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