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Schwartz’s
Principles of Surgery
Tenth Edition
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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.
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F. Charles Brunicardi, MD, FACS
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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.
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Seymour I. Schwartz, MD, FACS
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Part
Basic Considerations
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I
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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
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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
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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.)
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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
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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.
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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.)
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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.
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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
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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.
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Fundamental Principles of Leadership Training in Surgery
CONCLUSION
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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
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33. Goleman D. Leadership that gets results. Harvard Business
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34. Xirasagar S, Samuels ME, Stoskopf CH. Physician leadership
styles and effectiveness: an empirical study. Med Care Res Rev.
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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
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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
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39. Stoller JK, Rose M, Lee R, et al. Teambuilding and leadership
training in an internal medicine residency training program. J
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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.
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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:
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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
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48. Barondess JA. On mentoring. J R Soc Med. 1997;90:347-349.
49. Zuckerman H. Scientific Elite: Nobel Laureates in the United
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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.
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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.
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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.
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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.
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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”
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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.
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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
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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
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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.
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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.
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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.
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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.
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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,
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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
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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.
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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
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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
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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
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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
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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.)
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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.)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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BASIC CONSIDERATIONS
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PART I
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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)
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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
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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
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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
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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
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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.
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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).
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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.
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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
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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.
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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
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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.
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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
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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
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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
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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
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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.
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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.
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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,
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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
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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.
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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
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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
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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.
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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
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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.
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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.
DIC is characterized by systemic activation of the coagulation system, which results in the deposition of fibrin clots and
microvascular ischemia and may contribute to the development
of multiorgan failure. Consumption and subsequent exhaustion
of coagulation proteins and platelets due to the ongoing activation of the coagulation system may induce severe bleeding
complications.
Lastly, severe hemorrhagic disorders due to thrombocytopenia have occurred as a result of gram-negative sepsis.
Defibrination and hemostatic failure also may occur with meningococcemia, Clostridium perfringens sepsis, and staphylococcal
sepsis. Hemolysis appears to be one mechanism in sepsis leading
to defibrination.
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in primary hemostasis after massive transfusion. Surgery.
1985;98:836.
77. 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;63:805.
78. Holcomb JB, Wade CE, Michalek JE, et al. Increased
plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients.
Ann Surg. 2008;248:447-458.
79. Holcomb JB, del Junco DJ, Fox EE, et al, for the PROMMTT Study Group. The prospective, observational, multicenter, massive transfusion study, PROMMTT: comparative
effectiveness of a time-varying treatment and competing risks.
Arch Surg. 2012;15:1-10.
80. Cotton BA, Au BK, Nunez TC, et al. Predefined massive
transfusion protocols are associated with a reduction in organ
failure and postinjury complications. J Trauma. 2009;66:
41-48; discussion 48-49.
81. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model
for massive transfusion in combat casualty patients. J Trauma.
2008;64(2 Suppl):S57.
82. Yücel N, Lefering R, Maegele M, et al. Trauma-Associated
Severe Hemorrhage (TASH) score: probability of mass transfusion as surrogate for life threatening hemorrhage after multiple trauma. J Trauma. 2006;60:1228.
83. Moore FA, Nelson T, McKinley BA, et al. Massive transfusion in trauma patients: tissue hemoglobin oxygen saturation
predicts poor outcome. J Trauma. 2008;64:1010.
84. 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.
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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
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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.
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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.
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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
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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
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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
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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.
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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
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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.
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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
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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
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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
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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
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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.)
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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.)
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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.
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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
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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
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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.
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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.
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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
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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
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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
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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
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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”).
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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
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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
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Entries highlighted in bright blue are key references.
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131
Shock
Gastric Tonometry. Lactate and base deficit indicate global
resulted in reduction of cytochrome a,a3; this correlated with
tissue lactate elevation. NIR spectroscopy can be used to compare tissue oxyhemoglobin levels (indicating tissue O2 supply
to cytochrome a,a3 with mitochondrial O2 consumption), thus
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organ failure (89% vs. 13%).111,112
CHAPTER 5
a partial pressure of CO2 of 40 mmHg. It usually is measured
by arterial blood gas analysis in clinical practice as it is readily
and quickly available. 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. Transfusion requirements increased
as base deficit worsened, and ICU and hospital lengths of stay
increased. Mortality increased as base deficit worsened; the frequency of organ failure increased with greater base deficit.56
The probability of trauma patients developing ARDS has been
reported to correlate with severity of admission base deficit
and lowest base deficit within the first 24 hours postinjury.58
Persistently high base deficit is associated with abnormal O2
utilization and higher mortality. Monitoring base deficit in the
resuscitation of trauma patients assists in assessment of O2
transport and efficacy of resuscitation.57
Factors that may compromise the utility of the base deficit in estimating O2 debt are the administration of bicarbonate,
hypothermia, hypocapnia (overventilation), heparin, ethanol,
and ketoacidosis. However, the base deficit remains one of the
most widely used estimates of O2 debt for its clinical relevance,
accuracy, and availability.
132
PART I
BASIC CONSIDERATIONS
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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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,
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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
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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,
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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
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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
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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.
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Francisella tularensis (Tularemia)
CHAPTER 6
nonspecific symptoms, including malaise, myalgia, and fever.
Over a short period of time, these symptoms worsen, with
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a widened mediastinum and pleural effusions. A key aspect
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Rapid antigen tests are currently under development for identification of this gram-positive rod. Postexposure prophylaxis
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the patient should be switched to amoxicillin. Inhalational
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combination therapy with ciprofloxacin, clindamycin, and
rifampin; clindamycin added to block production of toxin,
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158
PART I
BASIC CONSIDERATIONS
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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.
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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
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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
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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
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PART I
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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
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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.
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PART I
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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.
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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.
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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.
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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.
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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.
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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.
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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