. Endovascular Repair of Abdominal Aortic Aneurysm Over a decade has passed since the first report of human implantation of a homemade stent graft for endovascular repair of an AAA by Parodi in 1991.3 Several prospective clinical trials across different devices and analysis of large Medicare administrative databases and meta-analyses of published literature have consistently demonstrated significantly decreased operative time, blood loss, hospital length of stay, and overall perioperative morbidity and mortality of endovascular repair compared with open surgical repair. For patients who are at increased risk for surgery because of age or comorbidity, endovascular repair is a superior minimally invasive alternative. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 854 UNIT II PART SPECIFIC CONSIDERATIONS Figure 23-31. Intraoperative view of a bifurcated graft used to repair an aortic aneurysm. The principle of endovascular repair of AAA involves the implantation of an aortic stent graft that is fixed proximally and distally to nonaneurysmal aortoiliac segment and thereby endoluminally excluding the aneurysm from the aortic circulation (Fig. 23-32). Unlike open surgical repair, the aneurysm sac is not A resected, which is subjected for potential aneurysm expansion or even rupture. Importantly, aortic branches, such as lumbar arteries or the inferior mesenteric artery (IMA), are occluded, which can lead to persistent aneurysm pressurization and aneurysm expansion. Currently, the following nine devices are available for elective repair of intact infrarenal AAA: AneuRx device (Medtronic/AVE, Santa Rosa, CA), Gore Excluder device (WL Gore & Associates, Flagstaff, AZ), Endologix Powerlink device (Endologix Inc., Irvine, CA), Zenith device (Cook Inc., Bloomington, IN), Talent device (Medtronic/AVE, Santa Rosa, CA), Endurant device (Medtronic/AVE, Santa Rosa, CA), AFX Endovascular AAA System (Endologix Inc., Irvine, CA), Aorfix Flexible Stent (Lombard Medical Inc., Framingham, MA), and Ovation Prime Stent (TriVascular Inc., Santa Rosa, CA). Despite some differences in physical appearance, mechanical properties, and materials, they will be discussed collectively for this chapter. Most of these devices are modular devices consisting of a primary device or main body and one or two iliac limbs that insert into the main body to complete the repair. Depending on the device, there are varying degrees of flexibility in the choice of iliac limbs that can be matched to the main body, which can impact the customizability for a particular anatomy. A severe limitation of the endovascular repair devices is the need for adequate proximal neck to achieve a durable sealing zone. Several techniques have been proposed to overcome this limitation. These include fenestrated or branched endografts and the “chimney,” “snorkel,” and “periscope” techniques. The fenestrated stent grafts rely on precise alignment between the fenestration and the corresponding visceral artery. 62 Multiple clinical trials using customized fenestrated stent graft for the treatment of short-necked and juxtarenal aortic aneurysm repair have shown promising short- and mid-term results.63,64 However, restricted access to these investigational devices and the delays due to device customization limit the current use of these devices to a few centers. Alternatively, some centers have reported good results with intraoperative surgeon-modified endograft to create fenestrations for the treatment of complex aortic aneurysms in high-risk patients.65 Further development Figure 23-32. A. An aortogram demonstrating a large infrarenal abdominal aortic aneurysm. B. Following endovascular stent graft implantation, the aortic aneurysm is successfully excluded. B VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Patient Selection for Endovascular Aortic Aneurysm Repair. Anatomic eligibility for endovascular repair is mainly based on three areas: the proximal aortic neck, common iliac arteries, and external iliac and common femoral arteries, which relate to the proximal and distal landing zones or fixation sites and the access vessels, respectively. The requirements for the proximal aortic neck are a diameter of 18 to 28 mm and a minimum length of 15 mm (Table 23-9). Usually, multiple measurements of the diameter are taken along the length of the neck to assess its shape. All diameter measurements are mid-wall to mid-wall of the vessel. Secondary considerations include mural calcifications (<50% circumference), luminal thrombus (<50% circumference), and angulation (<45°). Presence of a significant amount of any one of these secondary features in combination with a relatively short proximal neck may compromise successful short- and long-term fixation of the stent graft and exclusion of the aneurysm. The usual distal landing zone is the common iliac artery. The external iliac artery may serve as an alternate site when the ipsilateral common iliac artery is aneurysmal or Table 23-9 Ideal characteristics of an aneurysm for endovascular abdominal aortic aneurysm repair Neck length (mm) >15 Neck diameter (mm) >18, <32 Aortic Neck angle (degrees) <60 Neck mural calcification (% circumference) <50 Neck luminal thrombus (% circumference) <50 Common iliac artery diameter (mm) Between 8 and 20 Common iliac artery length (mm) >20 External iliac artery diameter (mm) >7 ectatic. The treatable diameters of common iliac arteries range from 8 to 20 mm, and there should be at least 20 mm of patent artery of uniform diameter to allow adequate fixation. Finally, at least one of two common femoral and external iliac arteries must be at least 7 mm in diameter in order to safely introduce the main delivery sheath. Slightly smaller iliac diameters may be tolerated depending on the specific device and in the absence of severe tortuosity and calcific disease. Difficult access is one of the main causes of increased procedural time and intraoperative complications. Using these criteria, approximately 60% of all AAAs are anatomic candidates for endovascular repair. The next step in the preoperative planning is device selection. Typically, the proximal diameter of the main device is oversized by 10% to 20% of the nominal diameter of the aortic neck. Distally, the iliac limbs are oversized by 1 to 4 mm depending on the individual device’s instructions for use. The biggest challenge to proper device selection remains determining the optimal length from the renal arteries to the hypogastric arteries. Despite availability of sophisticated three-dimensional reconstructions, the exact path that a device will take from the proximal aortic neck to the distal iliac arteries is difficult to predict. It is dependent on a host of factors related to the mechanical properties of the stent graft and the morphology of the aortoiliac flow lumen. “Plumb-line” measurements of axial CT images can be quite inaccurate, typically grossly underestimating the length, whereas center-line measurements usually overestimate the length. Angiographic measurements using a marker catheter are invasive, require contrast and radiation exposure, and are also inaccurate because they fail to account for the stiffness of the stent graft. The consequences of not choosing the correct length of the device include inadvertent coverage of the hypogastric artery if too long and the need for additional devices if too short. Advantages and Risks of Endovascular Repair. The obvious advantage of an endovascular AAA repair is its minimally invasive nature. Typically, patients who undergo this procedure stay in the hospital for only 1 to 3 days, in contrast to the 5- to 10-day stay required after conventional open surgical repair. In our institution, patients who have had an endovascular repair are routinely transferred to a general vascular ward from the postanesthesia recovery unit, avoiding admission to a more costly intensive care unit. Because an abdominal incision is not necessary in endovascular repair, the procedure is particularly beneficial in patients with severe pulmonary disease, such as chronic obstructive pulmonary disease or emphysema. Patients can sustain adequate breathing in the postoperative period, avoiding respiratory complications or prolonged mechanical ventilation. Because the abdominal cavity has not been entered, the risk of gastrointestinal complications, such as ileus, ventral hernia, or bowel obstruction due to intestinal adhesion, is also greatly reduced. Moreover, regional or epidural anesthesia can be used, avoiding the risks associated with general anesthesia in patients with severe cardiopulmonary dysfunction. Despite its many advantages, endovascular repair does have potential complications. Since the stent graft device is attached endoluminally within the abdominal aorta, an endoleak due to incomplete stent graft exclusion of the aneurysm can occur. With this type of leak, blood flow persists outside the lumen of the endoluminal graft but within an aneurysm sac. A meta-analysis of 1118 patients who underwent successful endovascular repair found an endoleak incidence of 24%.70 Although VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 855 CHAPTER 23 Arterial Disease of the fenestrated techniques also opens the way for endovascular treatment of suprarenal and thoracoabdominal aneurysm.66 Recently, an “off-the-shelf” Zenith Fenestrated AAA endovascular graft has been approved by the FDA. This device has fenestrations or scallops in the graft material to allow the proximal edge of the stent graft to be placed above the renal arteries while still permitting blood flow to vessels accommodated by the fenestrations or scallops. The “chimney” technique involves placing renal or mesenteric stents parallel to the aortic stent graft to preserve blood flow in the visceral aortic branches.67 This technique has been suggested as a rescue procedure for visceral arteries that have been covered by the stent graft during endovascular repair.68 The review of literature showed that open surgery remains a safe and effective treatment option for good-risk patients with juxtarenal aortic aneurysm.69 Fenestrated endovascular repair is associated with low mortality and compares favorably with open surgery in terms of morbidity, especially renal function impairment and cardiac complications.69 The “chimney” technique demonstrated feasibility, but because of the limited number of reports and the lack of long-term data, it should be considered only in acute poor surgical risk patients and in case of unintentional visceral artery coverage or elective poor surgical cases for fenestrated endovascular repair.69 856 UNIT II PART SPECIFIC CONSIDERATIONS a small endoleak usually poses little clinical significance because it will typically become thrombosed spontaneously, a large or persistent endoleak may lead to continuous aneurysm perfusion and ultimately to aneurysm rupture. The rupture rate following an endovascular AAA repair has been reported to be less than 0.8%.71 Stent graft iliac limb dysfunction resulting in thrombosis has been reported following endovascular repair.18,70 One possible cause is aneurysm remodeling, resulting in a shortening in the aortic length, which can cause the stent graft to kink. Alternatively, progression of an underlying iliac atherosclerotic lesion may cause compression of the iliac limb and ultimately result in graft-limb occlusion. Treatment options include thrombolysis or graft thrombectomy to determine the underlying cause and possibly additional stent graft placement. Renal artery occlusion may occur due to improper stent graft positioning or migration.18,60,70 Graft limb separation or dislocation has also been reported.18,60,70 In patients with AAA and concurrent iliac artery aneurysms who undergo preoperative coil embolization of the internal iliac artery, 20% to 45% experience symptoms of pelvic ischemia.72 These symptoms may include buttock claudication, impotence, gluteal skin sloughing, and colonic ischemia. Other complications pertaining to endovascular repair relate to the access site and include groin hematoma and wound infection. Occasionally, the stent graft device can malfunction by either failing to deploy or dislodging during the deployment procedure.18,71 If the device cannot be salvaged or rescued endoluminally, open surgical repair of the aneurysm may be necessary. the delivery catheter or the introducer sheath is advanced to the L1-L2 vertebral space, which typically marks the location of the renal arteries. An angiographic catheter is advanced from the contralateral femoral artery to the same level. A road-mapping aortogram is obtained to localize the renal arteries. The primary device is rotated to the desired orientation and deployed immediate below the lowest renal artery (Fig. 23-33). The angiographic catheter is replaced with a directional catheter and an angled guidewire, and the opening for the contralateral limb on the main device is cannulated. Intrastent passage of the guidewire is confirmed, and the angled guidewire is replaced with a stiff guidewire. The contralateral iliac limb is inserted into the docking opening of the primary device and deployed. A completion angiogram is performed looking for patency of the renal and hypogastric arteries, the device limbs, proximal and distal fixation, and endoleak. Adjunctive interventions including additional devices, balloons, and bare stents are performed as needed. The procedure is concluded with routine repairs of the femoral arteries and closure of the groin incisions. The patients recover in the recovery room for 2 to 4 hours and admitted to the general care floor. Although in the past, patients Technical Considerations of Endovascular Aortic Aneurysm Repair. Although endovascular AAA repair may be performed in any venue with appropriate digital fluoroscopic imaging capability, due to the need for absolute sterility and aseptic technique, it is most safely performed in a surgical suite. The patient is prepped and draped just as in open AAA repair. Patients with renal insufficiency should be started on perioperative oral N-acetylcysteine (Mucomyst) and sodium bicarbonate infusion to reduce the risk of contrast nephropathy. A variety of anesthetic options may be used. Regional anesthesia may be appropriate for patients with pulmonary disease. There are reports of success with local anesthetics alone, as the incisions are typically smaller than a typical open inguinal hernia repair.73 Bilateral transverse oblique incisions are made just below the inguinal ligament to expose approximately 2 to 3 cm of CFA and obtain proximal control. Special attention is paid to avoid the groin crease to decrease the risk of wound complications. Some have advocated a completely percutaneous access using the “pre-close” technique with the Perclose suture-mediated vascular closure device (Abbott Perclose, Redwood City, CA). Review of reported series on this technique suggest a technical success rate of 95% for medium-size sheaths ranging from 12 to 16 French, and 75% success for 18- to 24-French sizes. Transfemoral access is obtained using standard Seldinger technique. Initial soft-tipped starter guidewires are exchanged for stiff guidewires that are advanced to the thoracic arch. Intravenous heparin at 80 IU/kg are administered, and the activated clotting time is maintained at 200 to 250 seconds. These guidewires provide the necessary support for the subsequent introduction of the large-diameter delivery catheters and devices. In the absence of special anatomic considerations, the primary device is inserted through the right side and the contralateral iliac limb is inserted through the left side. After administration of heparin, A C B D Figure 23-33. A. During an endovascular aortic aneurysm repair, the main endograft device is inserted through a femoral artery approach. B. The device is deployed in the aorta just below the renal arteries. C. A contralateral iliac endograft device is inserted through a contralateral gate opening, which is next deployed. D. Completion of deployment of the endograft device should fully exclude an aortic aneurysm while preserving flow of the renal and hypogastric arteries. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ were admitted to the intensive care unit, this is rarely needed. Most patients can be started on a regular diet that evening and discharged the next morning. Surveillance Following Endovascular Aortic Aneurysm Repair. Life-long follow-up is essential to the long-term suc- Results from Clinical Studies Comparing Endovascular versus Open Repair The primary success rate after endovascular repair of AAA has been reported to be as high as 95%.18,59 The less invasive nature of this procedure is appealing to many physicians and patients. In addition, virtually all reports indicate a decreased blood loss, transfusion requirements, and length of intensive care unit and hospital stay for endovascular repair of AAAs compared with the standard surgical approach.18,59,74 With the advent of bifurcated grafts and improved delivery systems in the future, the only real limitation will be cost. When evaluating the literature for results from clinical series, it is important to look at a comparison of endoluminal versus open repair and device-specific outcome and cost analysis studies. Early reports on results with endovascular repair were often flawed due to selection biases. This is because from its inception, endovascular repair has been used mostly in patients who are at higher risk for open repair. At the same time, only patients with favorable anatomy including less tortuosity and the presence of a suitable infrarenal neck were considered for endovascular repair. Randomization is also difficult because most patients who anatomically qualify for endovascular repair would withdraw from the study if randomized to open repair. Consequently, there are very few randomized controlled trials that have compared outcomes in patients with similar risk factors and anatomy who are eligible for both types of repair. Two such European trials have recently published short-term outcome data that are unbiased in design. The DREAM trial is a multicenter randomized trial that compared open versus endovascular repair among a group of 345 patients at 28 European centers using multiple different devices including Gore, AneuRx, and Zenith.75 Patients were included only if they were considered to be candidates for both types of repairs. The operative mortality rate was 4.6% in the operative group versus 1.2% in the endoluminal group at 30 days. When looking at the combined rate of operative mortality and severe complications, there was an incidence of 9.8% in the open repair group versus 4.7% in the endoluminal group. Device-Specific Outcome. Matsumura and associates compared endoluminal versus open repair using the Excluder device.77 In their review, they demonstrated a 30-day mortality rate of 1% along with endoleak rates of 17% and 20% at 1- and 2-year intervals, respectively.77 The limb narrowing, limb migration, and trunk migration were all 1% at 2 years. There were no deployment failures or early conversions. There was an annual 7% reintervention rate. Aneurysm growth was demonstrated in 14% of patients at 2 years. The Zenith device by Cook has been studied by Greenberg and associates, who compared standard surgical repair with endoluminal repair in low-risk patients and endoluminal repair in high-risk patients.78 They reported a 30-day mortality rate of 3.5%, which was equal to the open group. The endoleak rates were 7.4% and 5.4% at 1- and 2-year intervals, respectively. There was a 5.3% migration of 5 mm at 1 year. Freedom from rupture was 100% in the low-risk group and 98.9% in the high-risk endoluminal group at 2 years. Experience with the AneuRx device has been reported by Zarins.79 In this 4-year review, they found a 30-day mortality rate of 2.8%. Endoleak rate at 4 years was 13.9%, aneurysm enlargement was 11.5%, and stent graft migration was 9.5%. Freedom from rupture was noted to be 98.4% at 4 years. Criado and associates have reported on their 1- year experience with the Talent LPS device by Medtronic.80 They report a 30-day mortality rate of 0.8%. Endoleak rate was 10%. Three deployment failures were noted, and freedom from rupture was 100%. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 857 CHAPTER 23 Arterial Disease cess after endovascular AAA repair. Indeed, one may go so far as to say that absence of appropriate follow-up is tantamount to not having had a repair at all. A triple-phase (noncontrast, contrast, and delayed) spiral CT scan and a four-view (anteroposterior, lateral, and two obliques) abdominal x-ray should be obtained within the first month. Subsequent imaging can be obtained at 6-month intervals in the first 1 to 2 years and yearly thereafter. After the first 6 months, patients who cannot travel easily may obtain their studies locally and submit them for review. The CT scan is for detection of endoleaks, subtle proximal migrations, and changes in aneurysm size. The abdominal x-ray gives a “birds-eye” view of the overall morphology of the stent graft. Subtle changes in conformation of the iliac limbs relative to each other and/or the spine can provide early signs of impending component separation or loss of fixation. Further, stent fractures and/or suture breaks that can compromise longterm device integrity can sometimes only be detected on a plain film and not on a CT scan. The difference here was largely due to the higher frequency of pulmonary complications seen in the open group. There was a higher incidence of graft-related complications in the endoluminal group. There was no difference in the nonvascular local complication rate among the two groups. The Endovascular Repair-1 (EVAR-1) trial is also a multicenter randomized trial that compared open to endoluminal repair.74 This study was conducted on 1082 patients at 34 centers in the United Kingdom using all available devices. Short-term mortality at 30 days was 4.7% in the open group and 1.7% in the endoluminal group. The in-hospital mortality rate was also increased in the open when compared to the endoluminal group (6.2% vs. 2.1%). As expected, the secondary intervention rate was higher in the endoluminal group (9.8% vs. 5.8%). Complication rates were not reported in the EVAR-1 trial. Criticisms can be applied to both of these trials. Patients had to be eligible for either type of repair in order to be included in the study. Consequently, these findings cannot be generalized to patients who are too sick to undergo open surgery or to patients whose anatomy precludes them from undergoing endovascular repair. The Open Versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study Group randomly assigned 881 patients with asymptomatic AAAs who were candidates for both procedures to either endovascular repair (n = 444) or open repair (n = 437) and followed them for up to 9 years.76 Reduction in perioperative mortality with endovascular repair was sustained at 3 years but not thereafter. There was no difference in primary outcome of all-cause mortality. Endovascular repair and open repair resulted in similar long-term survival. Six aneurysm ruptures were confirmed in the endovascular repair group versus none in the open repair group. Rupture after endovascular repair remains a concern. A significant interaction was observed between age and type of treatment. Endovascular repair led to increased long-term survival among younger patients but not among older patients, for whom a greater benefit from the endovascular approach had been expected. 858 Aneurysm growth and migration rates were divided into three different neck size groups. Patients with a wide neck (>26 mm) had a 3% growth and migration rate. Narrow-neck patients (<26 mm) had a 1% growth rate and a 2% migration neck. Interestingly, short-neck patients (<15 mm) had no aneurysm growths and a 2% migration rate. UNIT II PART SPECIFIC CONSIDERATIONS Cost Analysis. The current climate of cost containment and limited reimbursement for healthcare services mandates a critical analysis of the economic impact of any new medical technology on the market. The in-hospital costs for both endovascular and open repair include graft cost, operating room fees, radiology, pharmacy, ancillary care, intensive care unit charges, and floor charges. Despite the improved morbidity and mortality rates, several early studies have reported no cost benefit with the application of endovascular repair.81,82 The limiting factor appears to be the cost of the device. Despite commercialization of endovascular repair, the device costs are still in the range of $5000 to $6000 with no signs of abating. A recent report by Angle and associated further corroborates previous studies.83 In their review, despite decreased hospital and intensive care unit stays and utilization of pharmacy and respiratory services, cost of endovascular repair was 1.74 times greater than the standard surgical approach. In addition, these cost analysis studies are centered on in-hospital costs and do not even begin to address secondary costs such as postoperative surveillance that is required with endovascular repair. In the OVER trial, endovascular repair was found to be a cost-effective alternative to open repair in the U.S. Veterans Affairs healthcare system for at least the first 2 years.84 The primary outcomes were mean total healthcare cost per life-year and per quality-adjusted lifeyear. There were no differences found in survival, quality of life, and costs after 2 years between the endovascular and the open group. Although graft costs were higher in the endovascular group, length of stay was shorter, resulting in lower cost of AAA repair hospitalization in the endovascular group. Costs remained lower after 2 years in the endovascular group, but the difference was no longer significant. Classification and Management of Endoleak An endoleak is an extravasation of contrast outside the stent graft and within the aneurysm sac (Fig. 23-34). It can be present in up to 20% to 30% of all endovascular AAA repairs in the early postoperative period.85 In general, over half of these endoleaks will resolve spontaneously during the first 6 months, resulting in a 10% incidence of chronic endoleaks in all cases Type I endoleak Type II endoleak Type III endoleak Figure 23-35. A computed tomography scan demonstrating an endoleak (small arrow) as evidenced by contrast flow outside the aortic endograft (long arrow). beyond the first year of follow-up. Endoleaks can be detected using conventional angiography, contrast CT (Fig. 23-35), MRA, and color-flow duplex ultrasound. Although there is no recognized gold standard, in practice, angiography is considered the least sensitive but most specific for characterizing the source of the endoleak, whereas the CT scan is the most sensitive but least specific. Widespread availability and reliability that is relatively independent of technique have made the CT scan the de facto standard imaging modality for postoperative surveillance. Conversely, routine use of duplex ultrasound and MRA has been limited by the lack of proper equipment and local expertise. On the other hand, investigational techniques such as time-resolved MRA may provide greater sensitivity and specificity than either angiography or CT in the future. Four types of endoleaks have been described (Table 23-10). Type I endoleak refers to fixation-related leaks that occur at the proximal or distal attachment sites. These represent less than 5% of all endoleaks and are seen as an early blush of contrast into the aneurysm sac from the proximal or distal ends of the device during completion angiography.85,86 Although seen as marker of poor patient selection or inadequate repair, over 80% of these leaks spontaneously seal in the first 6 months. Persistent type I endoleaks, on the other hand, require prompt treatment. Type II Type IV endoleak VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Figure 23-34. The four types of endoleak include the following: type I endoleak = attachment site leak; type II endoleak = side branch leak caused by lumbar or side branches; type III endoleak = endograft junctional leak due to overlapping device components; and type IV endoleak = endograft fabric or porosity leak. Table 23-10 Endoleak classification Description Type I endoleak Attachment site leak Type II endoleak Side branch leak caused by lumbar or inferior mesenteric arteries Type III endoleak Junctional leak (of overlapping endograft components) and graft fabric defect Type IV endoleak Endograft fabric porosity leak endoleak refers to retrograde flow originating from a lumbar, inferior mesenteric, accessory renal, or hypogastric artery. They are the most common type of endoleak, accounting for 20% to 30% of all cases, and about half resolve spontaneously. On angiography, they are seen as a late filling of the aneurysm sac from a branch vessel(s). Type II endoleaks carry a relatively benign natural history and do not merit intervention unless associated with aneurysm growth. Type III endoleaks refer to failure of device integrity or component separation from modular systems. If detected intraoperatively or in the early perioperative period, it is usually from inadequate overlap between two stent grafts, whereas in the late period, the endoleak may be from a fabric tear or junctional separation from conformational changes of the aneurysm. Regardless of the etiology or timing, these should be promptly repaired. Finally, type IV endoleak refers to the diffuse, early blush seen during completion angiography due to graft porosity and/or suture holes of some Dacron-based devices. It does not have any clinical significance and usually cannot be seen after 48 hours and heparin reversal. Endoleaks that are initially considered type IV but persist become type III endoleaks by definition, because this indicates a more significant material defect than simple porosity or a suture hole. Endotension Following Endovascular Aortic Aneurysm Repair. In approximately 5% of cases after an apparently successful endovascular repair, the aneurysm continues to grow without any demonstrable endoleak.87 This phenomenon has been described as endotension. Although it was initially thought that an endoleak was really present but simply not detected, case have been reported where the aneurysm has been surgically opened and the contents were completely devoid of any blood and no extravasation could be found. The mechanism of continued pressurization of the aneurysm sac following successful exclusion from the arterial circulation remains unsolved at this time. One putative mechanism has been linked to a transudative process related to certain expanded PTFE graft materials.88 More importantly, however, the natural history of these enlarging aneurysms without endoleaks is unknown, but to date, there has been no evidence to suggest that they carry an increased risk of rupture. Conservatively speaking, until further long-term data become available, if the patient is a suitable surgical risk, elective open conversion should be considered. Secondary Interventions Following Endovascular Aortic Aneurysm Repair. There is approximately 10% to 15% per year risk of secondary interventions following endovascular AAA repair.18,78,89 These procedures are critical in the long-term MESENTERIC ARTERY DISEASE Vascular occlusive disease of the mesenteric vessels is a relatively uncommon but potentially devastating condition that generally presents in patients over 60 years of age, is three times more frequent in women, and has been recognized as an entity since 1936.96 The incidence of such a disease is low and represents 2% of the revascularization operations for atheromatous lesions. The most common cause of mesenteric ischemia is atherosclerotic vascular disease. Autopsy studies have demonstrated splanchnic atherosclerosis in 35% to 70% of cases.97 Other etiologies exist and include FMD, panarteritis nodosa, arteritis, and celiac artery compression from a median arcuate ligament, but they are unusual and have an incidence of one in nine compared with that of atherosclerosis. Chronic mesenteric ischemia is related to a lack of blood supply in the splanchnic region and is caused by disease in one or more visceral arteries: the celiac trunk, the superior mesenteric artery, and the IMA. Mesenteric ischemia is thought to occur when two of the three visceral vessels are affected with severe stenosis or occlusion; however, in as many as 9% of cases, only a single vessel is involved (SMA in 5% and celiac trunk in 4% of cases).98 This disease process may evolve in a chronic fashion, as in the case of progressive luminal obliteration due to atherosclerosis. On the other hand, mesenteric ischemia can occur suddenly, as in the case of thromboembolism. Despite recent progress in perioperative management and better understanding of pathophysiology, mesenteric ischemia is considered one of the most catastrophic vascular disorders with mortality rates ranging from 50% to 75%. Delays in diagnosis VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 859 CHAPTER 23 Arterial Disease Classification success of the primary procedure in prevention of aneurysm rupture and aneurysm-related death. These secondary procedures, in order of frequency, include proximal or distal extender placement for migrations, highly selective or translumbar embolization for type II endoleaks, direct surgical or laparoscopic branch vessel ligations, bridging cuffs for component separations, and late open surgical conversions. Multiple large series have reported that an annual rupture rate of approximately 1% to 1.5% per year after endovascular repair.18,78,89 The EUROSTAR registry reports a rupture rate of 2.3% over 15.4 months in patients with an endoleak, compared with 0.3% in those without.90 Various causes of late ruptures have been reported in the literature, although presence of a persistent endoleak with aneurysm enlargement remains a common culprit for this complication. It has been shown that even successfully excluded aneurysms can lead to the development of attachment-site leaks and device failure, caused in part by aneurysm remodeling resulting in stent migration or kinking.91 Mehta and colleagues reported that 63% of delayed AAA ruptures after endovascular repair were caused by type I endoleaks with endograft migration, 11% by type I without migration, 19% by type II, and the rest of unknown type.92 Treatment of rupture may be open conversion or endovascular stent graft placement. May and associates reported a mortality rate of 43% in those patients who underwent open conversion.93 Emergent endovascular repair should be considered in these patients since it is potentially much faster and less likely to cause physiologic stress than open conversion. Several reports have shown that endovascular repair can be performed successfully in patients previously treated with endoluminal prostheses.94,95 860 and treatment are the main contributing factors in its high mortality. It is estimated that mesenteric ischemia accounts for 1 in every 1000 hospital admissions in this country. The prevalence is rising due in part to the increased awareness of this disease, the advanced age of the population, and the significant comorbidity of these elderly patients. Early recognition and prompt treatment before the onset of irreversible intestinal ischemia are essential to improve the outcome. Anatomy and Pathophysiology UNIT II PART SPECIFIC CONSIDERATIONS Mesenteric arterial circulation is remarkable for its rich collateral network. Three main mesenteric arteries provide the arterial perfusion to the gastrointestinal system: the celiac artery (CA), the superior mesenteric artery (SMA), and the IMA. In general, the CA provides arterial circulation to the foregut (distal esophagus to duodenum), hepatobiliary system, and spleen; the SMA supplies the midgut (jejunum to mid-colon); and the IMA supplies the hindgut (mid-colon to rectum). The CA and SMA arise from the ventral surface of the infradiaphragmatic suprarenal abdominal aorta, whereas the IMA originates from the left lateral portion of the infrarenal aorta. These anatomic origins in relation to the aorta are important when a mesenteric angiogram is performed to determine the luminal patency. In order to fully visualize the origins of the CA and SMA, it is necessary to perform both an anteroposterior and a lateral projection of the aorta since most arterial occlusive lesions occur in the proximal segments of these mesenteric trunks. Because of the abundant collateral flow between these mesenteric arteries, progressive diminution of flow in one or even two of the main mesenteric trunks is usually tolerated, provided that uninvolved mesenteric branches can enlarge over time to provide sufficient compensatory collateral flow. In contrast, acute occlusion of a main mesenteric trunk may result in profound ischemia due to lack of sufficient collateral flow. Collateral networks between the CA and the SMA exist primarily through the superior and inferior pancreaticoduodenal arteries. The IMA may provide collateral arterial flow to the SMA through the marginal artery of Drummond, the arc of Riolan, and other unnamed retroperitoneal collateral vessels termed meandering mesenteric arteries (Fig. 23-36). Lastly, collateral visceral vessels may provide important arterial flow to the IMA and the hindgut through the hypogastric arteries and the hemorrhoidal arterial network. Regulation of mesenteric blood flow is largely modulated by both hormonal and neural stimuli, which characteristically regulate systemic blood flow. In addition, the mesenteric circulation responds to the gastrointestinal contents. Hormonal regulation is mediated by splanchnic vasodilators, such as nitric oxide, glucagon, and vasoactive intestinal peptide. Certain intrinsic vasoconstrictors, such as vasopressin, can diminish the mesenteric blood flow. On the other hand, neural regulation is provided by the extensive visceral autonomic innervation. Clinical manifestation of mesenteric ischemia is predominantly postprandial abdominal pain, which signifies that the increased oxygen demand of digestion is not met by the gastrointestinal collateral circulation. The postprandial pain frequently occurs in the mid-abdomen, suggesting that the diversion of blood flow from the SMA to supply the stomach impairs perfusion to the small bowel. This leads to transient anaerobic metabolism and acidosis. Persistent or profound mesenteric ischemia will lead to mucosal compromise with release of intracellular contents and by-products of anaerobic metabolism to Figure 23-36. An aortogram showing a prominent collateral vessel, which is the arc of Riolan (arrow) in a patient with an inferior mesenteric artery (IMA) occlusion. This vessel network provides collateral flow between the superior mesenteric artery and IMA. the splanchnic and systemic circulation. Injured bowel mucosa allows unimpeded influx of toxic substances from the bowel lumen with systemic consequences. If full-thickness necrosis occurs in the bowel wall, intestinal perforation ensues, which will lead to peritonitis. Concomitant atherosclerotic disease in cardiac or systemic circulation frequently compounds the diagnostic and therapeutic complexity of mesenteric ischemia. Types of Mesenteric Artery Occlusive Disease There are three major mechanisms of visceral ischemia involving the mesenteric arteries: (a) acute mesenteric ischemia, which can be either embolic or thrombotic in origin; (b) chronic mesenteric ischemia; and (c) nonocclusive mesenteric ischemia. Despite the variability of these syndromes, a common anatomic pathology is involved in these processes. The superior mesenteric artery (SMA) is the most commonly involved vessel in acute mesenteric ischemia. Acute thrombosis occurs in patients with underlying mesenteric atherosclerosis, which typically involves the origin of the mesenteric arteries while sparing the collateral branches. In acute embolic mesenteric ischemia, the emboli typically originate from a cardiac source and frequently occur in patients with atrial fibrillation or following myocardial infarction (Figs. 23-37 and 23-38). Nonocclusive mesenteric ischemia is characterized by a low flow state in otherwise normal mesenteric arteries and most frequently occurs in critically ill patients on vasopressors. Finally, chronic mesenteric ischemia is a functional consequence of a long-standing atherosclerotic process that typically involves at least two of the three main mesenteric vessels. The gradual development of the occlusive process allows the development of collateral vessels that prevent the manifestations of acute ischemia, but are not sufficient to meet the high postprandial intestinal oxygen requirements, giving rise to the classical symptoms of postprandial abdominal pain and the resultant food fear. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Clinical Manifestations Several less common syndromes of visceral ischemia involving the mesenteric arteries can also cause serious debilitation. Chronic mesenteric ischemic symptoms can occur due to extrinsic compression of the celiac artery by the diaphragm, which is termed median arcuate ligament syndrome or celiac artery compression syndrome. Acute visceral ischemia may occur following an aortic operation, due to ligation of the IMA in the absence of adequate collateral vessels. Furthermore, acute visceral ischemia may develop in aortic dissection, which involves the mesenteric arteries, or after coarctation repair. Finally, other unusual causes of ischemia include mesenteric arteritis, radiation arteritis, and cholesterol emboli. Diagnostic Evaluation Figure 23-38. A lateral mesenteric angiogram showing an abrupt cutoff of the proximal superior mesenteric artery (SMA), which is consistent with SMA embolism (arrow). The differential diagnosis of acute mesenteric ischemia includes other causes of severe abdominal pain of acute onset, such as perforated viscus, intestinal obstruction, pancreatitis, cholecystitis, and nephrolithiasis. Laboratory evaluation is neither sensitive nor specific in distinguishing these various diagnoses. In the setting of mesenteric ischemia, complete blood count may reveal hemoconcentration and leukocytosis. Metabolic acidosis develops as a result of anaerobic metabolism. Elevated serum amylase may indicate a diagnosis of pancreatitis but is also common in the setting of intestinal infarction. Finally, increased lactate levels, hyperkalemia, and azotemia may occur in the late stages of mesenteric ischemia. Plain abdominal radiographs may provide helpful information to exclude other causes of abdominal pain such as intestinal obstruction, perforation, or volvulus, which may exhibit symptoms mimicking intestinal ischemia. Pneumoperitoneum, VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Figure 23-37. An anteroposterior view of a selective superior mesenteric artery angiogram shows an abrupt cutoff of the middle colic artery, which was caused by emboli (arrow) due to atrial fibrillation. Abdominal pain out of proportion to physical findings is the classic presentation in patients with acute mesenteric ischemia and occurs following an embolic or thrombotic ischemic event of the SMA. Other manifestations include sudden onset of abdominal cramps in patients with underlying cardiac or atherosclerotic disease, often associated with bloody diarrhea, as a result of mucosal sloughing secondary to ischemia. Fever, nausea, vomiting, and abdominal distention are some common but nonspecific manifestations. Diffuse abdominal tenderness, rebound, and rigidity are late signs and usually indicate bowel infarction and necrosis. Clinical manifestations of chronic mesenteric ischemia are more subtle due to the extensive collateral development. However, when intestinal blood flow is unable to meet the physiologic gastrointestinal demands, mesenteric insufficiency ensues. The classical symptoms include postprandial abdominal pain, food fear, and weight loss. Persistent nausea and occasionally diarrhea may coexist. Diagnosis remains challenging, and most of the patients will undergo an extensive and expensive gastrointestinal tract workup for the above symptoms prior to referral to a vascular service. The typical patient who develops nonocclusive mesenteric ischemia is an elderly patient who has multiple comorbidities, such as congestive heart failure, acute myocardial infarction with cardiogenic shock, hypovolemic or hemorrhagic shock, sepsis, pancreatitis, and administration of digitalis or vasoconstrictor agents such as epinephrine. Abdominal pain is only present in approximately 70% of these patients. When present, the pain is usually severe but may vary in location, character, and intensity. In the absence of abdominal pain, progressive abdominal distention with acidosis may be an early sign of ischemia and impending bowel infarction. Abdominal pain due to narrowing of the origin of the CA may occur as a result of extrinsic compression or impingement by the median arcuate ligament (Fig. 23-39). This condition is known as celiac artery compression syndrome or median arcuate ligament syndrome. Angiographically, there is CA compression that augments with deep expiration and poststenotic dilatation. The celiac artery compression syndrome has been implicated in some variants of chronic mesenteric ischemia. Most patients are young females between 20 and 40 years of age. Abdominal symptoms are nonspecific, but the pain is localized in the upper abdomen, which may be precipitated by meals. 861 keep in mind that mesenteric ischemia is a rare entity and that a full diagnostic workup that should include CT scan of the abdomen and evaluation by gastroenterologist should be performed. Mesenteric occlusive disease may coexist with malignancy, and symptoms of mesenteric vessel stenosis may be the result of extrinsic compression by a tumor. Duplex ultrasonography is a valuable noninvasive means of assessing the patency of the mesenteric vessels. Moneta and associates evaluated the use of duplex ultrasound in the diagnosis of mesenteric occlusive disease in a blinded prospective study.99,100 A peak systolic velocity in the SMA >275 cm/s demonstrated a sensitivity of 92%, specificity of 96%, and overall accuracy of 96% for detecting >70% stenosis. The same authors found sensitivity and specificity of 87% and 82%, respectively, with an accuracy of 82% in predicting >70% celiac trunk stenosis. Duplex has been successfully used for follow-up after open surgical reconstruction or endovascular treatment of the mesenteric vessels to assess recurrence of the disease. Finally, spiral CT with three-dimensional reconstruction (Fig. 23-40) and MRA (Fig. 23-41) have been promising in providing clear radiographic assessment of the mesenteric vessels. The definitive diagnosis of mesenteric vascular disease is made by biplanar mesenteric arteriography, which should be performed promptly in any patient with suspected mesenteric occlusion. It typically shows occlusion or near-occlusion of the CA and SMA at or near their origins from the aorta. In most 862 UNIT II PART SPECIFIC CONSIDERATIONS Figure 23-39. A lateral projection of the magnetic resonance angiography of the aorta showing a chronic compression of the celiac artery by the median arcuate ligament (arrow). pneumatosis intestinalis, and gas in the portal vein may indicate infarcted bowel. In contrast, radiographic appearance of an adynamic ileus with a gasless abdomen is the most common finding in patients with acute mesenteric ischemia. Upper endoscopy, colonoscopy, or barium radiography does not provide any useful information when evaluating acute mesenteric ischemia. Moreover, barium enema is contraindicated if the diagnosis of mesenteric ischemia is being considered. The intraluminal barium can obscure accurate visualization of mesenteric circulation during angiography. In addition, intraperitoneal leakage of barium can occur in the setting of intestinal perforation, which can lead to added therapeutic challenges during mesenteric revascularization. Diagnosis of chronic mesenteric ischemia can be more challenging. Usually prior to the evaluation by a vascular service, the patients have undergone an extensive workup for the symptoms of chronic abdominal pain, weight loss, and anorexia. Rarely, the vascular surgeon is the first to encounter a patient with the above symptoms. In this situation, it is advisable to Figure 23-40. Computed tomography angiogram of the abdomen with three-dimensional reconstruction provides a clear view of the celiac artery, superior mesenteric artery (SMA), and inferior mesenteric artery (IMA). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ cases, the IMA has been previously occluded secondary to diffuse infrarenal aortic atherosclerosis. The differentiation of the different types of mesenteric arterial occlusion may be suggested with biplanar mesenteric arteriogram. Mesenteric emboli typically lodge at the orifice of the middle colic artery, which creates a “meniscus sign” with an abrupt cutoff of a normal proximal SMA several centimeters from its origin on the aorta. Mesenteric thrombosis, in contrast, occurs at the most proximal SMA, which tapers off at 1 to 2 cm from its origin. In the case of chronic mesenteric occlusion, the appearance of collateral circulation is typically present. Nonocclusive mesenteric ischemia produces an arteriographic image of segmental mesenteric vasospasm with a relatively normal-appearing main SMA trunk (Fig. 23-42). Figure 23-42. Mesenteric arteriogram showing nonocclusive mesenteric ischemia as evidenced by diffuse spasm of intestinal arcades with poor filling of intramural vessels. Surgical Repair Acute Embolic Mesenteric Ischemia. Initial management of patients with acute mesenteric ischemia includes fluid resuscitation and systemic anticoagulation with heparin to prevent further thrombus propagation. Significant metabolic acidosis not responding to fluid resuscitation should be corrected with sodium bicarbonate. A central venous catheter, peripheral arterial catheter, and Foley catheter should be placed for hemodynamic status monitoring. Appropriate antibiotics are given prior to surgical exploration. The operative management of acute mesenteric ischemia is dictated by the cause of the occlusion. It is helpful to obtain a preoperative mesenteric arteriogram to confirm the diagnosis and to plan appropriate treatment options. However, the diagnosis of mesenteric ischemia frequently cannot be established prior to surgical exploration, and therefore, patients in a moribund condition with acute abdominal symptoms should undergo immediate surgical exploration, avoiding the delay required to perform an arteriogram. The primary goal of surgical treatment in embolic mesenteric ischemia is to restore arterial perfusion with removal of the embolus from the vessel. The abdomen is explored through a midline incision, which often reveals variable degrees of intestinal ischemia from the mid-jejunum to the ascending or transverse colon. The transverse colon is lifted superiorly, and the small intestine is reflected toward the right upper quadrant. The SMA is approached at the root of the small bowel mesentery, usually as it emerges from beneath the pancreas to cross over the junction of the third and fourth portions of the duodenum. Alternatively, the SMA can be approached by incising the retroperitoneum lateral to the fourth portion of the duodenum, which is rotated medially to expose the SMA. Once the proximal SMA is identified and controlled with vascular clamps, a transverse arteriotomy is made to extract the embolus, using standard balloon embolectomy catheters. In the event the embolus has lodged more distally, exposure of the distal SMA may be obtained in the root of the small bowel mesentery by isolating individual jejunal and ileal branches to allow a more comprehensive thromboembolectomy. Following the restoration of SMA flow, an assessment of intestinal viability must be VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 863 CHAPTER 23 Arterial Disease Figure 23-41. A cross-sectional view of a magnetic resonance angiogram provides a clear view of the luminal patency of the superior mesenteric artery. Mesenteric arteriography can also play a therapeutic role. Once the diagnosis of nonocclusive mesenteric ischemia is made on the arteriogram, an infusion catheter can be placed at the SMA orifice, and vasodilating agents, such as papaverine, can be administered intra-arterially. The papaverine infusion may be continued postoperatively to treat persistent vasospasm, a common occurrence following mesenteric reperfusion. Transcatheter thrombolytic therapy has little role in the management of thrombotic mesenteric occlusion. Although thrombolytic agents may transiently recannulate the occluded vessels, the underlying occlusive lesions require definitive treatment. Furthermore, thrombolytic therapy typically requires a prolonged period of time to restore perfusion, during which the intestinal viability will be difficult to assess. A word of caution would be appropriate here regarding patients with typical history of chronic intestinal angina who present with an acute abdomen and classical findings of peritoneal irritation. Arteriography is the gold standard for the diagnosis of mesenteric occlusive disease; however, it can be a time-consuming diagnostic modality. In this group of patients, immediate exploration for assessment of intestinal viability and vascular reconstruction is the best choice. 864 made, and nonviable bowel must be resected. Several methods have been described to evaluate the viability of the intestine, which include intraoperative intravenous fluorescein injection and inspection with a Wood’s lamp, and Doppler assessment of antimesenteric intestinal arterial pulsations. A second-look procedure should be considered in many patients and is performed 24 to 48 hours following embolectomy. The goal of the procedure is reassessment of the extent of bowel viability, which may not be obvious immediately following the initial embolectomy. If nonviable intestine is evident in the second-look procedure, additional bowel resections should be performed at that time. UNIT II PART Acute Thrombotic Mesenteric Ischemia. Thrombotic mes- SPECIFIC CONSIDERATIONS enteric ischemia usually involves a severely atherosclerotic vessel, typically the proximal CA and SMA. Therefore, these patients require a reconstructive procedure to the SMA to bypass the proximal occlusive lesion and restore adequate mesenteric flow. The saphenous vein is the graft material of choice, and prosthetic materials should be avoided in patients with nonviable bowel, due to the risk of bacterial contamination if resection of necrotic intestine is performed. The bypass graft may originate from either the aorta or iliac artery. Advantages from using the supraceliac infradiaphragmatic aorta as opposed to the infrarenal aorta as the inflow vessel include a smoother graft configuration with less chance of kinking and the absence of atherosclerotic disease in the supraceliac aortic segment. Exposure of the supraceliac aorta is technically more challenging and time consuming than that of the iliac artery, which unless calcified is an appropriate inflow. Patency rates are similar regardless of inflow vessel choice.101 Chronic Mesenteric Ischemia. The therapeutic goal in patients with chronic mesenteric ischemia is to revascularize mesenteric circulation and prevent the development of bowel infarction. Mesenteric occlusive disease can be treated successfully by either transaortic endarterectomy or mesenteric artery bypass. Transaortic endarterectomy is indicated for 3 ostial lesions of patent CA and SMA. A left medial rotation is performed, and the aorta and the mesenteric branches are exposed. A lateral aortotomy is performed encompassing both the CA and SMA orifices. The visceral arteries must be adequately mobilized so that the termination site of endarterectomy can be visualized. Otherwise, an intimal flap may develop, which can lead to early thrombosis or distal embolization. For occlusive lesions located 1 to 2 cm distal to the mesenteric origin, mesenteric artery bypass should be performed. Multiple mesenteric arteries are typically involved in chronic mesenteric ischemia, and both the CA and SMA should be revascularized whenever possible. In general, bypass grafting may be performed either antegrade from the supraceliac aorta or retrograde from either the infrarenal aorta or iliac artery. Both autogenous saphenous vein grafts and prosthetic grafts have been used with satisfactory and equivalent success. An antegrade bypass also can be performed using a small-caliber bifurcated graft from the supraceliac aorta to both the CA and SMA, which yields an excellent long-term result.101 Celiac Artery Compression Syndrome. The decision to intervene in patients with CA compression syndrome should be based on both an appropriate symptom complex and the finding of celiac artery compression in the absence of other findings to explain the symptoms. The treatment goal is to release the ligamentous structure that compresses the proximal CA and to correct any persistent stricture by bypass grafting. Some surgeons advocate careful celiac plexus sympathectomy in addition to arcuate ligament decompression to ensure good treatment outcome.102 The patient should be cautioned that relief of the celiac compression cannot be guaranteed to relieve the symptoms. In a number of reports on endovascular management of chronic mesenteric ischemia, the presence of CA compression syndrome has been identified as a major factor of technical failure and recurrence. Therefore, angioplasty and stenting should not be undertaken if extrinsic compression of the CA by the median arcuate ligament is suspected based on preoperative imaging studies. Open surgical treatment should be performed instead.103,104 A recent review of laparoscopic and open median arcuate ligament release cases in the literature by Jimenez and colleagues showed both approaches to be effective in symptom relief (85%), with no difference in late symptom recurrence rate (6.8% in the open group and 5.7% in the laparoscopic group).105 Endovascular Treatment Chronic Mesenteric Ischemia. Endovascular treatment of mesenteric artery stenosis or short segment occlusion by balloon dilatation or stent placement represents a less invasive therapeutic alternative to open surgical intervention, particularly in patients whose medical comorbidities place them at a high operative risk category. Endovascular therapy is also suited in patients with recurrent disease or anastomotic stenosis following previous open mesenteric revascularization. Prophylactic mesenteric revascularization is rarely performed in the asymptomatic patient undergoing an aortic procedure for other indications.106 However, the natural history of untreated chronic mesenteric ischemia may justify revascularization in some minimally symptomatic or asymptomatic patients if the operative risks are acceptable, since the first clinical presentation may be acute intestinal ischemia in as many as 50% of the patients, with a mortality rate that ranges from 15% to 70%.106 This is particularly true when the SMA is involved. Mesenteric angioplasty and stenting is particularly suitable for this patient subgroup given its low morbidity and mortality. Because of the limited experience with stent use in mesenteric vessels, appropriate indications for primary stent placement have not been clearly defined. Guidelines generally include calcified ostial stenoses, high-grade eccentric stenoses, chronic occlusions, and significant residual stenosis >30% or the presence of dissection after angioplasty. Restenosis after PTA is also an indication for stent placement.107 Acute Mesenteric Ischemia. Catheter-directed thrombolytic therapy is a potentially useful treatment modality for acute mesenteric ischemia, which can be initiated with intra-arterial delivery of thrombolytic agent into the mesenteric thrombus at the time of diagnostic angiography. Various thrombolytic medications, including urokinase (Abbokinase; Abbott Laboratory, North Chicago, IL) or recombinant tissue plasminogen activator (Activase; Genentech, South San Francisco, CA), have been reported to be successful in a small series of case reports. Catheter-directed thrombolytic therapy has a higher probability of restoring mesenteric blood flow success when performed within 12 hours of symptom onset. Successful resolution of a mesenteric thrombus will facilitate the identification of the underlying mesenteric occlusive disease process. As a result, subsequent operative mesenteric revascularization or mesenteric balloon angioplasty and stenting may be performed VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Nonocclusive Mesenteric Ischemia. The treatment of nonocclusive mesenteric ischemia is primarily pharmacologic with selective mesenteric arterial catheterization followed by infusion of vasodilatory agents, such as tolazoline or papaverine. Once the diagnosis is made on the mesenteric arteriography (see Fig. 23-42), intra-arterial papaverine is given at a dose of 30 to 60 mg/h. This must be coupled with the cessation of other vasoconstricting agents. Concomitant intravenous heparin should be administered to prevent thrombosis in the cannulated vessels. Treatment strategy thereafter is dependent on the patient’s clinical response to the vasodilator therapy. If abdominal symptoms improve, mesenteric arteriography should be repeated to document the resolution of vasospasm. The patient’s hemodynamic status must be carefully monitored during papaverine infusion as significant hypotension can develop in the event that the infusion catheter migrates into the aorta, which can lead to systemic circulation of papaverine. Surgical exploration is indicated if the patient develops signs of continued bowel ischemia or infarction as evidenced by rebound tenderness or involuntary guarding. In these circumstances, papaverine infusion should be continued intraoperatively and postoperatively. The operating room should be kept as warm as possible, and warm irrigation fluid and laparotomy pads should be used to prevent further intestinal vasoconstriction during exploration. Techniques of Endovascular Interventions. To perform endovascular mesenteric revascularization, intraluminal access is performed via a femoral or brachial artery approach. Once an introducer sheath is placed in the femoral artery, an anteroposterior and lateral aortogram just below the level of the diaphragm is obtained with a pigtail catheter to identify the origin of the CA and SMA. Initial catheterization of the mesenteric artery can be performed using a variety of selective angled catheters, which include the RDC, Cobra-2, Simmons I (Boston Scientific/Meditech, Natick, MA), or SOS Omni catheter (Angiodynamics, Queensbury, NY). Once the mesenteric artery is cannulated, systemic heparin (5000 IU) is administered intravenously. A selective mesenteric angiogram is then performed to identify the diseased segment, which is followed by the placement of a 0.035-inch or less traumatic 0.014- to 0.018-inch guidewire to cross the stenotic lesion. Once the guidewire is placed across the stenosis, the catheter is carefully advanced over the guidewire across the lesion. In the event that the mesenteric artery is severely angulated as it arises from the aorta, a second stiffer guidewire (Amplatz or Rosen Guidewire, Boston Scientific) may be exchanged through the catheter to facilitate the placement of a 6-French guiding sheath (Pinnacle, Boston Scientific). With the image intensifier angled in a lateral position to fully visualize the proximal mesenteric segment, a balloon angioplasty is advanced over the guidewire through the guiding sheath and positioned across the stenosis. The balloon diameter should be chosen based on the vessel size of the adjacent normal mesenteric vessel. Once balloon angioplasty is completed, a postangioplasty angiogram is necessary to document the procedural result. Radiographic evidence of either residual stenosis or mesenteric artery dissection constitutes suboptimal angioplasty results that warrants mesenteric stent placement. Moreover, atherosclerotic involvement of the proximal mesenteric artery or vessel orifice should be treated with balloon-expandable stent placement. These stents can be placed over a low-profile 0.014or 0.018-inch guidewire system. It is preferable to deliver the balloon-mounted stent through a guiding sheath, which is positioned just proximal to the mesenteric orifice while the balloonmounted stent is advanced across the stenosis. The stent is next deployed by expanding the angioplasty balloon to its designated inflation pressure. The balloon is then deflated and carefully withdrawn through the guiding sheath. Completion angiogram is performed by hand injecting a small volume of contrast though the guiding sheath. It is critical to maintain the guidewire access until satisfactory completion angiogram is obtained. If the completion angiogram reveals suboptimal radiographic results, such as residual stenosis or dissection, additional catheter-based intervention can be performed through the same guidewire. These interventions may include repeat balloon angioplasty for residual stenosis or additional stent placement for mesenteric artery dissection. During the procedure, intra-arterial infusion of papaverine or nitroglycerine can be used to decrease vasospasm. Administration of antiplatelet agents is also recommended for at least 6 months or even indefinitely if other risk factors of cardiovascular disease are present. Complications of Endovascular Treatment. Complications are not common and rarely become life threatening. These include access site thrombosis, hematomas, and infection. Dissection can occur during PTA and is managed with placement of a stent. Balloon-mounted stents are preferred over the selfexpanding ones because of the higher radial force and the more precise placement. Distal embolization has also been reported, but it never resulted in acute intestinal ischemia, likely due to the rich network of collaterals already developed.108 Clinical Results of Interventions for Mesenteric Ischemia The first successful percutaneous angioplasty of the SMA was reported in 1980.109 Since 1995, multiple series and scattered case reports have reported results from endovascular management of mesenteric occlusive disease.101,108 A literature review by AbuRahma and colleagues in 2003 showed that endovascular intervention had an overall technical success rate of 91%, early and late pain relief rates of 84% and 71%, respectively, and 30-day morbidity and mortality rates of 16.4% and 4.3%, respectively. The average patency was 63% during an average 26-month follow-up.108 In our review of the literature from published series since 1995, restenosis developed in 22% of patients during 24.5 months of average follow-up.101 The long-term clinical relief without reintervention was 82%. Among the patients who experienced a technical failure, 15 were ultimately diagnosed VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 865 CHAPTER 23 Arterial Disease electively to correct the mesenteric stenosis. There are two main drawbacks with regard to thrombolytic therapy in mesenteric ischemia. Percutaneous catheter-directed thrombolysis does not allow the possibility to inspect the potentially ischemic intestine following restoration of the mesenteric flow. Additionally, a prolonged period of time may be necessary in order to achieve successful catheter-directed thrombolysis, due in part to serial angiographic surveillance to document thrombus resolution. An incomplete or unsuccessful thrombolysis may lead to delayed operative revascularization, which may further necessitate bowel resection for irreversible intestinal necrosis. Therefore, catheter-directed thrombolytic therapy for acute mesenteric ischemia should only be considered in selected patients under a closely scrutinized clinical protocol. 866 UNIT II PART SPECIFIC CONSIDERATIONS with median arcuate ligament syndrome and underwent successful surgical treatment, an observation that emphasizes the need for careful patient selection. Interestingly, the addition of selective stenting after PTA that was started in 1998, while it slightly increases the technical success rate, is not correlated with any substantial overall clinical benefit or improved longterm patency rates. In contrast to endovascular treatment, open surgical techniques have achieved an immediate clinical success rate that approaches 100%, a surgical mortality rate of 0% to 17%, and an operative morbidity rate that ranges from 19% to 54% in a number of different series.101,104,106 AbuRahma and colleagues reported their experience of endovascular interventions of 22 patients with symptomatic mesenteric ischemia due to either SMA or CA stenosis.108 They noted an excellent initial technical and clinical success rates, which were 96% (23 of 24 patients) and 95% (21 of 22 patients), respectively, with no perioperative mortality or major morbidity. During a mean follow-up of 26 months (range, 1–54 months), the primary late clinical success rate was 61%, and freedom from recurrent stenosis was 30%. The freedom from recurrent stenosis rates at 1, 2, 3, and 4 years were 65%, 47%, 39%, and 13%, respectively. The authors concluded that mesenteric stenting, which provides excellent early results, is associated with a relative high incidence of late restenosis.108 Several studies have attempted to compare the endovascular with the standard open surgical approach.110,111 The results of the open surgery appear to be more durable, but it tends to be associated with higher morbidity and mortality rates and an overall longer hospital stay. In one study that compared the clinical outcome of open revascularization with percutaneous stenting for patients with chronic mesenteric ischemia, 28 patients underwent endovascular treatment and 85 patients underwent open mesenteric bypass grafting.111 With both patient cohorts having similar baseline comorbidities and symptom duration, there was no difference in early in-hospital complication or mortality rates. Moreover, both groups had similar 3-year cumulative recurrent stenosis and mortality rates. However, patients treated with mesenteric stenting had a significantly higher incidence of recurrent symptoms. The authors concluded that operative mesenteric revascularization should be offered to patients with low surgical risk.111 Based on the above results one could argue that mesenteric angioplasty and stenting demonstrate an inferior technical and clinical success rate. Long-term patency rates appear to also be superior with the open technique. There is a general consensus, however, that the endovascular approach is associated with lower morbidity and mortality rates and is therefore more suitable for high-risk patients. One should also keep in mind that practices representing standard of care for stent placement today were absent in the early era of endovascular experience. These include perioperative heparinization and short-term antiplatelet therapy, use of stents with higher radial force, routine use of postoperative surveillance with arterial duplex and early reintervention to prevent a high-grade stenosis from progressing to occlusion, and placement of drug-eluting stents. One such example is a recent nonrandomized study to compare the outcomes of mesenteric angioplasty using covered stents or bare metal stents in patients undergoing primary or reintervention for chronic mesenteric ischemia. The study showed that covered stents are associated with less restenosis (18% vs. 47%), symptom recurrence (18% vs. 50%), and reintervention (9% vs. 44%) at 24 months and better primary patency at 3 years (92% vs. 52%) than bare metal stents in the primary intervention group.112 Similar results were found in the reintervention group as well. RENAL ARTERY DISEASE Obstructive lesions of the renal artery can produce hypertension, resulting in a condition known as renovascular hypertension, which is the most common form of hypertension amenable to therapeutic intervention, and affects 5% to 10% of all hypertensive patients in the United States.113 Patients with renovascular hypertension are at an increased risk for irreversible end-organ dysfunction, including permanent kidney damage, if inadequate pharmacologic therapies are used to control the blood pressure. The majority of patients with renal artery obstructive disease have vascular lesions of either atherosclerotic disease or fibrodysplasia involving the renal arteries. The proximal portion of the renal artery represents the most common location for the development of atherosclerotic disease. It is well established that renal artery intervention, either by surgical or endovascular revascularization, provides an effective treatment for controlling renovascular hypertension as well as preserving renal function. The decision for intervention is complex and needs to consider a variety of anatomic, physiologic, and clinical features, unique for the individual patient. Etiology Approximately 80% of all renal artery occlusive lesions are caused by atherosclerosis, which typically involves a short segment of the renal artery ostia and represents spillover disease from a severely atheromatous aorta (Fig. 23-43).114 Atherosclerotic lesions are bilateral in two thirds of patients. Individuals with this disease commonly present during the sixth decade of life. Men are affected twice as frequently as women. Atherosclerotic lesions in other territories such as the coronary, mesenteric, cerebrovascular, and peripheral arterial circulation are common. When a unilateral lesion is present, the disease process equally affects the right and left renal arteries.115 The second most common cause of renal artery stenosis is FMD, which accounts for 20% of cases and is most frequently encountered in young, often multiparous women.116 FMD of Figure 23-43. Occlusive disease of the renal artery typically involves the renal ostium (arrow) as a spillover plaque extension from aortic atherosclerosis. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ the renal artery represents a heterogeneous group of lesions that can produce histopathologic changes in the intima, media, or adventitia. The most common variety consists of medial fibroplasia, in which thickened fibromuscular ridges alternate with attenuated media producing the classic angiographic “string of beads” appearance (Figs. 23-44 and 23-45). The cause of medial fibroplasia remains unclear. Most common theories involve a modification of arterial smooth muscle cells in response to Figure 23-45. Magnetic resonance angiography of the abdominal aorta reveals the presence of a left renal artery fibromuscular dysplasia (arrows). 867 Clinical Manifestations CHAPTER 23 Arterial Disease Figure 23-44. Abdominal aortogram reveals a left renal artery fibromuscular dysplasia (arrows) with a characteristic “string of beads” appearance. estrogenic stimuli during the reproductive years, unusual traction forces on affected vessels, and mural ischemia from impairment of vasa vasorum blood flow.116 Fibromuscular hyperplasia usually affects the distal two thirds of the main renal artery, and the right renal artery is affected more frequently than the left. Other less common causes of renal artery stenosis include renal artery aneurysm (compressing the adjacent normal renal artery), arteriovenous malformations, neurofibromatosis, renal artery dissections, renal artery trauma, Takayasu’s arteritis, and renal arteriovenous fistula. Renovascular hypertension is the most common sequela of renal artery occlusive disease. Its prevalence varies from 2% in patients with diastolic blood pressure greater than 100 mmHg to almost 30% in those with diastolic blood pressure over 125 mmHg.114 Clinical features that may indicate the presence of renovascular hypertension include the following: (a) systolic and diastolic upper abdominal bruits; (b) diastolic hypertension of greater than 115 mmHg; (c) rapid onset of hypertension after the age of 50 years; (d) a sudden worsening of mild to moderate essential hypertension; (e) hypertension that is difficult to control with three or more antihypertensives; (f) development of renal insufficiency after angiotensin-converting enzyme inhibitors; and (g) development of hypertension during childhood. All patients with significant hypertension, especially elevated diastolic blood pressure, must be considered as suspect for renovascular disease. Young adults with hypertension have a great deal to gain by avoiding lifelong treatment if renovascular hypertension is diagnosed and corrected. Appropriate diagnostic studies and intervention must be timely instituted to detect the possibility of renovascular hypertension in patients with primary hypertension who present for clinical evaluation. Diagnostic Evaluation The diagnostic requisites for renovascular hypertension include both hypertension and renal artery stenosis. Impairment of the renal function may coexist, although the occurrence of renal insufficiency prior to the development of hypertension is uncommon. Nearly all diagnostic studies for renovascular hypertension evaluate either the anatomic stenosis or renal parenchymal dysfunction attributed to the stenosis. The following section provides an overview of the strengths and limitations of the most common tests used in the diagnostic evaluation of the patient with suspected renovascular hypertension prior to intervention. Captopril renal scanning is a functional study that assesses renal perfusion before and after administration of the angiotensinconverting enzyme inhibitor captopril. Captopril inhibits the secretion of angiotensin II. Through this mechanism, it reduces the efferent arteriole vasoconstriction and, as a result, the glomerular filtration rate (GFR). The test consists of a baseline renal scan and a second renal scan after captopril administration. A positive result indicates that captopril administration (a) increases the time to peak activity to more than 11 minutes or (b) the GFR ratio between sides increases to greater than 1.5:1 compared to a normal baseline scan. Significant parenchymal disease limits the reliability of this study. Renal artery duplex ultrasonography is a noninvasive test of assessing renal artery stenosis both by visualization of the vessel and measurement of the effect of stenosis on blood flow velocity and waveforms. The presence of a severe renal artery stenosis correlates with peak systolic velocities of greater than VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 868 Table 23-11 Renal duplex diagnostic criteria UNIT II PART Renal Artery Diameter Reduction Renal Artery PSV RAR Normal <180 cm/s <3.5 <60% ≥180 cm/s <3.5 ≥60% ≥180 cm/s ≥3.5 Occlusion No signal No signal PSV = peak systolic velocity; RAR = renal-to-aortic ratio. SPECIFIC CONSIDERATIONS 180 cm/s and the ratio of these velocities to those in the aorta of greater than 3.5 (Table 23-11). Renal artery duplex is a technically demanding exam, requiring a substantial amount of operator expertise. In addition, the presence of bowel gas and obesity make the exam difficult to perform and interpret. However, in experienced hands and with appropriate patient selection, it can be a high-yield exam and is typically the initial screening test for patients with suspected renal artery occlusive disease. Selective catheterization of the renal vein via a femoral vein approach for assessing renin activity is a more invasive test of detecting the physiologic sequelae of renal artery stenosis. If unilateral disease is present, the affected kidney should secrete high levels of renin while the contralateral kidney should have low renin production. A ratio between the two kidneys, or the renal vein renin ratio (RVRR), of greater than 1.5 is indicative of functionally important renovascular hypertension, and it also predicts a favorable response from renovascular revascularization. Since this study assesses the ratio between the two kidneys, it is not useful in patients with bilateral disease because both kidneys may secrete abnormally elevated renin levels. The renal:systemic renin index (RSRI) is calculated by subtracting systemic renin activity from individual renal vein renin activity and dividing the remainder by systemic renin activity. This value represents the contribution of each kidney to renin production. In the absence of renal artery stenosis, the renal vein renin activity from each kidney is typically 24% or 0.24 higher than the systemic level. As the result, the total of both kidneys’ renin activity is usually 48% greater than the systemic activity, a value that represents a steady state of renal renin activity. The RSRI of the affected kidney in patients with renovascular hypertension is greater than 0.24. In the case of unilateral renal artery stenosis with normal contralateral kidney, the increase in ipsilateral renin release is normally balanced by suppression of the contralateral kidney renin production, which results in a drop in its RSRI to less than 0.24. Bilateral renal artery disease may negate the contralateral compensatory response, and the autonomous release of renin from both diseased kidneys may result in the sum of the individual RSRIs to be considerably greater than 0.48. The prognostic value of RSRI remains limited in that approximately 10% of patients with favorable clinical response following renovascular revascularization do not exhibit contralateral renin suppression. As a result, the use of RSRI must be applied with caution in the management of patients with renovascular hypertension. MRA with intravenous gadolinium contrast enhancement has been increasingly used for renal artery imaging because of its ability to provide high-resolution images (Figs. 23-46 and 23-47) Figure 23-46. Magnetic resonance angiography of the abdominal aorta reveals bilateral normal renal arteries. while using a minimally nephrotoxic agent. Flow void may be inaccurately interpreted as occlusion or stenosis in MRA. Therefore, unless the quality of the image analysis software is superior, MRA should be interpreted with caution and used in conjunction with other modalities prior to making plans for operative or endovascular treatment. Figure 23-47. Magnetic resonance angiography of the abdominal aorta reveals bilateral ostial renal artery stenosis (arrows). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ DSA remains the gold standard to assess renal artery occlusive disease. A flush aortogram is performed first so that any accessory renal arteries can be detected and the origins of all the renal arteries are adequately displayed. The presence of collateral vessels circumventing a renal artery stenosis strongly supports the hemodynamic importance of the stenosis. A pressure gradient of 10 mmHg or greater is necessary for collateral vessel development, which is also associated with activation of the renin-angiotensin cascade. The therapeutic goals in patients with renovascular disease include: (a) improved blood pressure control, in order to prevent end-organ damage on systems such as the cerebral, coronary, pulmonary, and peripheral circulations; and (b) preservation and possibly improvement of the renal function (Table 23-12). The indications for endovascular treatment for renal artery occlusive disease include 70% or greater stenosis of one or both renal arteries and at least one of the following clinical criteria: • • • • Inability to adequately control hypertension despite appropriate antihypertensive regimen. Chronic renal insufficiency related to bilateral renal artery occlusive disease or stenosis to a solitary functioning kidney. Dialysis-dependent renal failure in a patient with renal artery stenosis but without another definite cause of endstage renal disease. Recurrent congestive heart failure or flash pulmonary edema not attributable to active coronary ischemia. Prior to 1990, the most common treatment modality in patients with renal artery occlusive disease is surgical revascularization, with either renal artery bypass grafting or renal artery endarterectomy. The advancement of endovascular therapy in the past decade has led to various minimally invasive treatment Table 23-12 Indications for renal artery revascularization Angiography Criteria • Documented renal artery stenosis (>70% diameter reduction) • Fibromuscular dysplasia lesion • Pressure gradient >20 mmHg • Affected/unaffected kidney renin ratio >1.5 to 1 Clinical Criteria • Refractory or rapidly progressive hypertension • Hypertension associated with flash pulmonary edema without coronary artery disease • Rapidly progressive deterioration in renal function • Intolerance to antihypertensive medications • Chronic renal insufficiency related to bilateral renal artery occlusive disease or stenosis to a solitary functioning kidney • Dialysis-dependent renal failure in a patient with renal artery stenosis but without another definite cause of endstage renal disease • Recurrent congestive heart failure or flash pulmonary edema not attributable to active coronary ischemia 869 Surgical Reconstruction The typical approach for surgical renal artery revascularization involves a midline xiphoid-to-pubis incision. The posterior peritoneum is incised, and the duodenum is mobilized to the right, starting at the ligament of Treitz. The left renal hilum can be exposed by extending the retroperitoneal dissection to the left along the avascular plane along the inferior border of the pancreas. Mobilization of the left renal vein is essential in these cases and can be achieved by dividing the gonadal, iliolumbar, and adrenal veins. The proximal portion of the right renal artery can be exposed through the base of the mesentery by retraction of the left renal vein cephalad and the vena cava to the right. Accessing the most distal portion of the right renal artery requires a Kocher maneuver and duodenal mobilization. Another approach useful for treating bilateral renal artery lesions involves mobilization of the entire small bowel and the right colon, with a dissection that starts at the ligament of Treitz and proceeds toward the cecum and then along the line of Todd in the right paracolic gutter. Simultaneous dissection along the inferior border of the pancreas provides additional visualization of the left renal artery. Finally, division of the diaphragmatic crura that encircle the suprarenal aorta may sometimes be necessary to achieve suprarenal clamping. Types of Surgical Reconstruction. Aortorenal bypass is the most frequently performed reconstruction of ostial occlusive renal artery disease. After proximal and distal control is obtained, an elliptical segment of the aorta is excised, and the proximal anastomosis is performed in end-to-side fashion. Autologous vein is the preferred conduit. If the vein is not suitable, then prosthetic material can be used. An end-to-end anastomosis is then performed between the conduit of choice and the renal artery using either a 6-0 or 7-0 polypropylene suture. The length of the arteriotomy needs to be at least three times the diameter of the renal artery to prevent anastomotic restenosis. In the event that the surgeon plans to perform a side-to-side anastomosis between the conduit and the renal artery, this is performed first, and the aortic anastomosis follows. Endarterectomy, either transrenal or transaortic, is an alternative to bypass for short ostial lesions or in patients with multiple renal arteries. The transrenal endarterectomy is performed with a transverse longitudinal incision on the aorta that extends into the diseased renal artery. After plaque removal, the arteriotomy is closed with a prosthetic patch. Transaortic endarterectomy is well suited for patients with multiple renal arteries and short ostial lesions. The aorta is opened longitudinally and aortic sleeve endarterectomy is performed, followed by eversion endarterectomy of the renal arteries. Adequate mobilization of the renal arteries is essential for a safe and complete endarterectomy. Hepatorenal and splenorenal bypass are alternative options of revascularization for patients who might not tolerate aortic clamping or for those with calcified aorta that precludes adequate control. For hepatorenal bypass, a right subcostal incision is used, and the hepatic artery is exposed with an incision in the lesser omentum. A Kocher maneuver is performed, the right renal vein is identified and mobilized, and the right renal artery is identified and controlled posteriorly to the vein. Greater saphenous vein is the conduit of choice. The anastomosis is performed end-to-side with the common hepatic artery, and endto-end with the renal artery anterior to the inferior vena cava. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Treatment Indications strategies such as renal artery balloon angioplasty or stenting to control hypertension or to preserve renal function. 870 The splenorenal bypass is performed via a left subcostal incision. The splenic artery is mobilized from the lesser sac, brought through a retropancreatic plane, and anastomosed end-to-end to the renal artery. Reimplantation of the renal artery is an attractive option of reconstruction in children or in adults with ostial lesions. A redundant renal artery is a prerequisite for the procedure. After mobilization, the artery is transected and spatulated, eversion endarterectomy is performed if necessary, and an end-to-side anastomosis with the aorta is created. UNIT II PART Clinical Results of Surgical Repair SPECIFIC CONSIDERATIONS Results reflect the need for performance of renal artery bypass in high-volume and experienced centers. In a review from a large tertiary center, 92% of the patients with nonatherosclerotic vascular disease had improvement in hypertension, but only 43% were completely cured and taken off antihypertensives.117 Patients younger than age 45 fair better, with a cure rate of 68% and improvement rate of 32%. In patients with atherosclerotic renal artery disease, the cure rate was even smaller (12%), and the overall response to hypertension rate was 85%. The operative mortality rates were 3.1% and 0% in the atherosclerotic and nonatherosclerotic groups, respectively. Renal function improvement occurs within the first week of the operation in approximately two thirds of patients. A progressive decrease in the GFR is seen after this initial improvement, but the rate of decrease is less compared with patients who did not respond at all to operative intervention. Up to three quarters of patients were permanently removed from dialysis in a large series.118 Favorable response of renal function to revascularization improves overall survival. Endovascular Treatment Endovascular treatment of renal artery occlusive disease was first introduced by Grüntzig who successfully dilated a renal artery stenosis using a balloon catheter technique. This technique requires passage of a guidewire under fluoroscopic control typically from a femoral artery approach to across the stenosis in the renal artery. A balloon dilating catheter is passed over the guidewire and positioned within the area of stenosis and inflated to produce a controlled disruption of the arterial wall. Alternatively, a balloon-mounted expandable stent can be used to primarily dilate the renal artery stenosis. Completion angiography is usually performed to assess the immediate results. The technical aspect of an endovascular renal artery revascularization is discussed below. Techniques of Renal Artery Angioplasty and Stenting. Access to the renal artery for endovascular intervention is typically performed via a femoral artery approach, although a brachial artery approach can be considered in the event of severe aortoiliac occlusive disease, aortoiliac aneurysm, or severe caudal renal artery angulation. Once an introducer sheath is placed in the femoral artery, an aortogram is performed with a pigtail catheter placed in the suprarenal aorta. Additional oblique views are frequently necessary to more precisely visualize the orifice of the stenosed renal artery and thoroughly assess the presence of accessory renal arteries. Noniodinated contrast agents, such as carbon dioxide and gadolinium, can be used in endovascular renal intervention in patients with renal dysfunction or history of allergic reaction. After systemic heparinization, catheterization of the renal artery can be performed using a variety of selective angled catheters, including the RDC, Cobra-2, Simmons I, or SOS Omni catheter. A selective renal angiogram is then performed to confirm position, and the lesion is crossed with either 0.035inch or a 0.018- to 0.014-inch guidewires. It is important to maintain the distal wire position without movement in the tertiary renal branches during guiding sheath placement to reduce the possibility of parenchymal perforation and spasm. A guiding sheath or a guiding catheter is then advanced at the orifice of the renal artery and provides a secure access for balloon and stent deployment. Balloon angioplasty is performed with a balloon sized to the diameter of the normal renal artery adjacent to the stenosis. Choosing a balloon with diameter 4 mm is a reasonable first choice. The luminal diameter of the renal artery can be further assessed by comparing it to the fully inflated balloon. Such a comparison may provide a reference guide to determine whether renal artery dilatation with a larger diameter angioplasty balloon is necessary. Once balloon angioplasty of the renal artery is completed, an angiogram is performed to document the procedural result. Radiographic evidence of either residual stenosis or renal artery dissection constitutes suboptimal angioplasty results, which warrants an immediate renal artery stent placement. Moreover, atherosclerotic involvement of the very proximal renal artery that involves the vessel orifice typically requires stent placement. A balloon-expandable stent is typically used and is positioned in such a way that it protrudes into the aorta by 1 to 2 mm. The size of the stent is determined by the size of the renal artery, taking into account a desirable 10% to 20% oversizing. After the stent deployment, the angiogram is repeated, and upon a satisfactory result, the devices are withdrawn. It is critical to maintain the guidewire access across the renal lesion until satisfactory completion angiogram is obtained. Spasm of the branches of the renal artery will usually respond to nitroglycerin 100 to 200 μg administered through the guiding sheath directly into the renal artery. While endovascular therapy of renal artery occlusive disease is considerably less invasive than conventional renal artery bypass operation, complications relating to this treatment modality can occur. In a study in which Guzman and colleagues compared the complications following renal artery angioplasty and surgical revascularization, the authors noted that major complication rates following endovascular and surgical treatment were 17%, and 31 %, respectively.119 In contrast, significantly greater minor complications were associated with the endovascular cohort, with a minor complication rate of 48% compared with 7% in the surgical group.119 In a prospective randomized study that compared the clinical outcome of renal artery balloon angioplasty versus stenting for renal ostial atherosclerotic lesion, comparable complications rates were found in the two groups (39% vs. 43%, respectively). However, the incidence of restenosis at 6 months was significantly higher in the balloon angioplasty cohort than the stenting group (48% vs. 14%, respectively). This study underscores the clinical superiority of renal stenting compared to renal balloon angioplasty alone in patients with ostial stenosis.120 Deterioration in renal function, albeit transient, is a common complication following endovascular renal artery intervention. This is most likely the combined result of the use of iodinated contrast and the occurrence of renal parenchymal embolism due to wire and catheter manipulation. In most cases, this is a temporary problem, as supportive care with adequate VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ fluid hydration is sufficient to reverse the renal dysfunction. However, transient hemodialysis may become necessary in approximately 1% of patients. Other complications include vascular access complications (bleeding, hematoma, femoral nerve injury, arteriovenous fistula, and pseudoaneurysm), target vessel dissection, perinephric hematoma, early postoperative renal artery thrombosis, and extremity atheroembolism from thrombus in the aorta or the iliac arteries. Percutaneous Transluminal Balloon Angioplasty. FMD of the renal artery is the most common treatment indication for percutaneous transluminal balloon angioplasty. Patients with symptomatic FMD such as hypertension or renal insufficiency usually respond well to renal artery balloon angioplasty alone.121 In contrast, balloon angioplasty generally is not an effective treatment for patients with renal artery stenosis or proximal occlusive disease of the renal artery, due to the high incidence of restenosis with balloon angioplasty alone. In the latter group of patients, primary stent placement is the preferred endovascular treatment. The long-term benefit of renal artery balloon angioplasty in patients with FMD was reported by Surowiec and colleagues.121 They followed 14 patients who underwent 19 interventions on 18 renal artery segments. The technical success rate of balloon angioplasty for FMD was 95%. Primary patency rates were 81%, 69%, 69%, and 69% at 2, 4, 6, and 8 years, respectively. Assisted primary patency rates were 87%, 87%, 87%, and 87% at 2, 4, 6, and 8 years, respectively. The restenosis rate was 25% at 8 years. Clinical benefit, as defined by either improved or cured hypertension, was found in 79% of patients overall, with two thirds of patients having maintained this benefit at 8 years. The authors concluded that balloon angioplasty is highly effective in symptomatic FMD with excellent durable functional benefits.121 The utility of balloon angioplasty alone in the treatment of renovascular hypertension appears to be limited. van Jaarsveld and associates performed a prospective study in which patients with renal artery stenosis were randomized to either drug therapy or balloon angioplasty treatment.122 A total of 106 patients with 50% diameter stenosis or greater plus hypertension or renal insufficiency were randomized in the study. A Renal Artery Stenting. Endovascular stent placement is the treatment of choice for patients with symptomatic or high-grade renal artery occlusive disease (Fig. 23-48) This is due in part to the high incidence of restenosis with balloon angioplasty alone, particularly in the setting of ostial stenosis. Renal artery stenting is also indicated for renal artery dissection caused by balloon angioplasty or other catheter-based interventions. Numerous studies have clearly demonstrated the clinical efficacy of renal artery stenting when compared to balloon angioplasty alone in patients with high-grade renal artery stenosis. White and colleagues conducted a study to evaluate the role of renal artery stenting in patients with poorly controlled hypertension and renal artery lesions that did not respond well to balloon angioplasty alone.123 The technical success of the procedure was 99%. The mean blood pressure values were 173 ± 25/88 ± 17 mmHg prior to stent implantation and 146 ± 20/77 ± 12 mmHg 6 months after renal artery stenting (P <0.01). Angiographic follow-up with 67 patients (mean 8.7 ± 5 months) demonstrated that restenosis, as defined by 50% or greater luminal narrowing, occurred in 15 patients (19%). The study concluded that renal artery stenting is a highly effective treatment for renovascular hypertension, with a low angiographic restenosis rate. In another similar study, Blum and colleagues prospectively performed renal artery stenting in 68 patients (74 lesions) with ostial renal artery stenosis and suboptimal balloon angioplasty.124 Patients were followed for a mean of 27 months with measurements of blood pressure and serum creatinine, duplex sonography, and intra-arterial angiography. Five-year patency was 84.5% (mean follow-up, 27 months). Restenosis occurred in 8 of 74 arteries (11%), but after reintervention, the secondary 5-year patency rate was 92.4%. Hypertension was cured or improved in 78% of patients. The authors concluded that primary Figure 23-48. Renal artery stenting. A. Focal lesion in the renal artery (arrow). B. Poststenting angiogram reveals a satisfactory result following a renal artery stenting placement (arrow). B VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 871 CHAPTER 23 Arterial Disease Clinical Results of Endovascular Interventions At 3 months, there was no difference in the degree to which blood pressure was controlled between the two groups. However, the degree and dose of antihypertensive medications were slightly lowered in the balloon angioplasty group. The above advantage of the angioplasty group completely disappeared at 12 months, making the authors conclude that in the treatment of patients with hypertension and renal artery stenosis, percutaneous transluminal balloon angioplasty alone offers minimal advantage over antihypertensive drug therapy. 872 AORTOILIAC OCCLUSIVE DISEASE UNIT II PART SPECIFIC CONSIDERATIONS stent placement is an effective treatment for renal artery stenosis involving the ostium. The clinical utility of renal artery stenting in renal function preservation was analyzed by several studies, which measured serial serum creatinine levels to determine the response of renal function following endovascular intervention.125 In a study reported by Harden and colleagues who performed 33 renal artery stenting procedures in 32 patients with renal insufficiency, they noted that renal function improved or stabilized in 22 patients (69%).126 In a similar study, Watson and associates evaluated the effect of renal artery stenting on renal function by comparing the slopes of the regression lines derived from the reciprocal of serum creatinine versus time.125 A total of 61 renal stenting procedures were performed in 33 patients, and the authors found that after stent placement, the slopes of the reciprocal of the serum creatinine (1/Scr) were positive in 18 patients and less negative in 7 patients. The study concluded that in patients with chronic renal insufficiency due to obstructive renal artery stenosis, renal artery stenting is effective in improving or stabilizing renal function. The clinical outcome of several large clinical studies of renal artery stenting in the treatment of renovascular hypertension or chronic renal insufficiency is shown in Table 23-13.123,124,126-132 These studies uniformly demonstrated an excellent technical success rate with low incidence of restenosis or procedural-related complications. A similar analysis was reported by Leertouwer and colleagues who performed a meta-analysis of 14 studies comparing patients with renal arterial stent placement to those who underwent balloon angioplasty alone for renal arterial stenosis.133 The study found that stent placement proved highly successful, with an initial technical success of 98%. The overall cure rate for hypertension was 20%, whereas hypertension was improved in 49%. Renal function improved in 30% of patients and stabilized in 38% of patients. The restenosis rate at follow-up of 6 to 29 months was 17%. Renal stenting resulted in a higher technical success rate and a lower restenosis rate when compared to balloon angioplasty alone. The distal abdominal aorta and the iliac arteries are common sites affected by atherosclerosis. The symptoms and natural history of the atherosclerotic process affecting the aortoiliac arterial segment are influenced by the disease distribution and extent. Atherosclerotic plaques may cause clinical symptoms by restricting blood flow due to luminal obstruction or by embolizing atherosclerotic debris to the lower extremity circulation. If the aortoiliac plaques reach sufficient mass and impinge on the arterial lumen, obstruction of blood flow to lower extremities occurs. Various risk factors exist that can lead to the development of aortoiliac occlusive disease. Recognition of these factors and understanding of this disease entity will enable physicians to prescribe the appropriate treatment strategy, which may alleviate symptoms and improve quality of life. Diagnostic Evaluation On clinical examination patients often have weakened femoral pulses and a reduced ABI. Verification of iliac occlusive disease is usually made by color duplex scanning, which reveals either a peak systolic velocity ratio ≥2.5 at the site of stenosis and or a monophasic waveform. Noninvasive tests such as pulse volume recordings (PVRs) of the lower extremity with estimation of the thigh-brachial pressure index may be suggestive of aortoiliac disease. MRA and multidetector CTA are increasingly being used to determine the extent and type of obstruction. DSA offers the interventionalist the benefit of making a diagnosis and the option of performing an endovascular treatment in a single session. Angiography provides important information regarding distal arterial runoff vessels as well as the patency of the PFA. Presence of pelvic and groin collaterals is important to provide crucial collateral flow in maintaining lower limb viability. It must be emphasized, however, that patients should be subjected to angiography only if their symptoms warrant surgical intervention. Differential Diagnosis Degenerative hip or spine disease, lumbar disk herniation, spinal stenosis, diabetic neuropathy, and other neuromuscular Table 23-13 Clinical outcome of renal artery stent placement in the treatment of renovascular hypertension and renal insufficiency Renal Renovascular Insufficiency (%) Hypertension (%) Patient Technical Follow-Up No. Success (%) (months) Stable Improved Cured Complica- Restenosis Improved tion (%) (%) Author Year Iannone130 1996 63 99 10 45 36 4 35 13 14 Harden126 1997 32 100 6 34 34 N/A N/A 3 13 Blum 1997 68 100 27 N/A N/A 16 62 0 11 124 White 1997 100 99 6 N/A 20 N/A N/A 2 19 Shannon132 1998 21 100 9 29 43 N/A N/A 9 0 Rundback 1998 45 94 17 N/A N/A N/A N/A 9 25 123 Dorros 131 1998 163 100 48 N/A N/A 3 51 11 N/A Henry129 1999 210 99 25 N/A 29 19 61 3 9 Bush 2001 73 89 20 21 38 13 61 12 16 128 127 N/A = not applicable. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ problems can produce symptoms that may be mistaken for vascular claudication. Such cases can be distinguished from true claudication by the fact that the discomfort from neuromuscular problems is often relieved by sitting or lying down, as opposed to cessation of ambulation. In addition, complaints that are experienced upon standing suggest nonvascular causes. When confusion persists, the use of noninvasive vascular laboratory testing modalities, including treadmill exercise, can help establish the diagnosis. Type I Type II Type III The principal collateral pathways in severe aortoiliac artery occlusive disease or chronic aortic occlusion that may provide blood flow distal to the aortoiliac lesion include: (a) the superior mesenteric artery to the distal IMA via its superior hemorrhoidal branch to the middle and inferior hemorrhoidals to the internal iliac artery (39%); (b) the lumbar arteries to the superior gluteal artery to the internal iliac system (37%); (c) the lumbar arteries to the lateral and deep circumflex arteries to the CFA (12%); and (d) Winslow’s pathway from the subclavian to the superior epigastric artery to the inferior epigastric artery to the external iliac arteries at the groin (Fig. 23-49). In general, treatment indications for aortoiliac artery occlusive disease include disabling claudication, ischemic rest pain, nonhealing lower extremity tissue wound, and lower extremity microembolization that arises from aortoiliac lesions. Figure 23-50. Aortoiliac disease can be classified into three types. Type I represents focal disease affecting the distal aorta and proximal common iliac artery. Type II represents diffuse aortoiliac disease above the inguinal ligament. Type III represents multisegment occlusive diseases involving aortoiliac and infrainguinal arterial vessels. Based on the atherosclerotic disease pattern, aortoiliac occlusive disease can be classified into three types (Fig. 23-50). Type I aortoiliac disease, which occurs in 5% to 10% of patients, is confined to the distal abdominal aorta and common iliac vessels (Fig. 23-51). Due to the localized nature of this type of aortic obstruction and formation of collateral blood flow around the occluded segment, limb-threatening symptoms are rare in the absence of more distal disease (Fig. 23-52). This type of aortoiliac occlusive disease occurs in a relatively younger group of patients (in their mid-50s), compared with patients who have more femoropopliteal disease. Patients with a type I disease pattern have a lower incidence of hypertension and diabetes, but a Figure 23-49. Pertinent collateral pathways are developed in the event of chronic severe aortoiliac occlusive disease. As illustrated in this multidetector computed tomography angiography, these collaterals include epigastric arteries (large white arrows), an enlarged inferior mesenteric artery (arrowhead), and enlarged lumbar arteries (black arrows). Figure 23-51. Type I aortoiliac disease is confined to the distal abdominal aorta (long arrow) or proximal common iliac arteries. Due to the localized nature of this type of aortic obstruction and formation of collateral blood flow around the occluded segment (short arrows), limb-threatening symptoms are rare in the absence of more distal disease. Disease Classification VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Collateral Arterial Network 873 874 UNIT II PART SPECIFIC CONSIDERATIONS Figure 23-52. A. Multidetector computed tomography angiography of the aortoiliac artery circulation in a 63-year-old male with buttock claudication. B. Three-dimensional image reconstruction shows intra-arterial calcification of the aorta (large arrow) and right common iliac artery (small arrow). This is consistent with type I aortoiliac occlusive disease. significant frequency of abnormal blood lipid levels, particularly type IV hyperlipoproteinemia. Symptoms typically consist of bilateral thigh or buttock claudication and fatigue. Men report diminished penile tumescence and may have complete loss of erectile function. These symptoms in the absence of femoral pulses constitute Leriche’s syndrome. Rest pain is unusual with isolated aortoiliac disease unless distal disease coexists. Occasionally patients report a prolonged history of thigh and buttock claudication that recently becomes more severe. It is likely that this group has underlying aortoiliac disease that has progressed to acute occlusion of the terminal aorta. Others may present with “trash foot,” which represents microembolization into the distal vascular bed (Fig. 23-53). Type II aortoiliac disease represents a more diffuse atherosclerotic progression that involves pre- dominately the abdominal aorta with disease extension into the common iliac artery. This disease pattern affects approximately 25% patients with aortoiliac occlusive disease. Type III aortoiliac occlusive disease, which affects approximately 65% of patients with aortoiliac occlusive disease, is widespread disease that is seen above and below the inguinal ligament (Fig. 23-54). Patients with “multilevel” disease are older, more commonly male (with a male-to-female ratio of 6:1), and much more likely to have diabetes, hypertension, and associated atherosclerotic disease involving cerebral, coronary, and visceral arteries. Progression of the occlusive process is more likely in these patients than in those with localized aortoiliac disease. For these reasons, most patients with a type III pattern tend to present with symptoms of advanced ischemia and require revascularization for Figure 23-53. Atherosclerotic disease involving the aortoiliac segment can result in microembolization of the lower leg circulation, resulting in trash foot or digital gangrene of toes. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 875 Table 23-14 TASC classification of aortoiliac occlusive lesions Type A lesions • Unilateral or bilateral stenoses of CIA • Unilateral or bilateral single short (≤3 cm) stenosis of EIA Type C lesions • Bilateral CIA occlusions • Bilateral EIA stenoses 3–10 cm long not extending into the CFA • Unilateral EIA stenosis extending into the CFA • Unilateral EIA occlusion that involves the origins of internal iliac artery and/or CFA • Heavily calcified unilateral EIA occlusion with or without involvement of origins of internal iliac artery and/or CFA Figure 23-54. Type III aortoiliac occlusive disease is a multilevel disease pattern that affects the aortoiliac segment as well as infrainguinal femoropopliteal vessels. Most patients with this disease pattern tend to present with symptoms of advanced ischemia and require revascularization for limb salvage rather than for claudication. limb salvage rather than for claudication. These patients have a decreased 10-year life expectancy when compared to patients with localized aortoiliac disease. The most commonly used classification system of iliac lesions has been set forth by the TransAtlantic Inter-Society Consensus (TASC) group with recommended treatment options. This lesion classification categorizes the extent of atherosclerosis and has suggested a therapeutic approach based on this classification (Table 23-14 and Fig. 23-55).2 According to this consensus document, endovascular therapy is the treatment of choice for type A lesions, and surgery is the treatment of choice for type D lesions. Endovascular treatment is the preferred treatment for type B lesions, and surgery is the preferred treatment for good-risk patients with type C lesions. In comparison to the 2000 TASC document, the commission has not only made allowances for treatment of more extensive lesions, but also takes into account the continuing evolution of endovascular technology and the skills of individual interventionalists when stating that the patient’s comorbidities, fully informed patient preference, and the local operator’s long-term success rates must be considered when making treatment decisions for type B and type C lesions.2,134 Type D lesions • Infrarenal aortoiliac occlusion • Diffuse disease involving the aorta and both iliac arteries requiring treatment • Diffuse multiple stenoses involving the unilateral CIA, EIA, and CFA • Unilateral occlusions of both CIA and EIA • Bilateral occlusions of EIA • Iliac stenoses in patients with AAA requiring treatment and not amenable to endograft placement or other lesions requiring open aortic or iliac surgery AAA = abdominal aortic aneurysm; CFA = common femoral artery; CIA = common iliac artery; EIA = external iliac artery. may improve walking efficiency, endothelial function, and metabolic adaptations in skeletal muscle, but, there is usually minimal improvement in patients with aortoiliac disease who are treated with these measures. Failure to respond to exercise and/or drug therapy should prompt consideration for limb Type A lesions Type C lesions Type B lesions Type D lesions General Treatment Considerations There is no effective medical therapy for the management of aortoiliac disease, but control of risk factors may help slow progression of atherosclerosis. Patients should have hypertension, hyperlipidemia, and diabetes mellitus controlled. They should be advised to stop smoking. Most patients are empirically placed on antiplatelet therapy. A graduated exercise program Figure 23-55. Schematic depiction of the TransAtlantic InterSociety Consensus classification of aortoiliac occlusive lesions. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ CHAPTER 23 Arterial Disease Type B lesions • Short (≤3 cm) stenosis of infrarenal aorta • Unilateral CIA occlusion • Single or multiple stenosis totaling 3–10 cm involving the EIA not extending into the CFA • Unilateral EIA occlusion not involving the origins of internal iliac artery or CFA 876 revascularization. Patients with buttock claudication and reduced or absent femoral pulses who fail to respond to exercise and drug therapy should be considered for revascularization because they are less likely than patients with more distal lesions to improve without concomitant surgical or endovascular intervention. Surgical Reconstruction of Aortoiliac Occlusive Disease Aortobifemoral Bypass. Surgical options for treatment of UNIT II PART SPECIFIC CONSIDERATIONS aortoiliac occlusive diseases consist of various configurations of aortobifemoral bypass grafting, various types of extra-anatomic bypass grafts, and aortoiliac endarterectomy. The proce4 dure performed is determined by several factors, including anatomic distribution of the disease, clinical condition of the patient, and personal preference of the surgeon. In most cases, aortobifemoral bypass is performed because patients usually have disease in both iliac systems. Although one side may be more severely affected than the other, progression does occur, and bilateral bypass does not complicate the procedure or add to the physiologic stress of the operation. Aortobifemoral bypass reliably relieves symptoms, has excellent long-term patency (approximately 70%–80% at 10 years), and can be completed with a tolerable perioperative mortality (2%–3%).135 Technical Considerations for Aortobifemoral Bypass. Both femoral arteries are initially exposed to ensure that they are adequate for the distal anastomoses. The abdomen is then opened in the midline, the small intestine is retracted to the right, and the posterior peritoneum overlying the aorta is incised. A retroperitoneal approach may be selected as an alternative in certain situations. This approach involves making a left flank incision and displacing the peritoneum and its contents to the right. Such an approach is contraindicated if the right renal artery is acutely occluded, since visualization from the left flank is very poor. Tunneling of a graft to the right femoral artery is also more difficult from a retroperitoneal approach, but can be achieved. The retroperitoneal approach has been reputed to be better tolerated than midline laparotomy for patients with multiple previous abdominal operations and with severe pulmonary disease. Further proposed advantages of the retroperitoneal approach include less gastrointestinal disturbance, decreased third space fluid losses, and ease with which the pararenal aorta can be accessed. There are randomized reports, however, that support and refute the superiority of this approach. A collagen-impregnated, knitted Dacron graft is used to perform the proximal aortic anastomosis, which can then be made in either an end-toend or end-to-side fashion using 3-0 polypropylene suture. The proximal anastomosis should be made as close as possible to the renal arteries to decrease the incidence of restenosis from progression of the atherosclerotic occlusive process in the future. An end-to-end proximal aortic anastomosis is necessary in patients with an aortic aneurysm or complete aortic occlusion extending up to the renal arteries (Fig. 23-56). Although in theory the end-to-end configuration allows for less turbulence and less chance of competitive flow with still patent host iliac vessels, there have not been consistent results to substantiate differences in patency between end-to-end and end-to-side grafts. Relative indications for an end-to-side proximal aortic anastomosis include the presence of large aberrant renal arteries, an unusually large IMA with poor back-bleeding suggesting Figure 23-56. In an end-to-end proximal aortic anastomosis, the aorta is divided in half. The proximal end of the aorta is anastomosed to the end of a prosthetic graft, while the distal divided aortic stump is oversewn. inadequate collateralization, and/or occlusive disease involving bilateral external iliac arteries. Under such circumstances, end-to-end bypass from the proximal aorta to the femoral level devascularizes the pelvic region because there is no antegrade or retrograde flow in the occluded external iliac arteries to supply the hypogastric arteries. As a result of the pelvic devascularization, there is an increased incidence of impotence, postoperative colon ischemia, buttock ischemia, and paraplegia secondary to spinal cord ischemia despite the presence of excellent femoral and distal pulses. An end-to-side proximal aortic anastomosis can be associated with certain disadvantages, which include the potential for distal embolization when applying a partially occlusive aortic clamp (Fig. 23-57). Furthermore, the distal aorta often proceeds to total occlusion after an end-to-side anastomosis. There may also be a higher incidence of aortoenteric fistula following construction of end-to-side proximal anastomoses because the anterior projection makes subsequent tissue coverage and reperitonealization of the graft more difficult. The limbs of the Figure 23-57. In an end-to-side aortic anastomosis, the end of a prosthetic graft is connected to the side of an aortic incision. VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Aortic Endarterectomy. Aortoiliac endarterectomy is rarely performed because it is associated with greater blood loss and greater sexual dysfunction and is more difficult to perform. Long-term patency is comparable with aortobifemoral grafting, and thus it remains a reasonable option in cases in which the risk of infection of a graft is excessive, because it involves no prosthetic tissue. Aortoiliac endarterectomy was useful when disease was localized to either the aorta or common iliac arteries; however, at present, aortoiliac PTA, stents, and other catheter-based therapies have become first-line treatment in this scenario. Endarterectomy should not be performed if the aorta is aneurysmal because of continued aneurysmal degeneration of the endarterectomized segment. If there is total occlusion of the aorta to the level of the renal arteries, aortic transection several centimeters below the renal arteries with thrombectomy of the aortic cuff followed by graft insertion is easier and more expeditious when compared to endarterectomy. Involvement of the external iliac artery makes aortic endarterectomy more difficult to complete because of decreased vessel diameter, increased length, and exposure issues. The ability to establish an appropriate endarterectomy plane is compromised due to the muscular and inherently adherent nature of the media in this location. There is a higher incidence of early thrombosis and late failure with extended aortoiliofemoral endarterectomy when compared to bypass grafting as a result of recurrent stenosis. Axillofemoral Bypass. An axillofemoral bypass is an extraanatomic reconstruction that derives arterial inflow from the axillary artery to the femoral artery. This is a treatment option for patients with medical comorbidities that prohibit an abdominal vascular reconstruction. It may be performed under local anesthesia and is used for limb salvage. Extra-anatomic bypasses have lower patency when compared to aortobifemoral and, therefore, are seldom recommended for claudication. Before performing this operation, the surgeon should check pulses and blood pressure in both arms to ensure that there is no obvious disease affecting flow through the axillary system. Angiography of the axillosubclavian vasculature is not necessary, but can be helpful if performed at the time of aortography. The axillary artery is exposed below the clavicle, and a 6- to 8-mm externally reinforced PTFE graft is tunneled subcutaneously down the lateral chest wall and lateral abdomen to the groin. It is anastomosed ipsilaterally at the CFA bifurcation into the SFA and PFA. A femorofemoral crossover graft using a 6- to 8-mm externally reinforced PTFE graft is then used to revascularize the opposite extremity if necessary. Reported patency rates over 5 years vary from 30% to 80%.136 Paradoxically, although it is a less complex procedure than aortofemoral grafting, the mortality rate is higher (10%), reflecting the compromised medical status of these patients.136 Iliofemoral Bypass. One option for patients with unilateral occlusion of the distal common iliac or external iliac arteries is iliofemoral grafting (Fig. 23-58). Long-term patency is comparable to aortounifemoral bypass, and because the procedure can be performed using a retroperitoneal approach without clamping the aorta, the perioperative mortality is less.136 Femorofemoral Bypass. A femorofemoral bypass is another option for patients with unilateral stenosis or occlusion of the common or external iliac artery who have rest pain, tissue loss, or intractable claudication. The primary (assisted) patency at 5 years is reported to be 60% to 70%, and although this is inferior when compared to aortofemoral bypass, there are physiologic benefits, especially for patients with multiple comorbidities because it is not necessary to cross-clamp the aorta.137 There are no studies supporting the superiority of unsupported or externally supported PTFE over Dacron for choice of conduit. The fear of the recipient extremity stealing blood from the extremity ipsilateral to the donor limb is not realized unless the donor iliac artery and donor outflow arteries are diseased.137 Depending on the skills of the interventionalist or surgeon, many iliac lesions classified as TASC B, C, or D can now be addressed using an endovascular approach, thus obviating the need to perform a femorofemoral bypass. Additionally, femorofemoral bypass can be used as an adjuvant procedure after iliac inflow has been optimized with endovascular methods. A B Figure 23-58. A. Skin markings showing the incisions of an iliofemoral bypass. B. A prosthetic bypass graft is used for an iliofemoral artery bypass in which the proximal anastomosis is connected to the common iliac artery (long arrow) while the distal anastomosis is connected to the common femoral artery (short arrow). VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 877 CHAPTER 23 Arterial Disease graft are tunneled through the retroperitoneum to the groin, where an end-to-side anastomosis is fashioned between the graft and the bifurcation of the CFA using 5-0 polypropylene suture. Endarterectomy or patch angioplasty of the profunda femoris may be required concurrently. Once the anastomoses have been fashioned and the graft thoroughly flushed, the clamps are removed and the surgeon carefully controls the degree of aortic occlusion until full flow is re-established. During this period, the patient must be carefully monitored for hypotension. Declamping hypotension is a complication of sudden restoration of aortic flow, particularly following prolonged occlusion. Once flow has been re-established, the peritoneum is carefully reapproximated over the prosthesis to prevent fistulization into the intestine. Despite the presence of multilevel disease in most patients, a properly performed aortobifemoral operation can provide arterial inflow and alleviate claudication symptoms in 70% to 80% of patients; however, 10% to 15% of patients will require simultaneous outflow reconstruction to address distal ischemia and facilitate limb salvage. The advantage of concomitant distal revascularization is avoidance of reoperation in a scarred groin. As a rule, if the profunda femoris can accept a 4-mm probe and if a No. 3 Fogarty embolectomy catheter can be passed distally for 20 cm or more, the PFA will be sufficient for outflow, and concomitant distal revascularization is not necessary. 878 Obturator Bypass. An obturator bypass is used to reconstruct UNIT II PART SPECIFIC CONSIDERATIONS arterial anatomy in patients with groin sepsis resulting from prior prosthetic grafting, intra-arterial drug abuse, groin neoplasm, or damage from prior groin irradiation. This bypass can originate from the common iliac artery, external iliac artery, or uninvolved limb of an aortobifemoral bypass. A conduit of Dacron, PTFE, or autologous vein is tunneled through the anteromedial portion of the obturator membrane to the distal SFA or popliteal artery. The obturator membrane must be divided sharply so as avoid injury to adjacent structures, and care must be taken to identify the obturator artery and nerve that pass posterolaterally. After the bypass is completed and the wounds isolated, the infected area is entered, the involved arteries are débrided to healthy tissue, and vascularized muscle flaps are mobilized to cover the ligated ends.138 There have been varied results in terms of patency and limb salvage for obturator bypass. Some authors have reported 57% 5-year patency and 77% 5-year limb salvage rates, whereas others have shown a high rate of reinfection and low patency requiring reintervention.138,139 Thoracofemoral Bypass. The indications for thoracofemoral bypass are (a) multiple prior surgeries with a failed infrarenal aortic reconstruction and (b) infected aortic prosthesis. This procedure is more physiologically demanding than other extra-anatomic reconstructions because the patient must not only tolerate clamping the descending thoracic aorta but also performance of a left thoracotomy. The graft is tunneled to the left CFA from the left thorax posterior to the left kidney in the anterior axillary line using a small incision in the periphery of the diaphragm and an incision in the left inguinal ligament to gain access to the extraperitoneal space from below. The right limb is tunneled in the space of Retzius in an attempt to decrease kinking that is more likely to occur with subcutaneous, suprapubic tunneling. Thoracofemoral bypass has long-term patency comparable to aortofemoral bypass. Complications of Surgical Aortoiliac Reconstruction With current surgical techniques and conduits, early postoperative hemorrhage is unusual and occurs in 1% to 2%. It is usually the result of technical oversight or coagulation abnormality.140 Acute limb ischemia occurring after aortoiliac surgery may be the result of acute thrombosis or distal thromboembolism. The surgeon can prevent thromboembolic events by (a) avoiding excessive manipulation of the aorta, (b) ensuring adequate systemic heparinization, (c) judicious placement of vascular clamps, and (d) thorough flushing prior to restoring blood flow. Acute thrombosis of an aortofemoral graft limb in the early perioperative period occurs in 1% to 3% of patients.140 Thrombectomy of the graft limb is performed through a transverse opening in the hood of the graft at the femoral anastomosis. With this approach it is possible to inspect the interior of the anastomosis and pass embolectomy catheters distally to clear the superficial femoral and profunda arteries. Various complications may be encountered following aortoiliac or aortobifemoral reconstruction (Table 23-15). Intestinal ischemia following aortic reconstruction occurs in approximately 2% of cases; however, with colonoscopy mucosal ischemia, which is a milder form, is seen more frequently. The surgeon can identify patients who require concomitant revascularization of the IMA, hypogastric arteries, or mesenteric arteries by examining the preoperative arteriogram for the presence of associated occlusive lesions in the celiac Table 23-15 Perioperative complications of aortobifemoral bypass grafting Medical Complications • Perioperative myocardial infarction • Respiratory failure • Ischemia-induced renal failure • Bleeding from intravenous heparinization • Stroke Procedure-Related Complications Early • Declamping shock • Graft thrombosis • Retroperitoneal bleeding • Groin hematoma • Bowel ischemia/infarction • Peripheral embolization • Erectile dysfunction • Lymphatic leak • Chylous ascites • Paraplegia Late • Graft infection • Anastomotic pseudoaneurysm • Aortoenteric fistula • Aortourinary fistula • Graft thrombosis axis, the superior mesenteric arteries, or both. Likewise, patients with a patent and enlarged IMA or a history of prior colonic resections will benefit from IMA reimplantation. In a comprehensive review of 747 patients who had aortoiliac operations for occlusive disease, secondary operations for late complications such as reocclusion, pseudoaneurysms, and infection were necessary in 21% over a 22-year period.141 The most frequent late complication is graft thrombosis. Limb occlusion occurs in 5% to 10% of patients within 5 years of the index operation and in 15% to 30% of patients ≥10 years after the index operation.140,141 Anastomotic pseudoaneurysms occur in 1% and 5% of femoral anastomoses in patients with aortofemoral grafts.142 Predisposing factors to pseudoaneurysm formation include progression of degenerative changes within the host artery, excessive tension at the anastomosis, and infection.142 Due to the associated risks of thrombosis, distal embolization, infection, and rupture, anastomotic aneurysms should be repaired expeditiously. Infection following aortoiliac reconstruction is a devastating complication that occurs in 1% of cases. Femoral anastomoses of aortofemoral reconstructions and axillofemoral bypasses are prone to infection.141,142 Use of prophylactic antibiotics and meticulous surgical technique are vital in preventing contamination of the graft at the time of implantation. If infection appears localized to a single groin, graft preservation and local measures such as antibiotic irrigation, aggressive debridement, and soft tissue coverage with rotational muscle flaps may prove successful. Most patients with infected aortoiliofemoral reconstructions usually require graft excision and revascularization via remote uncontaminated routes or the use of in situ replacement to clear the infective process and maintain limb viability. Aortoenteric VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ fistula and associated gastrointestinal hemorrhage are devastating complications, with a 50% incidence of death or limb loss. The incidence of aortoenteric fistula formation appears to be higher after an end-to-side proximal anastomosis, because it is more difficult to cover the prosthesis with viable tissue and avoid contact with the gastrointestinal tract with this configuration.141,142 Treatment of aortoenteric fistula requires resection of all prosthetic material, closure of the infrarenal abdominal aorta, repair of the gastrointestinal tract, and revascularization by means of an extra-anatomic graft. Although aortofemoral bypass surgery has excellent long-term patency and can be performed with low mortality rates, there are patients who are unable to withstand the physiologic stress of longer open procedures performed under general anesthesia, which require aortic cross-clamping and which are associated with greater blood loss. These patients are more suited to endovascular interventions despite the decreased durability and requirement for more frequent reinterventions. Focal Aortic Stenosis. The endovascular technique used to treat infrarenal aortic stenoses is similar to that used for iliac artery disease. Bilateral CFA access is established followed by insertion of a 10-French sheath. The lesion is crossed using a hydrophilic wire and a supporting selective catheter and then changed for a stiffer guidewire. A self-expanding nitinol stent or a balloon-expandable stent mounted on a larger-caliber angioplasty balloon is implanted followed by adequate postdilation. At the physician’s discretion, “kissing” stents, simultaneous bilateral proximal iliac stents, are deployed if the lesion is in the distal aorta in the proximity of the aortic bifurcation. The role of covered stents such as cuffs made for endoluminal AAA repair has not been rigorously studied. The aortic diameter should be sized with a calibrated catheter during the angiography or by preintervention CT scanning to avoid undersizing. Balloon size will range from 12 to 18 mm in most cases. A single stent is generally sufficient in most cases. Large Palmaz-type stents mounted on XXL balloons (Meditech, Westwood, MA) have been successfully used and may be inflated up to 25 mm in diameter if needed. Newer self-expanding stents have also been used. Concentric aortic stenosis may encroach upon the IMA, and coverage of this vessel may be unavoidable. Care should be taken to use low inflation pressures (5 mmHg) to minimize the risk of aortic rupture. Patient complaints of back or abdominal pain during balloon inflation should be taken seriously as they may suggest impending rupture. In case of a calcified small-caliber, hypoplastic aorta (≤12 mm, typically in female patients), it is recommend to use smaller diameter stents. To achieve clinical improvement, these patients can be recanalized to an aortic diameter of 8 or 9 mm. Distal embolization is one of the potential complications of endovascular treatment for aortic stenoses. Full heparinization, meticulous technique during wire and catheter manipulations, and primary stenting reduce the risk of this complication. Since calcified aortic stenoses are prone to rupture during dilation, it is recommended to be cognizant of the extent of the calcification with preoperative CT scans. In case of aortic rupture, as long as wire access has been maintained, an occlusion balloon can be inflated proximal to the disrupted segment to achieve hemostasis, and the rupture can be covered with a stent graft or repaired with open surgery. Occlusive Lesions of the Aortic Bifurcation. Occlusive lesions are treated with the kissing balloon technique to avoid Endovascular Treatment for Iliac Artery Disease Percutaneous Transluminal Angioplasty. PTA is most useful in the treatment of isolated iliac stenoses of less than 4 cm in length. When used for stenoses rather than occlusion, a 2-year patency of 86% can be achieved.147 The complication rate is approximately 2%, consisting of distal embolization, medial dissection, and acute thrombosis. Technical Considerations for Iliac Interventions. Crossing a high-grade stenosis or occlusion can be challenging in the iliac arteries. It is vital to image the lesion well because multiple views and use of the image intensifier will frequently uncover the anatomic reason for the difficulty. Frequently, the difficulty is the result of vessel tortuosity that cannot be appreciated on the original view. Use of an angled hydrophilic guidewire and an angled catheter can provide steering and add extra support for the wire trying to cross the lesion. Patience, persistence, and periodic reimaging will facilitate the crossing of a lesion in the great majority of cases. Guidewire traversal must be achieved for performance of endovascular iliac intervention. Over 90% of iliac occlusions can be passed with simple guidewire techniques. The preferred approach for recanalizing a common iliac artery occlusion is retrograde passage of devices from an ipsilateral CFA puncture because, in this manner, distance to the lesion is short and access is straighter. A stenosis is normally crossed using a combination of a soft-tip 0.035-inch guidewire (i.e., Bentson-type wire) or hydrophilic wire and a 5-French straight or selective catheter. One of the hazards of retrograde recanalization is that the guidewire stays in a subintimal location and cannot be redirected into the true lumen at the aortic bifurcation. There are several approaches that can be used to achieve re-entry of total chronic occlusions. Specialized catheters allow passage of a needle and guidewire across the intima distal to the occlusion. Intravascular ultrasound can be used for true lumen re-entry under fluoroscopic guidance. Another method of achieving true lumen re-entry involves performing the recanalization from an antegrade contralateral VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 879 CHAPTER 23 Arterial Disease Endovascular Treatment for Aortic Disease dislodging aortic plaque. Two angioplasty balloons of equal size are positioned across the ostia of the common iliac arteries, using a retrograde approach, and inflated. Simultaneous balloon dilatation at the origins of both common iliac arteries is advocated, even in the presence of unilateral lesion, to protect the contralateral common iliac artery from dissection or plaque embolization. Calcified lesions that typically occur at the aortic bifurcation are not amenable to balloon dilatation and frequently require that a distal aortic reconstruction be performed using “kissing stents.” Fears that the proximal ends of the stents that extend into the distal aorta will become a nidus for thrombus formation or cause hemolysis have not been realized. The results are difficult to interpret because these bifurcation lesions are usually included in studies with iliac artery lesions. Patency rates for aortic bifurcation PTA range from 76% to 92% at 3 years.143 The largest series reported to date includes 79 patients with aortic bifurcation lesions. The cumulative clinical success rate at a mean of 4 years was 93%.144 In more recent years, stents have been used to reconstruct the aortic bifurcation.145 The kissing stent technique is well-suited for orificial lesions. Technical success with kissing stents at the aortic bifurcation has been reported to be 95% to 100%.145 In the largest series reported, the primary patency at 3 years was 79%.146 880 UNIT II PART SPECIFIC CONSIDERATIONS CFA approach. A 4-French Berenstein catheter (Cordis Corp., Miami Lakes, FL) is used to probe the occlusion. The lesion can be crossed in most instances (5%–20% failure rate) with a hydrophilic guidewire or occasionally with its stiffer back end. As soon as the guidewire has crossed the obstruction and lies within the ipsilateral external iliac artery lumen, it is snared and partially pulled out of the ipsilateral CFA. A short catheter is then inserted in a retrograde fashion over the wire end into the abdominal aorta proximal to the lesion. The hydrophilic guidewire is then exchanged for a stiffer Amplatz (Boston Scientific, Natick, MA) guidewire to facilitate iliac stenting. Obtaining arterial access when there are absent femoral pulsations is aided by the use of ultrasound guidance and “roadmap” imaging software, which is available on modern angiographic equipment. When the lesion is successfully crossed, balloons of an appropriate size and length are selected for the angioplasty. Most common iliac arteries will accommodate 8- to 10-mm diameter balloons, whereas most external iliac arteries will accommodate 6- to 8-mm diameter balloons. Inflation is performed with caution, especially if there is heavy calcification, and should be guided by patient discomfort, pressure gauge readings, and changes in balloon outline. If guidewire traversal is straightforward, consideration should be given to the presence of an acute thrombosis that may benefit from catheter-directed thrombolysis. If guidewire traversal is challenging, it is unlikely that catheter-directed thrombolysis will be beneficial. Investigators have found that routine thrombolysis and balloon dilation of occluded arteries prior to stent placement are associated with an increased incidence of distal embolic events.148 Stents should be placed after inadequate angioplasty. Stents are warranted when there is a greater than 30% residual stenosis, when there is a flow-limiting dissection, or when there is a pressure gradient of ≥5 mmHg across the treated segment.149 Placement of stents can precipitate distal embolization in up to 10%, especially if lesions are friable and vulnerable to manipulation. Routine primary stent placement is not recommended because it has not been found to be superior to selective stenting in terms of outcomes or cost.150 Primary Stenting versus Selective Stenting in Iliac Arteries. Primary stenting rather than selective stenting should be considered for longer iliac lesions and for all TASC C and D lesions. The primary patency rates at 1, 2, and 3 years were 96%, 90%, and 72%, respectively, for longer lesions (>5 cm) that were primarily stented versus 46%, 46%, and 28%, respectively, with selective stenting.150 Primary stenting is generally advocated for chronic iliac artery occlusions, recurrent stenosis after previous iliac PTA, and complex stenoses with eccentric, calcified, ulcerated plaques or plaques with spontaneous dissection. All of these lesions are prone to distal embolization during manipulation of wires and angioplasty balloons. Distal embolization with isolated PTA is not common for uncomplicated lesions, but can occur in up to 24% of cases, when treating ulcerated plaques, aortoiliac bifurcation lesions, or iliac occlusions.150 It is believed that direct stent placement without predilation significantly reduces the risk of distal embolization by trapping potentially embologenic material between the arterial wall and the stent mesh. While PTA has demonstrated excellent results in focal stenoses of the abdominal aorta and iliacs, primary stenting in these locations is safe, improves patency rates, reduces the degree of restenosis when compared with PTA alone, and decreases the risk of distal embolization. Additional potential advantages of direct stenting include shorter procedural time and less radiation exposure. The Dutch Iliac Stent Trial has provided evidence that refutes the superiority of primary stenting over angioplasty alone.151 Most interventionalists continue to perform angioplasty first and stent selectively for inadequate results. The approach to aortoiliac stenting is intuitive. Individual judgment and experience are important in the decision-making process, and there are lesions with unstable morphology such as long occlusions, ulceration, and dissection that warrant primary stenting. Stent Graft Placement for Aortoiliac Interventions. Stent grafts have been used to treat complex iliac lesions in an attempt to exclude these sources of embolization. A recent report suggested that the use of stent grafts was beneficial for TASC C and D lesions.152 Bosiers and colleagues published a series of 91 limbs with diseased iliacs that they treated with 107 stent grafts. They reported successful deployment in all patients without distal embolization or vessel rupture and a primary patency rate of 91.1% at 1 year.153 The authors commented about their concerns of causing embolization during placement of the stent grafts and recommended that once an occlusion was traversed with the guidewire, to gently predilate with a 5-mm balloon, followed by smooth stent graft insertion into the newly created channel. The role of stent grafts in aortoiliac occlusive disease has not been fully elucidated yet. Complications of Endovascular Aortoiliac Interventions Iliac artery angioplasty is associated with a 2% to 4% major complication rate and 4% to 15% minor complication rate. Many of these minor complications are related to the arterial puncture site. The most frequent complications relate to access site cannulation. Hemorrhage can range from the more common access site hematoma to the rarer retroperitoneal and intraperitoneal hemorrhage. Distal embolization occurs in 2% to 10% of iliac PTA and stenting procedures.140 Percutaneous catheter aspiration should be the initial treatment for calf vessel embolization, but, for larger emboli, such as those that lodge in the profunda femoris or common femoral arteries, surgical embolectomy may be required because the embolic material contains atherosclerotic plaque, which is not amenable to transcatheter aspiration or catheter-directed thrombolysis. The incidence of pseudoaneurysm formation at the puncture site is 0.5%. The treatment of choice for pseudoaneurysms >2 cm in diameter is percutaneous thrombin injection under ultrasound guidance. Arterial rupture may complicate the procedure in 0.3% of cases. Tamponade of the ruptured artery with an occlusion balloon should be performed, and a covered stent should be placed. In case of failure, surgical treatment is required. Clinical Results Comparing Surgical and Endovascular Treatment of Aortoiliac Disease The mortality risk of aortobifemoral bypass in patients with isolated, localized aortoiliac disease is relatively low, whereas for patients with concomitant atherosclerosis in coronary, carotid, and visceral vessels, mortality and morbidity are higher. For this reason, the cumulative long-term survival rate for patients receiving aortoiliac reconstruction remains 10 to 15 years less anticipated for a normal age- and sex-matched popu5 than lation. Twenty-five percent to 30% of patients with concomitant atherosclerosis in other vascular distributions are dead within 5 years, and 50% to 60% will have died by 10 years.142 VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ of the common iliac artery, patency rates were 81% and 52% at 1 and 6 years, respectively; whereas, after external iliac artery angioplasty, they were 74% and 48% at 1 and 4 years, respectively.158 Although some literature supports location of the lesion in the external iliac artery as a factor that adversely affects both primary and assisted-primary patency, this has not been a universal finding.158 Female patients are also reported to have lower patency rates than males following iliac PTA, with or without stent placement in the external iliac artery.159 Stenting of the iliac arteries provides a durable and curative treatment, with a 3-year patency rate of 41% to 92% for stenosis and a 3-year patency rate of 64% to 85% and 4-year patency rate of 54% to 78% for occlusions.157 A meta-analysis of 2116 patients by Bosch and Hunink showed that aortoiliac stenting resulted in a 39% improvement in long-term patency compared to balloon angioplasty, despite the fact that complication rates and 30-day mortality rates did not differ significantly.160 Park and colleagues presented long-term follow-up results in a cohort of patients with all four TASC types of iliac lesions. The authors presented primary patency rates of 87%, 83%, 61%, and 49% at 3, 5, 7, and 10 years, respectively, after the index intervention.161 Leville and colleagues achieved primary and secondary patency rates of 76% and 90%, respectively, after 3 years, in a cohort of patients who received stents for iliac occlusions.162 The authors postulated that endovascular treatment for iliac occlusive disease should be extended to type C and D lesions, because they observed no detectable differences between the four TASC classifications in terms of primary and secondary patency rates.162 They concluded that presence of TASC C and D lesions should not preclude endovascular treatment and believe that endovascular attempts should be exhausted before open surgical repair of iliac occlusions is attempted because of the decreased perioperative morbidity and good midterm durability. Not all results have been in favor of stenting, and at present, universal primary stenting cannot be recommended. Although stents are often used to improve the outcome of PTA, there is no general consensus that stenting should be mandatory in all iliac lesions. Complex, ulcerated iliac lesions with high embologenic potential or recanalized chronic iliac occlusions may be an exception. In the Dutch Iliac Stent Trial, primary stenting did not prove to be superior to iliac angioplasty and selective stenting. The researchers in this prospective randomized multicenter study concluded that balloon angioplasty with selective stenting had comparable 2-year patency rates with primary stenting (77% and 78%, respectively). It must be noted, however, that it was necessary to stent 43% of the patients in the PTA treatment group due to unsatisfactory angioplasty results.151 The 5-year outcomes between the two groups were also similar, with 82% and 80% of the treated iliac segments remaining free of the need for new revascularization procedures after a mean follow-up of 5.6 ± 1.3 years.151 LOWER EXTREMITY ARTERIAL OCCLUSIVE DISEASE The symptoms of lower extremity occlusive disease are classified into two large categories: acute limb ischemia (ALI) and chronic limb ischemia (CLI). Ninety percent of acute ischemia cases are either thrombotic or embolic. Frequently, sudden onset of limb-threatening ischemia may be the result of acute exacerbation of the pre-existing atherosclerotic disease. Chronic ischemia is largely due to atherosclerotic changes of the lower VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ 881 CHAPTER 23 Arterial Disease Compared with conventional aortobifemoral bypass, common iliac angioplasty was shown to have a 10% to 20% lower overall patency rate. It should be noted that these results were reported in early trials that used older generations of endovascular equipment. With continued progress and newer angioplasty balloons and stenting practices, more comparable outcomes are being reported. Review of the literature confirms that there is an 85% to 90% graft patency rate at 5 years and a 70% to 75% graft patency rate at 10 years after aortobifemoral reconstruction.154 Due in part to factors including continued refinements in anesthetic management, intraoperative monitoring, and postoperative intensive care, low perioperative mortality rates for aortobifemoral bypass can be achieved commonly in today’s clinical practice. The most recent systematic review and metaanalysis of 5358 patients who underwent direct open bypass or endovascular treatment for aortoiliac occlusive disease demonstrated superior durability for open bypass, although with longer length of stay and increased risk for complications and mortality, when compared to the endovascular approach.155 In this study, poor preoperative runoff was greater in the open bypass group (50.0% vs. 24.6%). Mean length of hospital stay was 13 days for open bypass versus 4 days for endovascular treatment procedures. The open bypass group experienced more complications (18.0% vs. 13.4%) and greater 30-day mortality (2.6% vs. 0.7%). At 1, 3, and 5 years, pooled primary patency rates were greater in the open bypass group (94.8% vs. 86.0%, 86.0% vs. 80.0%, and 82.7% vs. 71.4%, respectively); the same was true for secondary patency (95.7% vs. 90.0%, 91.5 vs. 86.5%, and 91.0% vs. 82.5%, respectively). Despite its lower long-term success, common iliac angioplasty is a useful procedure in patients with focal disease and mild symptoms in whom a major surgical revascularization is not justified. Angioplasty of the iliac vessels can be a useful adjunct to distal surgical bypass as well, increasing the success of distal revascularization and eliminating the risks associated with aortoiliac bypass. Thus, with long-term patency less than, but comparable to, open surgical bypass, and with more favorable morbidity rates, iliac angioplasty has become a wellaccepted modality of treatment for iliac occlusive disease. Ideal iliac angioplasty lesions are nonocclusive and short. Patency after intervention is better when lesions occur in larger diameter vessels, when stenoses rather than occlusions are treated, when runoff vessels are patent, and when the indication for intervention is lifestyle-limiting claudication rather than critical limb ischemia. Becker and colleagues estimated a 5-year patency rate of 72% in an analysis of 2697 cases of iliac angioplasty and noted a better patency (79%) in claudicants.156 Less favorable results are obtained with long stenoses, external iliac stenoses, and tandem lesions. The reported technical and initial clinical success of balloon angioplasty in iliac artery stenoses exceeds 90% in most series, and the 5-year patency rates range from 54% to 92%.157 The reported technical and initial clinical success of balloon angioplasty in iliac artery occlusions ranges from 78% to 98%, and the 3-year patency rates range from 48% to 85%.157 Factors reported to affect the patency of aortoiliac endovascular interventions adversely include quality of runoff vessels, severity of ischemia, and length of diseased segments treated. Likewise as vessel diameter and flow rates change, so do success rates after angioplasty. It was reported in the literature that location of the lesion at the external iliac artery adversely affects both primary and assisted-primary patency. Following angioplasty 882 extremity that manifest from asymptomatic to limb-threatening gangrene. As the population ages, the prevalence of chronic occlusive disease of the lower extremity is increasing, and it significantly influences lifestyle, morbidity, and mortality. In addition, multiple comorbid conditions increase risks of surgical procedures. Endovascular interventions become an important alternative in treating lower extremity occlusive disease. However, despite rapidly evolving endovascular technology, lower extremity endovascular intervention continues to be one of the most controversial areas of endovascular therapy. UNIT II PART Epidemiology SPECIFIC CONSIDERATIONS In a detailed review of the literature, McDaniel and Cronenwett concluded that claudication occurred in 1.8% of patients under 60 years of age, 3.7% of patients between 60 and 70 years of age, and 5.2% of patients over 70 years of age.163 Leng and his colleagues scanned 784 subjects using ultrasound in a random sample of men and women age 56 to 77 years. Of the subjects who were scanned, 64% demonstrated atherosclerotic plaque.164 However, a large number of patients had occlusive disease without significant symptoms. In a study by Schroll and Munck, only 19% of patients with peripheral vascular disease were symptomatic.165 Using ABIs, Stoffers and colleagues scanned 3171 individuals between the ages of 45 and 75 and identified that 6.9% of patients had ABIs <0.95, only 22% of whom had symptoms.166 In addition, they demonstrated that concomitant cardiovascular and cerebrovascular diseases were three to four times higher among the group with asymptomatic peripheral vascular diseases than those without peripheral vascular disease. Furthermore, they confirmed that 68% of all peripheral arterial obstructive diseases were unknown to the primary care physician, and this group mainly represented less advanced cases of atherosclerosis. However, among patients with an ABI ratio <0.75, 42% were unknown to the primary physicians. Diagnostic Evaluation The diagnosis of lower extremity occlusive disease is often made based on a focused history and physical examination and confirmed by the imaging studies. A well-performed physical examination often reveals the site of lesions by detecting changes in pulses, temperature, and appearances. The bedside ABIs using blood pressure cuff also aid in diagnosis. Various clinical signs and symptoms are useful to differentiate conditions of viable, threatened, and irreversible limb ischemia caused by arterial insufficiency (Table 23-16). Noninvasive studies are important in documenting the severity of occlusive disease objectively. Ultrasound Dopplers measuring ABIs and segmental pressures are widely used in North America and Europe. Normal ABI is greater than 1.0. In patients with claudication, ABIs decrease to 0.5 to 0.9 and to even lower levels in patients with rest pain or tissue loss.167 Segmental pressures are helpful in identifying the level of involvement. Decrease in segmental pressure between two segments indicates significant disease. Ultrasound duplex scans are used to identify the site of lesion by revealing flow disturbance and velocity changes. A meta-analysis of 71 studies by Koelemay and associates confirmed that duplex scanning is accurate for assessing arterial occlusive disease in patients suffering from claudication or critical ischemia with a accumulative sensitivity of 80% and specificity of over 95%.168 Adding an ultrasound contrast agent further increases the sensitivity and specificity of ultrasound technology.169 Other noninvasive imaging technologies, such as MRA and CTA, are rapidly evolving and gaining popularity in the diagnosis of lower extremity occlusive disease (Figs. 23-59 and 23-60). Contrast angiography remains the gold standard imaging study. Using contrast angiography, interventionists can locate and size the anatomic significant lesions and measure the pressure gradient across the lesion, as well as plan for potential intervention. Angiography is, however, semi-invasive and should be confined to patients for whom surgical or percutaneous intervention is contemplated. Patients with borderline renal function may need to have alternate contrast agents, such as gadolinium or carbon dioxide, to avoid contrast-induced nephrotoxicity. Differential Diagnosis Arterial insufficiency frequently leads to muscle ischemic pain involving the lower extremity muscles, particularly during exercise. Intermittent claudication is pain affecting the calf and, less commonly, the thigh and buttock that is induced by exercise and relieved by rest. Symptom severity varies from mild to severe. Intermittent claudication occurs as a result of muscle ischemia during exercise caused by obstruction to arterial flow. Regarding the differential diagnosis of intermittent claudication, there are a variety of neurologic, musculoskeletal, and venous conditions that may produce symptoms of calf pain (Table 23-17). Additionally, various nonatherosclerotic conditions can also cause symptoms consistent with intermittent lower extremity claudication (Table 23-18). Nocturnal calf muscle spasms or night cramps are not indicative of arterial disease. They are common but are difficult to diagnose with certainty. Foot ulceration is not always the result of arterial insufficiency. Ischemic ulcers occur on the toes or lateral side of the foot and are painful. By comparison, venous ulcers, which are also common, occur above the Table 23-16 Signs and symptoms of acute limb ischemia Category Description Viable Threatened Clinical description Not immediately threatened Salvageable if promptly treated Major tissue loss, amputation unavoidable Capillary return Intact Intact, slow Absent (marbling) Muscle weakness None Mild, partial Profound, paralysis (rigor) Sensory loss None Mild, incomplete Profound anesthetic Inaudible or audible Inaudible Arteriovenous Doppler finding Audible VRG RELEASE: tahir99 https://kickass.to/user/tahir99/uploads/ Irreversible 883 Figure 23-59. High-resolution computed tomography angiography of a patient with normal right lower extremity arterial circulation. Distal occlusive disease is noted in the left tibial arteries (arrow). medial malleolus, usually in an area with the skin changes of lipodermatosclerosis, and cause mild discomfort. Neuropathic ulcers are usually found on weight-bearing surfaces, have thick calluses, and are pain free. Ulcers may be the result of more than one etiology. Rest pain must be distinguished from peripheral neuropathy, which is prevalent in diabetic patients. Patients with diabetic neuropathy tend to have decreased vibration and position sense and decreased reflexes. Spinal stenosis causes pain that is exacerbated with standing and back extension. Lower Extremity Occlusive Disease Classification Lower extremity occlusive disease may range from exhibiting no symptoms to limb-threatening gangrene. There are two major classifications developed based on the clinical presentations. The Fontaine classification uses four stages: Fontaine I is the stage when patients are asymptomatic; Fontaine II is when they have mild (IIa) or severe (IIb) claudication; Fontaine III is when they have ischemic rest pain; and Fontaine IV is when patients suffer tissue loss, such as ulceration or gangrene (Table 23-19).170 The Rutherford classification has four grades (0–III) and seven categories (0–6). Asymptomatic patients are classified B Figure 23-60. Multidetector computed tomography angiography of a patient with an (A) infrapo