Schwartz's Principles of Surgery - PDF Free Download (2024)

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Preface When I was asked to serve as editor-in-chief of this historic textbook of surgery, my goal was to preserve its excellent reputation, honoring the commitment of Dr. Seymour Schwartz and previous co-editors and contributors who upheld the highest standard for seven prior editions. I would like to thank all who helped achieve this goal, namely the outstanding contributions by the individual chapter authors and the meticulous dedication of the editorial board, all of whom share a passion for patient care, teaching, and surgery. It is this shared passion that has been channeled now into the creation of this new ninth edition; updating, improving, and finetuning it to secure its place as a leading international textbook of surgery. Each chapter has either been fastidiously updated or created anew by leaders in their respective surgical fields to ensure the highest quality of surgical teaching. Additionally, each chapter has been outfitted with quick-reference key points; highlighted evidenced-based references; and full-color illustrations, images, and information tables. Two new chapters have been added to this edition: Accreditation Council for Graduate Medical Core Competencies and Ethics, Palliative Care, and Care at the End of Life. One new component of this edition is the inclusion of a digital video disc of surgical videos. Many students already augment their more traditional classroom and practical education through the breadth of information available in the electronic realm, such as that available on AccessSurgery.com. This collection of operative and instructional videos, generously provided by chapter authors and editors, provides accurate visual instruction and technique to round out students' surgical training. It is the sincere hope of all who have contributed to this textbook that the knowledge of craft contained within will provide a solid foundation for the acquisition of skill, a haven for the continuation of education, and motivation for the pursuit of excellence. I wish to thank all of those responsible for the publication of this new edition, including the newest member of the editorial board, Dr. Jeffrey Matthews, as well as those who fearlessly signed on as contributors to our newly established international editorial board to provide regional perspective and commentary. I extend many thanks and gratitude to Marsha Loeb, Christie Naglieri, and all at McGraw-Hill for their guidance and knowledge throughout this process. I wish to thank Katie Elsbury for her dedication to the organization and editing of this textbook. I would also like to thank our families, whose love and support continue to make this book possible. F. Charles Brunicardi, MD, FACS

Copyright Information Schwartz's Principles of Surgery, Ninth Edition Copyright © 2010, 2005, 1999, 1994, 1989, 1984, 1979, 1974, 1969 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher. Book ISBN 978-0-07-1547703 Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The editors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the editors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Contributors Editor-in-Chief F. Charles Brunicardi, MD, FACS DeBakey/Bard Professor and Chairman, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas

Associate Editors Dana K. Andersen, MD, FACS Professor and Vice-Chair, Department of Surgery, Johns Hopkins University School of Medicine, Surgeon-in-Chief, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Timothy R. Billiar, MD, FACS George Vance Foster Professor and Chairman of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania David L. Dunn, MD, PhD, FACS Vice President for Health Sciences, State University of New York, Buffalo, Buffalo, New York John G. Hunter, MD, FACS Mackenzie Professor and Chair, Department of Surgery, Oregon Health and Science University, Portland, Oregon Jeffrey B. Matthews, MD, FACS Dallas B. Phemister Professor and Chairman, Department of Surgery, University of Chicago, Chicago, Illinois Raphael E. Pollock, MD, PhD, FACS Head, Division of Surgery, Professor and Chairman, Department of Surgical Oncology, Senator A.M. Aiken, Jr., Distinguished Chair, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Contributors Louis H. Alarcon, MD Assistant Professor of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 13, Physiologic Monitoring of the Surgical Patient Dana K. Andersen, MD, FACS Professor and Vice-Chair, Department of Surgery, Johns Hopkins University School of Medicine, Surgeon-in-Chief, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Chapter 33, Pancreas Peter Angelos, MD Professor of Surgery and Chief of Endocrine Surgery, University of Chicago Medical Center, Chicago, Illinois Chapter 48, Ethics, Palliative Care, and Care at the End of Life Peter B. Angood, MD Senior Advisor for Patient Safety, National Quality Forum, Washington, DC Chapter 12, Patient Safety Stanley W. Ashley, MD Frank Sawyer Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Samir S. Awad, MD Associate Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies

Adrian Barbul, MD Professor of Surgery, Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Chapter 9, Wound Healing Joel A. Bauman, MD Resident Physician, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania Chapter 42, Neurosurgery Carlos Bechara, MD Assistant Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Greg J. Beilman, MD Professor of Surgery and Anesthesia, Chief of Surgical Critical Care/Trauma, University of Minnesota, Minneapolis, Minnesota Chapter 6, Surgical Infections Richard H. Bell Jr., MD Assistant Executive Director, American Board of Surgery, Philadelphia, Pennsylvania Chapter 33, Pancreas Robert L. Bell, MD, MA, FACS Director, Minimally Invasive Surgery, Director, Bariatric Surgery, Associate Professor of Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut Chapter 35, Abdominal Wall, Omentum, Mesentery, and Retroperitoneum Arie Belldegrun, MD Director, Institute of Urologic Oncology at UCLA, Professor and Chief, Division of Urologic Oncology, Roy and Carol Doumani Chair in Urologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 40, Urology Peleg Ben-Galim, MD Assistant Professor, Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery David H. Berger, MD Professor and Vice Chair, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies Chapter 30, The Appendix Walter L. Biffl, MD Associate Professor, Department of Surgery, Denver Health Medical Center/University of Colorado-Denver, Denver, Colorado Chapter 7, Trauma Timothy R. Billiar, MD, FACS George Vance Foster Professor and Chairman of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 5, Shock Kirby I. Bland, MD Fay Fletcher Kerner Professor and Chairman, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama Chapter 17, The Breast Mary L. Brandt, MD Professor and Vice Chair, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies F. Charles Brunicardi, MD, FACS DeBakey/Bard Professor and Chairman, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies

Chapter 15, Molecular and Genomic Surgery Chapter 33, Pancreas Chapter 37, Inguinal Hernias Jamal Bullocks, MD Assistant Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Catherine Cagiannos, MD Assistant Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Joanna M. Cain, MD Chace/Joukowsky Chair of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Brown University, Portland, Oregon Chapter 41, Gynecology Rakesh K. Chandra, MD Assistant Professor, Department of Otolaryngology, Head and Neck Surgery, Northwestern University, Chicago, Illinois Chapter 18, Disorders of the Head and Neck Catherine L. Chen, MPH Fellow, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland Chapter 12, Patient Safety Changyi J. Chen, PhD Molecular Surgery Endowed Chair, Professor of Surgery and Molecular and Cellular Biology, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Orlo H. Clark, MD Professor of Surgery, Department of Surgery, UCSF/Mt. Zion Medical Center, San Francisco, California Chapter 38, Thyroid, Parathyroid, and Adrenal Patrick Cole, MD Resident, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Edward M. Copeland III, MD Emeritus Distinguished Professor of Surgery, Department of Surgery, University of Florida, College of Medicine, Gainesville, Florida Chapter 17, The Breast Janice N. Cormier, MD Associate Professor of Surgery, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 36, Soft Tissue Sarcomas Joseph S. Coselli, MD Professor and Cullen Foundation Endowed Chair, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection C. Clay Cothren, MD Associate Professor of Surgery, Department of Surgery, University of Colorado, Denver, Denver, Colorado Chapter 7, Trauma Gregory A. Crooke, MD Assistant Professor of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease Daniel T. Dempsey, MD Professor and Chair, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania

Chapter 26, Stomach Robert S. Dorian, MD Chairman and Program Director, Department of Anesthesia, Saint Barnabas Medical Center, Livingston, New Jersey Chapter 47, Anesthesia of the Surgical Patient David L. Dunn, MD, PhD, FACS Vice President for Health Sciences, State University of New York, Buffalo, Buffalo, New York Chapter 6, Surgical Infections Chapter 11, Transplantation Geoffrey P. Dunn, MD Medical Director, Department of Surgery, Hamot Medical Center, Erie, Pennsylvania Chapter 48, Ethics, Palliative Care, and Care at the End of Life Kelli M. Bullard Dunn, MD Associate Professor of Surgery, Department of Surgical Oncology, State University of New York, Buffalo, Buffalo, New York Chapter 29, Colon, Rectum, and Anus David T. Efron, MD Associate Professor of Surgery, Chief, Division of Trauma, Critical Care, and Emergency Surgery, Johns Hopkins Hospital, Baltimore, Maryland Chapter 9, Wound Healing Wafic M. ElMasri, MD Cancer Research Training Award Postdoctoral Fellow, Medical Oncology Branch, Molecular Signaling Section, National Institutes of Health, National Cancer Institute, Bethesda, Maryland Chapter 41, Gynecology Fred W. Endorf, MD Clinical Associate Professor, Department of Surgery, University of Minnesota, St. Paul, Minnesota Chapter 8, Burns Xin-Hua Feng, PhD Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 15, Molecular and Genomic Surgery William E. Fisher, MD Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 33, Pancreas Henri R. Ford, MD Vice President and Surgeon-in-Chief, Children's Hospital Los Angeles, Professor of Surgery and Vice Dean for Medical Education, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Aubrey C. Galloway, MD Seymour Cohn Professor, Chairman Department of Cardiothoracic Surgery, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease Francis H. Gannon, MD Associate Professor of Pathology and Orthopedic Surgery, Staff Pathologist, DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery David A. Geller, MD Richard L. Simmons Professor of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 31, Liver

Nicole S. Gibran, MD Professor, Department of Surgery, Harborview Medical Center, Seattle, Washington Chapter 8, Burns Michael Gimbel, MD Assistant Professor of Surgery, Division of Plastic and Reconstructive Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Carlos D. Godinez Jr., MD Fellow and Clinical Instructor, Minimally Invasive Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland Chapter 34, Spleen Ernest A. Gonzalez, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Health Science Center, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion John A. Goss, MD Professor of Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 31, Liver M. Sean Grady, MD Charles Harrison Frazier Professor, Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Chapter 42, Neurosurgery Tom Gregory, MD Associate Professor, Department of Obstetrics and Gynecology, Division of Urogynecology, Oregon Health and Science University, Portland, Oregon Chapter 41, Gynecology Tracy C. 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 Eugene A. Grossi, MD Professor of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease David J. Hackam, MD, PhD Roberta Simmons Associate Professor of Pediatric Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 39, Pediatric Surgery Daniel E. Hall, MD Division of Trauma and General Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 48, Ethics, Palliative Care, and Care at the End of Life Rosemarie E. Hardin, MD Resident Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 46, Surgical Considerations in the Elderly Michael H. Heggeness, MD, PhD Chairman, Division of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery Lior Heller, MD Associate Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas

Chapter 16, The Skin and Subcutaneous Tissue Daniel B. Hinshaw, MD Veterans Administration Medical Center Chapter 48, Ethics, Palliative Care, and Care at the End of Life John B. Holcomb, MD Professor, Department of Surgery and Director, Center for Translational Injury Research, University of Texas Health Science Center, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion Larry H. Hollier, MD Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Abhinav Humar, MD Professor of Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 11, Transplantation Kelly K. Hunt, MD Professor of Surgery, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 17, The Breast John G. Hunter, MD, FACS Mackenzie Professor and Chair, Department of Surgery, Oregon Health and Science University, Portland, Oregon Chapter 14, Minimally Invasive Surgery, Robotics, and Natural Orifice Transluminal Endoscopic Surgery Chapter 25, Esophagus and Diaphragmatic Hernia Chapter 32, Gallbladder and the Extrahepatic Biliary System Tam T. Huynh, MD Associate Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Bernard M. Jaffe, MD Professor Emeritus, Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana Chapter 30, The Appendix Badar V. Jan, MD PGY-4 Surgical Resident, Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey Chapter 2, Systemic Response to Injury and Metabolic Support Kenneth M. Jastrow, MD Surgery Resident, Department of Surgery, University of Texas Health Science Center, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion Blair A. Jobe, MD Associate Professor of Surgery, The Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 14, Minimally Invasive Surgery, Robotics, and Natural Orifice Transluminal Endoscopic Surgery Chapter 25, Esophagus and Diaphragmatic Hernia Tara B. Karamlou, MD, MSc Cardiothoracic Surgery Fellow, University of Michigan, Ann Arbor, Michigan Chapter 20, Congenital Heart Disease Elise C. Kohn, MD Senior Investigator and Section Head, Department of Molecular Signaling Section, Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland Chapter 41, Gynecology Panagiotis Kougias, MD

Assistant Professor, Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Rosemary A. Kozar, MD Associate Professor of Surgery, Department of Surgery, Memorial Hermann Hospital, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion Jeffrey La Rochelle, MD Fellow and Clinical Instructor, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 40, Urology Geeta Lal, MD Assistant Professor of Surgery, University of Iowa Health Care, Carver College of Medicine, Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Iowa City, Iowa Chapter 38, Thyroid, Parathyroid, and Adrenal Thu Ha Liz Lee, MD Assistant Professor of Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies Scott A. LeMaire, MD Associate Professor and Director of Research, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection Timothy K. Liem, MD Associate Professor of Surgery, Adjunct Associate Professor of Radiology, Division of Vascular Surgery, Oregon Health and Science University, Portland, Oregon Chapter 24, Venous and Lymphatic Disease Scott D. Lifchez, MD Assistant Professor, Department of Surgery, Division of Plastic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Chapter 44, Surgery of the Hand and Wrist Peter H. Lin, MD Associate Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Xia Lin Associate Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 15, Molecular and Genomic Surgery Joseph E. Losee, MD Associate Professor of Surgery and Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Stephen F. Lowry, MD Professor and Chair, Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey Chapter 2, Systemic Response to Injury and Metabolic Support James D. Luketich, MD 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 Emeritus Professor of Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California Chapter 37, Inguinal Hernias

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 Mark Ravitch Chair in General Surgery, Associate Professor of Health Policy, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland Chapter 12, Patient Safety Jeffrey B. Matthews, MD, FACS Dallas B. Phemister Professor and Chairman, Department of Surgery, University of Chicago, Chicago, Illinois Funda Meric-Bernstam, MD Associate Professor, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 10, Oncology Gregory L. Moneta, MD Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Oregon Health and Science University, Portland, Oregon Chapter 24, Venous and Lymphatic Disease Ernest E. Moore, MD Vice Chairman and Professor, Department of Surgery, University of Colorado, Denver, Denver, Colorado Chapter 7, Trauma Katie S. Nason, MD 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 Kurt D. Newman, MD Professor of Surgery and Pediatrics, Division of Surgery, George Washington University School of Medicine, Washington, DC Chapter 39, Pediatric Surgery Lisa A. Newman, MD Professor, Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan Chapter 17, The Breast Margrét Oddsdóttir, MD* Professor of Surgery, Chief of General Surgery, Landspitali-University Hospital, Reykjavik, Iceland Chapter 32, Gallbladder and the Extrahepatic Biliary System Adrian E. Park, MD Campbell and Jeanette Plugge Professor and Vice Chair, Division of General Surgery, University of Maryland Medical Center, Baltimore, Maryland Chapter 34, Spleen Timothy M. Pawlik, MD Johns Hopkins University, 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 Jeffrey H. Peters, MD Chairman, Department of Surgery, University of Rochester Medical Center, Rochester, New York Chapter 25, Esophagus and Diaphragmatic Hernia Thai H. Pham, MD

Fellow, Department of General Surgery, Oregon Health and Science University, Portland, Oregon Chapter 32, Gallbladder and the Extrahepatic Biliary System Raphael E. Pollock, MD, PhD, FACS Head, Division of Surgery, Professor and Chairman, Department of Surgical Oncology, Senator A.M. Aiken, Jr., Distinguished Chair, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 10, Oncology Chapter 36, Soft Tissue Sarcomas Charles A. Reitman, MD Associate Professor, Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery David A. Rothenberger, MD Professor and Deputy, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 29, Colon, Rectum, and Anus J. Peter Rubin, MD Director of the Life After Weight Loss Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Ashok K. Saluja, MD Professor and Vice Chair, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 33, Pancreas Philip R. Schauer, MD Chief of Minimally Invasive General Surgery, Cleveland Clinic, Cleveland, Ohio Chapter 27, The Surgical Management of Obesity Bruce Schirmer, MD Stephen H. Watts Professor of Surgery, University of Virginia Health System, Charlottesville, Virginia Chapter 27, The Surgical Management of Obesity Charles F. Schwartz, MD Assistant Professor of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease Subhro K. Sen, MD Clinical Assistant Professor, Division of Plastic & Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, California Chapter 44, Surgery of the Hand and Wrist 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 Associate Professor of Surgery, Associate Director Trauma Services, Department of Surgery, Duke University Medical Center, Durham, North Carolina Chapter 12, Patient Safety Kapil Sharma, MD Assistant Professor, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection Vadim Sherman, MD, FRCSC Assistant Professor of Surgery, Director, Comprehensive Bariatric Surgery Center, Program Director, Minimally Invasive Fellowship, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas

Chapter 37, Inguinal Hernias G. Tom Shires III, MD Chair, Surgical Services, Presbyterian Hospital of Dallas, Dallas, Texas Chapter 3, Fluid and Electrolyte Management of the Surgical Patient Brian Shuch, MD Chief Resident, Department of Urology, David Geffen School of Medicine, Los Angeles, California Chapter 40, Urology Michael L. Smith, MD Assistant Professor, Department of Neurosurgery, Albert Einstein College of Medicine, Bronx, New York Chapter 42, Neurosurgery Samuel Stal, MD Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Ali Tavakkolizadeh, MB BS Assistant Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Allan Tsung, MD Assistant Professor, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 31, Liver Ross M. Ungerleider, MD Professor of Surgery, Department of Surgery, Oregon Health and Science University, Portland, Oregon Chapter 20, Congenital Heart Disease Christopher G. Wallace, MD Clinical and Research Microsurgery Fellow, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University and Medical College, Taipei, Taiwan Chapter 45, Plastic and Reconstructive Surgery Kasper S. Wang, MD Assistant Professor of Surgery, Department of Pediatric Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Randal S. Weber, MD Professor and Hubert L. and Olive Stringer Distinguished Professor for Cancer Research and Chairman, Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 18, Disorders of the Head and Neck Fu-Chan Wei, MD, FACS Professor and Chancellor, Department of Plastic Surgery, College of Medicine, Chang Gung University, Chang Gung Memorial Hospital, Taipei, Taiwan Chapter 45, Plastic and Reconstructive Surgery Richard O. Wein, MD Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Tufts New England Medical Center, Boston, Massachusetts Chapter 18, Disorders of the Head and Neck Jacob Weinberg, MD Assistant Professor, Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery Karl F. Welke, MD Assistant Professor, Division of Cardiothoracic Surgery, Oregon Health and Science University, Portland, Oregon

Chapter 20, Congenital Heart Disease Edward E. Whang, MD Associate Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Michael E. Zenilman, MD Clarence and Mary Dennis Professor and Chairman, Department of Surgery, SUNY Downstate Medical Center, Brooklyn, New York Chapter 46, Surgical Considerations in the Elderly Michael J. Zinner, MD Moseley Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Brian S. Zuckerbraun, MD Assistant Professor of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 5, Shock

Video Contributors Daniel Albo, MD, PhD Chief, General Surgery and Surgical Oncology, Director, Colorectal Cancer Center, Michael E. DeBakey VAMC, Houston, Texas Hand Assisted Laparoscopic LAR Hand Assisted Laparoscopic Right Hemi-Colectomy John Bozinovski, MD, MSc, FRCSC Attending Cardiac Surgeon, Department of Surgery, Royal Jubilee Hospital, Victoria, British Columbia, Canada Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms F. Charles Brunicardi, MD, FACS DeBakey/Bard Professor and Chairman, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Knot Tying Suturing Laparoscopic Cholecystectomy on a Patient with Biliary Colic and Gall Stones Laparoscopic Nissen Fundoplication Laparoscopic Distal Pancreatectomy Totally Extra-Peritoneal (TEP) Hernia Repair Laparoscopic Adjustable Gastric Band and Hiatal Hernia Repair Laparoscopic Sleeve Gastrectomy Joseph F. Buell, MD Professor of Surgery, University of Louisville, Louisville, Kentucky Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass Orlo H. Clark, MD Professor of Surgery, Department of Surgery, UCSF/Mt. Zion Medical Center, San Francisco, California Bilateral Exploration Parathyroidectomy Steven D. Colquhoun, MD Surgical Director, Liver Transplantation, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Associate Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Joseph S. Coselli, MD Professor and Cullen Foundation Endowed Chair, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms David A. Geller, MD Richard L. Simmons Professor of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania

Laparoscopic Left Hepatic Lobectomy for Hepatocellular Carcinoma Carlos D. Godinez, MD Fellow and Clinical Instructor, Minimally Invasive Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland Laparoscopic Splenectomy Marlon Guerrero, MD Assistant Professor and Director of Endocrine Surgery, Department of Surgery, University of Arizona, Tucson, Arizona Bilateral Exploration Parathyroidectomy Shahzeer Karmali, BSc, MD, FRCSC Assistant Professor of Surgery, Minimally Invasive and Bariatric Surgery, University of Alberta, Edmonton, Alberta, Canada Laparoscopic Sleeve Gastrectomy Laparoscopic Adjustable Gastric and Hiatal Hernia Repair Geeta Lal, MD Assistant Professor of Surgery, University of Iowa Health Care, Carver College of Medicine, Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Iowa City, Iowa Bilateral Exploration Parathyroidectomy Scott A. LeMaire, MD Associate Professor and Director of Research, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms Richard E. Link, MD Associate Professor of Urology, Director, Division of Endourology and Minimally Invasive Surgery, The Scott Department of Urology, Baylor College of Medicine, Houston, Texas Robotic-Assisted Laparoscopic Partial Nephractomy Robotic-Assisted Laparoscopic Radial Prostatectomy Paul Martin, MD Professor of Medicine, Chief, Division of Hepatology, Schiff Liver Institute/Center for Liver Dieseases, University of Miami Miller School of Medicine, Miami, Florida Right-Lobe Living Donor Liver Transplantation Jeffrey B. Matthews, MD, FACS Dallas B. Phemister Professor and Chair, Department of Surgery, University of Chicago, Chicago, Illinois Laparoscopic Cystogastrostomy for Pancreatic Pseudocyst Nicholas N. Nissen, MD Assistant Surgical Director of the Multi-Organ Transplant Program, Center for Liver Diseases and Transplantation, Ceders-Sinai Medical Center, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Adrian E. Park, MD Campbell and Jeanette Plugge Professor and Vice Chair, Division of General Surgery, University of Maryland Medical Center, Baltimore, Maryland Laparoscopic Splenectomy Fred Poordad, MD Chief, Hepatology and Liver Transplantation, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Associate Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Vivek N. Prachand, MD Assistant Professor of Surgery, Department of Surgery, University of Chicago, Chicago, Illinois Laparoscopic Cystogastrostomy for Pancreatic Pseudocyst Steven Rudich, MD, PhD

Associate Professor of Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass Christopher R. Shackleton, MD Principal, QV Research Consultancy, Formerly Professor, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Vadim Sherman, MD, FRCSC Assistant Professor of Surgery, Director, Comprehensive Bariatric Surgery Center, Program Director, Minimally Invasive Fellowship, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Laparoscopic Sleeve Gastrectomy Totally Extra-Peritoneal (TEP) Hernia Repair Laparoscopic Adjustable Gastric and Hiatal Hernia Repair Amit D. Tevar, MD Assistant Professor of Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass Mark C. Thomas, MD Assistant Professor, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass Tram Tran, MD Assisant Professor of Medicine, Geffen (UCLA) School of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation John Moore Vierling, MD Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Right-Lobe Living-Donor Liver Transplantation Scott Weldon, MA, CMI Supervisor, Medical Illustrator, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms Steve Woodle, MD Professor, Chief, Division of Transplant Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass

International Advisory Board Gaurav Agarwal, MS (Surgery), FACS Additional Professor, Department of Endocrine and Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Äke Gösta Andrén-Sandberg, MD Chief, Department of Surgery, Karolinska University Hospital at Huddinge, Stockholm, Sweden Claudio Bassi, MD, FRCS Professor, Surgical and Gastroenterological Department, University of Verona, Verona, Italy Jacques Belghiti, MD Professor, Department of Surgery, University of Paris VII, Hospital Beaujon, Clichy, France Kent-Man Chu, MD Professor of Surgery, Chief, Division of Upper Gastrointestinal Surgery, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China Eugen H. K. J. Faist, MD

Department of Surgery, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany Mordechai Gutman, MD Head, Department of General Surgery, Meir Hospital, Kfar Saba, Israel Serafin C. Hilvano, MD, FPCS, FACS Professor and Chair, Department of Surgery, College of Medicine- Philippine General Hospital, University of the Philippines, Manila, Manila, Philippines Jamal J. Hoballah, MD, MBA Professor and Chairman, Department of Surgery, American University of Beirut Medical Center, Hamra District, Beirut, Lebanon Seon-Hahn Kim, MD Director of Robotic and MIS Center, Head of Colorectal Division, Professor, Department of Surgery, Korea University Anam Hospital, SungBook-gu, Seoul, South Korea Yuko Kitagawa, MD Professor, Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan J. E. J. Krige, MD, FRCS, FACS, FCS (SA) Professor of Surgery, Surgical Gastroenterology, Department of Surgery, University of Cape Town, Cape Town, South Africa Miguel Angel Mercado Diaz, MD Professor and Chairman, Department of General Surgery, National Institute of Medical Science and Nutrition, Mexico DF, Mexico Gerald C. O'Sullivan, MD, FRCSI, FACS (Hon) Professor of Surgery, University College Cork, Mercy University Hospital, Cork, Ireland Ori D. Rotstein, MD Surgeon-in-Chief, St. Michael's Hospital, Professor, Department of Surgery, University of Toronto, Toronto, Ontario, Canada John F. Thompson, MD Melanoma Institute Australia, Royal Prince Alfred and Mater Hospitals, Sydney, Australia, Discipline of Surgery, The University of Sydney, Sydney, Australia Garth Warnock, MD, MSc, FRCSC Professor and Head, Department of Surgery, Universtiy of British Columbia, Surgeon-in-Chief, Vancouver Teaching Hospitals, Vancouver, British Columbia, Canada Liwei Zhu, MD Department of Surgery, Tianjin Medical University Hospital, Tianjin, China *Deceased

KEY POINTS 1. The Accreditation Council for Graduate Medical Education (ACGME) Outcomes Project changes the focus of graduate medical education from how programs are potentially educating residents to how programs are actually educating residents through assessment of competencies. 2. The six core competencies are patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice. 3. The Residency Review Committee recognizes the importance of simulators for technical training and mandated that all training programs have a skills laboratory by July 2008. A Surgical Skills Curriculum Task Force has developed a National Skills Curriculum to assist programs with training and assessing competency through simulators. 4. The ACGME has developed a professional development tool called the ACGME Learning Portfolio. This interactive webbased portfolio can be used as a tool for residents, faculty, and programs directors to allow for reflection, competency assessment, and identification of weaknesses. 5. There is much to be learned still, and programs should continue to share their experiences to identify benchmark programs.

ACCREDITATION COUNCIL FOR GRADUATE MEDICAL EDUCATION OUTCOMES PROJECT Technologic and molecular advances have fundamentally changed the way medicine is practiced. The Internet has revolutionized the way both physicians and patients learn about diseases. In addition, political and economic pressures have altered the way society views and reimburses medical care. The end result of these changes is that access to medical care, access to information about medical care, and the very nature of the doctor-patient relationship has changed. 1 In response to this situation, the Accreditation Council for Graduate Medical Education (ACGME) Outcomes Project was developed. Dr. Leach stated that this initiative was based on three principles: (1) whatever we measure we tend to improve; (2) focusing on outcomes instead of processes allows programs flexibility to adapt based on their needs and resources; and (3) the public deserves to have access to data demonstrating that graduating physicians are competent. 2 This initiative changed the focus of graduate medical education from how programs were potentially educating residents by complying with the accreditation requirements to how programs are actually educating residents through assessment of the program's outcomes. In 1999, the Outcomes Project identified six core competencies that would provide a conceptual framework to train residents to competently and compassionately treat patients in today's changing health care system. The six core competencies as designated by the ACGME are patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice (Table 1-1). 3 Starting in July 2001, the ACGME

implemented a 10-year timeline to implement these concepts into medical education. The timeline was divided into four phases, allowing flexibility for individual programs to meet these goals (Table 1-2). 4 Table 1-1 Accreditation Council for Graduate Medical Education Core Competencies Core Competency

Description

Patient care

To be able to provide compassionate and effective health care in the modern-day health care 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 health care 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 health care delivery system and to be able to use the system to support patient care Table 1-2 Accreditation Council for Graduate Medical Education Timeline Phase

Dates

1. Forming an initial response to changes in requirements

July 2001– June 2002

Program Focus Define objectives for residents to demonstrate learning the competencies Review current approaches to evaluation of resident learning

Accreditation Focus Develop operational definitions of compliance Provide constructive citations and recommendations with no consequences

Begin integrating the teaching and learning of competencies into residents' didactic and clinic experience

2. Sharpening the focus

July 2002– June 2006

Provide learning opportunities in all six competencies

Review evidence that programs are teaching and assessing the competencies

Improve evaluation process to obtain accurate resident performance on the six core competencies

Provide constructive citations early in the phase and transition to citations with consequences later

Provide aggregated resident performance data for the program's GMEC internal review

3. Full integration

July 2006– June 2011

Use resident performance data as basis for improvement and provide evidence for accreditation review Use external measures to verify resident and program performance

Review evidence that GMECs' internal reviews of programs include consideration of aggregated performance data

Review evidence that programs are making data-driven improvements Review external program performance measures and input from GMECs as evidence for achieving educational goals

levels

4. Expansion

July — 2011– beyond

Identify benchmark programs Adapt and adopt generalizable information about models of excellence Invoke community about building knowledge about good graduate medical education

GMEC = graduate medical education committee.

CORE COMPETENCIES The core competencies include six specific areas that have been designated as critical for general surgery resident training. Each surgical training program must provide an environment that is conducive to learning the core competencies, establish a curriculum that addresses each of the competencies, and assess that learning has taken place (see Table 1-1). The six core competencies are as follows 5 : 1. Patient Care. Residents must be able to provide patient care that is compassionate, appropriate, and effective for the treatment of health problems and the promotion of health. Residents: a. Will demonstrate manual dexterity appropriate for their level; b. Will develop and execute patient care plans appropriate for the resident's level, including management of pain; c. Will participate in a program that must document a clinical curriculum that is sequential, comprehensive, and organized from basic to complex. The clinical assignments should be carefully structured to ensure that graded levels of responsibility, continuity in patient care, a balance between education and service, and progressive clinical experience are achieved for each resident. 2. Medical Knowledge. Residents must demonstrate knowledge of established and evolving biomedical, clinical, epidemiological, and social-behavioral sciences, as well as the application of this knowledge to patient care. Residents: a. Will critically evaluate and demonstrate knowledge of pertinent scientific information, and b. Will participate in an educational program that should include the fundamentals of basic science as applied to clinical surgery, including applied surgical anatomy and surgical pathology; the elements of wound healing; homeostasis, shock and circulatory physiology; hematologic disorders; immunobiology and transplantation; oncology; surgical endocrinology; surgical nutrition, fluid and electrolyte balance; and the metabolic response to injury, including burns. 3. Practice-Based Learning and Improvement. Residents must demonstrate the ability to investigate and evaluate their care of patients, to appraise and assimilate scientific evidence, and to continuously improve patient care based on constant selfevaluation and life-long learning. Residents are expected to develop skills and habits to be able to meet the following goals: a. Identify strengths, deficiencies, and limits in one's knowledge and expertise; b. Set learning and improvement goals; c. Identify and perform appropriate learning activities; d. Systematically analyze practice using quality improvement methods, and implement changes with the goal of practice improvement; e. Incorporate formative evaluation feedback into daily practice; f. Locate, appraise, and assimilate evidence from scientific studies related to their patients' health problems;

g. Use information technology to optimize learning; h. Participate in the education of patients, families, students, residents and other health professions; i. Participate in mortality and morbidity conferences that evaluate and analyze patient care outcomes; and j. Utilize an evidence-based approach to patient care. 4. Interpersonal and Communication Skills. Residents must demonstrate interpersonal and communication skills that result in effective exchange of information and collaboration with patients, their families, and health professionals. Residents are expected to: a. Communicate effectively with patients, families, and the public, as appropriate, across a broad range of socioeconomic and cultural backgrounds; b. Communicate effectively with physicians, other health professionals, and health related agencies; c. Work effectively as a member or leader of a health care team or other professional group; d. Act in a consultative role to other physicians and health professionals; e. Maintain comprehensive, timely, and legible medical records, if applicable. f. Counsel and educate patients and families; and g. Effectively document practice activities. 5. Professionalism. Residents must demonstrate a commitment to carrying out professional responsibilities and an adherence to ethical principles. Residents are expected to demonstrate: a. Compassion, integrity, and respect for others; b. Responsiveness to patient needs that supersedes self-interest; c. Respect for patient privacy and autonomy; d. Accountability to patients, society and the profession; e. Sensitivity and responsiveness to a diverse patient population, including but not limited to diversity in gender, age, culture, race, religion, disabilities, and sexual orientation; f. High standards of ethical behavior; and g. A commitment to continuity of patient care. 6. Systems-Based Practice. Residents must demonstrate an awareness of and responsiveness to the larger context and system of health care, as well as the ability to call effectively on other resources in the system to provide optimal health care. Residents are expected to: a. Work effectively in various health care delivery settings and systems relevant to their clinical specialty; b. Coordinate patient care within the health care system relevant to their clinical specialty; c. Incorporate considerations of cost awareness and risk-benefit analysis in patient and/or population-based care as appropriate; d. Advocate for quality patient care and optimal patient care systems; e. Work in inter-professional teams to enhance patient safety and improve patient care quality; f. Participate in identifying system errors and implementing potential systems solutions; g. Practice high quality, cost effective patient care;

h. Demonstrate knowledge of risk-benefit analysis; and i. Demonstrate an understanding of the role of different specialists and other health care professionals in overall patient management. The goal of any surgical training program is to train physicians to provide the highest quality of patient care. The core competency mandates have set into motion changes in education that result in measurable outcome-based training. The challenge of the surgical educator is to develop innovative and focused learning techniques to accomplish this mandate within an 80-hour work week.

Patient Care Patient care is the foundation for the practice of clinical medicine and must be addressed early and continuously during residency. Historically, patient care has been taught by an apprenticeship model; in other words, by the residents' spending time with attending physicians on the wards or in the operating rooms.6 However, this training method has to be reevaluated as a result of the ever-increasing constraints and changes in our health care system. Increasing public awareness of medical legal errors has resulted in heightened scrutiny with regard to patient safety issues. 1 In addition, there are increasing concerns related to the perceived financial setback and medical-legal impact of resident training in the operating room.7 Even with the inherent flexibility provided by the ACGME, all of these factors, coupled with the work hour restrictions, 8 make surgical training in the modern health care system an especially challenging endeavor. Not only must educators impart the medical knowledge of caring for patients and new advances in patient care, but they must also impart the technical skills necessary to perform complex surgical procedures. One of the subcompetencies under patient care is that residents "will demonstrate manual dexterity appropriate for their level."5 Traditionally, the operating room has been used to train residents in the technical aspects of patient care by "see one, do one, and teach one." A study by Velmahos and colleagues evaluated the knowledge and technical skills of residents who were randomly assigned either to training using the traditional approach or to training in a surgical skills laboratory using the principles of cognitive task analysis. This study revealed that the residents who trained using the laboratory approach had improved medical knowledge and technical skills.9 Multiple studies like the one previously mentioned have revealed improved performance with simulators and advocated their use in technical skills training. 10–12 Having recognized the importance of incorporating simulation training into today's residency, the Residency Review Committee (RRC) mandated that all surgery programs be required to have a surgical skills laboratory by July 2008 to maintain their accreditation.13 To assist programs, the Surgical Skills Curriculum Task Force, a joint project of the American College of Surgeons (ACS) and the Association of Program Directors in Surgery, developed a standardized skills curriculum. 14,15 This curriculum was developed in three phases (Table 1-3): phase I with modules for junior residents, phase II for senior residents, and phase III for team training. Another resource that programs may use in developing a surgical skills curriculum is the Fundamentals of Laparoscopic Surgery (FLS) program. This program is endorsed by the ACS and the Society of Gastrointestinal and Endoscopic Surgeons. The FLS consists of a comprehensive curriculum with hands-on skills training and an assessment tool designed to teach and assess the fundamentals of laparoscopic surgery. 16 Future goals for surgical education include a method to ensure that residents are "certified" and deemed competent to perform a procedure in a simulator environment before allowing residents to perform that particular procedure in the operating room.17 Table 1-3 National Skills Curriculum Phases and Launch Dates Phase

Dates

I

Basic/core skills and tasks

July 2007

II

Advanced procedures

January 2008

III

Team-based skills

July 2008

The RRC has mandated that all residency programs develop a surgical skills laboratory, and the majority of program directors feel that this is an important part of residency training. However, a study by Korndorffer and associates just before the mandate was issued revealed that only 55% of the 162 programs that replied to the survey had a surgical skills laboratory facility.18 The average cost to develop a laboratory has been reported as $133,000 to $450,000, but the cost can range from $300 to $3 million. 18,19 Kapadia and colleagues surveyed 40 programs with surgical skills laboratories in place and found that funding came from industry (68%), surgery departments (64%), hospitals (46%), and other sources (29%). They also found a wide variation in the size of the facility, location, availability of simulators, protected time for skills training, and curriculum. This study also revealed that 65% of the programs believed that it was somewhat difficult to recruit faculty members to staff the laboratory; however, this could be related to the fact that 69% of the laboratories did not offer any faculty incentive to teach. 19 These studies suggest that although most surgical educators believe that surgical skills laboratories are important for resident education, there is still much room for improvement and standardization. In addition to technical competency, residents are expected to "develop and execute patient care plans appropriate for the resident's level, including management of pain." 5 This can be reinforced during attendance at rounds and integrated into many of the conferences that are currently available in many surgery programs, such as grand rounds and the morbidity and mortality conference. 20,21 Prince and others demonstrated in an institutional study that use of an interactive format for the morbidity and mortality conference improved the educational value of the conference for residents at all levels. 22 Rosenfeld restructured the morbidity and mortality conference to make it more competence based. For example, each patient case was further divided into separate categories such as patient communication, ethical dilemmas, system problems, and practicebased improvement to enhance patient care. 20 Stiles and associates developed a morning report conference after the implementation of the night float system to improve patient sign-out procedures. They found that this forum not only helped to improve communication but also allowed for teaching, discussion of patient care plans, and direct evaluation of resident competence. 23

Medical Knowledge The ACGME has mandated that "residents must demonstrate knowledge of established and evolving biomedical, clinical, epidemiological, and social-behavioral sciences, as well as the application of this knowledge to patient care." 5 Surgery has undergone an exponential growth in new procedures and technology. With this explosion in medical innovation, training programs are posed with the daunting task of not only teaching the technical aspects of surgery, but also imparting the basic science and fundamentals of surgical diseases. Furthermore, development of the field of molecular biology and its application to surgical diseases has mandated that surgeons understand the basic molecular mechanisms of each disease process. 24,25 The new era of molecular biology requires understanding the complex science that can lead to advances such as molecular fingerprinting techniques to tailor treatments that are specific for each individual patient. Other, more cognitive tools such as how to critically review literature and how to logically evaluate the relevance of a study must also be imparted to residents so that they can correctly apply findings of the latest medical studies to each individual patient. The ACGME mandates that residents "will participate in an educational program that should include the fundamentals of basic science as applied to clinical surgery, including applied surgical anatomy and surgical pathology; the elements of wound

healing; homeostasis, shock and circulatory physiology; hematologic disorders; immunobiology and transplantation; oncology; surgical endocrinology; surgical nutrition, fluid and electrolyte balance; and the metabolic response to injury, including burns."5 The ability of a surgical program to adequately meet this educational challenge can be improved by using innovative learning techniques. Educational systems such as the SQR3 (Survey, Question, Read, Recite, and Review) system of studying,26 the Pimsleur model, 27 and Rosetta Stone learning techniques 28 are all tools that can aid in the understanding and application of advances in a rapidly changing surgical field. The authors' surgery residency program combined adult learning principles with some of these learning techniques into a problem-based learning program that met weekly after grand rounds. This mandatory, focused curriculum for the residents incorporated both basic science and its clinical application in an interactive and collaborative format. This educational format led to high resident satisfaction and also a sustainable increase in resident American Board of Surgery In-Training Examination scores.29,30 Residents are also expected to "critically evaluate and demonstrate knowledge of pertinent scientific information." 5 Residents can be taught early how to critically review the literature using the format of a journal club. The journal club is a widely used technique through which to disseminate the latest in medical knowledge. Even as early as the late 1980s, a study in the Journal of the American Medical Association found that residents who participated in a journal club had improved reading habits and improved medical knowledge compared with their peers who did not participate in a journal club.31 The wide use of journal clubs in surgery education can be seen as a necessary foundation for medical education. In one survey, over 65% of general surgery residency programs have a journal club that meets at least once a month to discuss relevant surgical and medical topics.32 MacRae and others took this approach a step further by evaluating the effect of a multifaceted Internetbased journal club and found that this learning format improved the skills of the surgical residents to critically appraise the medical literature.33 Many online resources are available for residents that provide an abundant amount of material for study, reference, and interactive learning. 34–36 In particular, AccessSurgery provides an extensive online resource with medical data and operative techniques, with a core curriculum organized around the ACGME mandates.34 Finally, and perhaps most importantly, it must be conveyed to surgical trainees that surgery is a lifelong learning process, and the ability to continue building on one's medical knowledge is critical for a successful surgical career.

Practice-Based Learning and Improvement The third ACGME mandate states that "residents must demonstrate the ability to investigate and evaluate their care of patients, to appraise and assimilate scientific evidence, and to continuously improve patient care based on constant selfevaluation and life-long learning." 5 This mandate comes from the increasing public demand for accountability and increased demand for data regarding outcomes for specific surgeon.2 Practice-based learning and improvement involves a cycle of four steps: identify areas for improvement, engage in learning, apply the new knowledge and skills to a practice, and check for improvement. 37 This ability to critically and impartially analyze one's practice patterns to continually improve patient care should start early during training, so that this behavior becomes second nature for residents when they become practicing surgeons. In residency training, the simplest example of practice-based learning is the surgical morbidity and mortality conference. This conference traditionally allows for in-depth discussions of surgical cases and adverse patient outcomes. Complications are categorized (preventable, probably preventable, possibly preventable, and unpreventable) and areas of improvement are identified. Rosenfeld as well as Williams and Dunnington have reformatted this conference to make it more competence based by having residents assess themselves. Residents are required to fill out a practice-based improvement form and identify areas of improvement. 20,38 Another innovative modality to teach practice-based learning was described by Canal and

colleagues, who developed a 6-week curriculum in continuous quality improvement for surgery residents that included a specific project. In this project, the residents identified a need for quality improvement, implemented a plan for improvement, and developed a method to measure the improvement. These residents scored significantly higher in knowledge of and experience in quality improvement after completing this curriculum and felt that it was an effective and formal way to teach them the science of practice-based improvement. 39 Clearly, for surgeons to identify areas of improvement, there has to be some method to allow for comparison and reflection. An interesting Internet-based learning portfolio called Computerized Obstetrics and Gynecology Automated Learning Analysis (KOALA) was developed for the obstetrics and gynecology residents in Canada. This portfolio encouraged self-analysis and self-directed learning by allowing residents to log patient encounters, list critical events and questions derived from these events, look up data used to answer these questions, and state how their practice patterns would be altered based on their reflections. Residents who used this method to reflect and critically analyze their performance scored significantly higher on the Self-Directed Learning Readiness Scale, looked forward to learning for life, and had a strong desire to learn new things. 40 An avenue currently available for practicing surgeons and residents to analyze their outcomes is the ACS Case Log System. This system was developed to support practice-based learning and improvement by allowing surgeons to voluntarily report their own results and compare them to those of other surgeons enrolled in the system. This allows surgeons to critically evaluate their practice outcomes and identify areas that need improvement. 41 To further improve practice patterns, the ACGME has mandated that trainees must understand the use of information technology systems to manage patient information and support clinical care. Technology is rapidly improving, and hospitals are increasing their efficiency by using electronic medical records. One of the best examples of this is the Computerized Patient Record System (CPRS) used by the Veterans Affairs (VA) hospital system. This fully computerized patient database allows easy access to all patient clinical data, including laboratory tests, radiographic studies, physician notes, and appointment times. Use of this central core information system also has allowed the VA health system to develop the National Surgical Quality Improvement Program (NSQIP). 42 Using information from the CPRS, nurse reviewers are able to gather and input information into the NSQIP system. NSQIP has been the first prospective risk-adjusted outcomes-based program for comparing and improving surgical outcomes across multiple institutions. This program has revolutionized the reporting and quality control of surgical services within the VA system. Practice-based learning is complex and involves many components, including self-awareness, critical thinking, problem solving, self-directed learning, analysis of outcomes, use of information technology, and focus on evidence-based medicine to improve practice outcomes and patient care. 5 This competency is multifaceted, and an extensive literature review by Ogrinc and associates found little instruction on how to impart these important skills to our residents. Much work appears to be needed before an ideal curriculum can be developed. Future plans should be made for faculty to develop these skills and for programs to continually share their experiences. 43

Interpersonal and Communication Skills The fourth competency mandated by the ACGME is that "residents must demonstrate interpersonal and communication skills that result in effective exchange of information and collaboration with patients, their families, and health professionals." 5 Effective communication between physicians, patients, and other health care professionals is essential to the successful and competent practice of medicine and patient care. Studies reveal that physicians with good communication and interpersonal skills have improved patient outcomes and are subject to less medical litigation. 44–46 In support of this, a root cause analysis by the Joint Commission identified breakdown in communication as the leading cause of wrong-site operations and

other sentinel events. 47 The ACS has developed a Task Force on Communication and Interpersonal Skills to specifically address this issue and encourage practicing surgeons to develop these important skills.48 The goal of this task force is to appropriately address the core competency of interpersonal skills and communication and to use novel educational techniques to improve these skills. Certain areas, such as palliative care and patient mortality, have not been a focus for surgeons or surgical trainees but are critical in the surgeon-patient relationship. Four areas in which surgeons can improve their communication skills have been identified in palliative care: the preoperative visit, and discussion of a poor prognosis, surgical complications, and death. 49 These are situations that all surgeons will face at some point in their careers, and the ability to communicate effectively and compassionately with patients during these stressful times is an important skill to develop. Fortunately, multiple techniques for imparting this particular skill have been described in the literature. The group at Southern Illinois University had teams of senior surgical faculty and a faculty member from the Department of Medical Humanities develop a case-based ethics curriculum that covered topics such as resource allocation, research ethics, substituted consent, competition of interests, truth telling, and communication. 17 Other methods to teach communication skills have relied on the use of standardized patients.38,50,51 Yudkowsky and associates assessed the use of a patient-based communication skills examination. Their conclusion was that the use of a patient-based examination was able to demonstrate consistent results and that verbal feedback was beneficial for resident education on improvement of communication skills.50 Other recommended teaching strategies include observation with real-time feedback, role modeling, self-assessment, and videotaping. 52 Residents also are expected to "work effectively as a member or leader of a health care team or other professional group" 5 (Fig. 1-1). This is particularly important for surgeons, because caring for surgical patients requires a team approach to safely get the patient from the preoperative evaluation process, to the operating room, and through the postoperative course. Surgeons are typically the leaders of such teams; hence, it is important for residents to develop the necessary leadership skills during training. With less time spent in the hospital, the ability to learn from real-life situations is limited. Therefore, these principles need to be taught through other creative means such as didactic lectures or problem-based learning. Studies have revealed that formal leadership training not only improves communication skills 53,54 but also helps to develop conflict resolution skills.55 Awad and colleagues instituted a formal collaborative leadership training program and found that this format significantly increased the residents' views of leadership in the areas of alignment, communication, and integrity.56 Having recognized leadership training as a necessity for surgeons to thrive in today's medical environment, the ACS offers a course called "Surgeons as Leaders: From Operating Room to Boardroom," whose purpose is to provide surgeons with the skills needed for effective leadership. 57 Fig. 1-1.

Establishing interpersonal and communication skills equips residents with the necessary tools to communicate effectively with both patients and health professionals. A subcompetency under communication and interpersonal skills is to "maintain comprehensive, timely, and legible medical records." 5 Not only does communication occur in person, but physicians commonly communicate their plans and thoughts in the medical record. One of the predominant issues in health care is medical errors related to poor communication. The consequences of poor communication have been shown to cause delays in patient care, improper use of resources, and serious adverse events that lead to significant morbidity and mortality.58 This is especially important now, as many programs have instituted the night float system to maintain compliance with the work hour restrictions. For this system to work effectively, communication is integral for safe patient care during shift changes.59,60 One example of a creative approach to this new challenge of information transfer is a web-based system that allows for secure storage of patient information, maintenance of patient lists, access to laboratory values and vital sign data, and ability to compile this information to a signout list that can be passed on to a coverage team. 61 The residents that participated in the study of this system reported better sign-out quality, decreased time collecting data on prerounds, increased patient contact time, and improved continuity of care. Other medical centers also have begun to institute the use of computerized web-based systems for resident signout, and this format may become more widespread as the efficiency and safety of these systems become more apparent. Not only should surgeons be technically competent and medically knowledgeable, but interpersonal and communication skills are also vital to patient care. The inherent nature of surgery often requires the bearing of bad news, disclosure of complications, and discussion of end-of-life issues. Learning and harnessing the skill of doing these things well during residency will provide a lifelong tool to effectively and compassionately care for patients.

Professionalism The core competency of professionalism is expressed as follows: "residents must demonstrate a commitment to carrying out professional responsibilities, adherence to ethical principles, and sensitivity to a diverse patient population." 5 The trainee

should demonstrate respect, compassion, and integrity while involved in patient care. In addition, residents should understand that their patients' needs supersede their own self-interest and that they are to be held accountable to their patients, society, and the profession. 5 The ACS endorsed the Charter of Medical Professionalism as its Code of Professional Conduct in 2002.62,63 This model of professionalism is based on three principles. First, the physician should be dedicated to the patient's welfare. This should supersede all financial, societal, and administrative forces. Second, the physician should have respect for the patient's autonomy. This entails being honest and providing the patient with all the necessary information to make an informed decision. Third, the medical profession should promote justice in the health care system by removing discrimination due to any societal barriers. 64 The ACS also has developed a Task Force on Professionalism to address the competency of professionalism for practicing surgeons and surgical residents. In 2004, this task force stated that professionalism is not just a desirable trait for surgeons to acquire peripherally but is the "central core" of the profession of surgery. The task force has stated the principles of professionalism and defined the responsibility of surgeons to commit to excellence.65 In addition, it also has created a multimedia program geared toward teaching residents and surgeons about the principles of professionalism through clinical vignettes and discussions. 66 Kumar and associates evaluated this learning tool and found that residents who watched the ACS DVD had improved conceptual understanding of professionalism and scored higher on tests that evaluated these concepts than their peers who had not watched the video. 67 Professionalism also has been taught by various other methods reported in the literature. A training program at the University of Washington set out to see if professionalism was teachable, learnable, and measurable. This group defined professionalism, developed a curriculum to teach professionalism, and evaluated these traits by a previously validated tool known as the Global Resident Competency Rating Form. They found that, after implementation of the curriculum, residents evaluated by the faculty were given significantly higher scores for traits that demonstrate professionalism such as (a) demonstrating respect, compassion, integrity, and reliability; (b) showing commitment to ethical principles; and (c) displaying sensitivity to patient culture, age, sex, and disabilities. 68 Rosenfeld also described a curriculum for professionalism taught by leaders in the community. This 2-year course on professionalism dealt with various topics such as ethics, communication, professional development, respect, sensitivity, and health care delivery. The topics were presented in various formats via lectures, discussion panels, small groups, and videos. The residents were then assessed for competency through quizzes on clinical vignettes and 360-degree evaluations. The preliminary results revealed that residents were treating their patients and other health care workers in a more professional manner.69 Heru described the use of role playing and instructional videotapes in teaching professionalism to residents. The residents who were taught using this format showed an increased awareness of unprofessional behavior and increased sensitivity to others, and were able to better deal with conflict. 70 Teaching residents how to navigate through difficult situations and manage conflict is also another important aspect of professionalism, which can further promote an environment of integrity and mutual respect. Fisher and Ury have described four principles for successful conflict resolution: (a) maintain objectivity by not focusing on the participants but focusing on the problem, (b) relinquish the position of power and inflexibility to concentrate more on individual interests, (c) create outcomes in which both parties will have gains, and (d) make sure there are objective criteria for the negotiating process. All of these principles are related to maintaining an open mind and dialogue and yielding to principles, not pressure. 71 These four principles can be integrated into a curriculum through various teaching techniques to help residents deal with conflict in a nonhostile and productive manner. The ACS has set standards on professional behavior in the Code of Professional Conduct. With these standards used as a

conceptual framework, the development of professionalism should be a continuous process for any physician. Surgeons should constantly analyze and reflect on their behavior and continue to work toward actions based on integrity, honesty, respect, altruism, compassion, accountability, excellence, and leadership. This is an area in which surgical educators, acting as mentors and role models through daily interactions with their patients, residents, and peers, may be the most powerful teaching tool (Fig. 1-2). 72,73 Fig. 1-2.

Dr. Michael E. DeBakey, a surgical pioneer and transformational health care leader, served as a mentor and role model to generations of residents and inspired professionalism and the pursuit of excellence. He is pictured here with a group of chief residents at the Baylor College of Medicine.

Systems-Based Practice The ACGME has mandated that "residents must demonstrate an awareness of and responsiveness to the larger context and system of health care, as well as the ability to call effectively on other resources in the system to provide optimal health care." 5 In today's medical world, resources and finances are limited, and each health care provider must understand that the business aspect of medicine is closely interrelated with the effective delivery of care. As health care costs have grown, so have health care management organizations. Learning how to interact with these organizations is crucial for the improvement of health care delivery and allocation of resources. Some reports have demonstrated that surgeons feel deficient in the understanding of public health and the business aspects of surgery. 74 The ACS has developed a Task Force on Systems-Based Practice to specifically address this particular competency. 75 Systems-based practice is not inherently integrated into the surgical curriculum; therefore, it may be more challenging to incorporate and teach. Several methods for educating residents about systems-based practice have been described in the literature. Dunnington and Williams have arranged for residents to participate in hospital committees that focus on quality improvement and patient safety. The residents keep a journal of the issues that are discussed during the meetings and reflect on how these issues will affect the way that they practice medicine in the future. Both committee members and

residents have found this to be a constructive learning process. 17 Davison and colleagues described a longitudinal systemsbased practice into their 3-year-long core curriculum which included group discussions (risk management, discharge planning, patient relations), didactic lectures (structure of health care, pathway to surgery, current procedural terminology, governance, contract negotiations), and hospital training sessions. Personnel with expertise in health care delivery systems and health care management were enlisted to teach some of these courses. 76 Englander and associates applied systemsbased practice by involving residents in the process of cost-reduction efforts. The residents identified a project that was cost inefficient then identified key issues, devised improvement plans, and subsequently implemented them. This educational exercise saved the hospital over $500,000 per year. The authors concluded that involving residents in cost-reduction efforts helps to teach and assess the skill of systems-based practice.77 Conferences such as grand rounds, morbidity and mortality conferences, and morning reports have also been modified to teach the principles of systems-based practice.20,21,23 Given today's changing health care economics, surgeons are faced with the need to understand the business aspects of medicine to care optimally for patients. This involves being able to work effectively in different health care settings, incorporating cost awareness and risk-benefit analysis in patient care, improving patient safety and quality of care, and identifying system errors and implementing solutions (Fig. 1-3). 5 Unfortunately, this has not been an inherent part of surgical training, and many physicians do not feel that they have an adequate understanding of these concepts. 74 However, there are strides in the right direction with various novel methods to incorporate systems-based practice into surgical curriculums. Fig. 1-3.

One of the ACGME core competencies requires that residents demonstrate an awareness of and responsiveness to the larger context and system of health care, as well as the ability to call effectively on other resources in the system to provide optimal health care. The Texas Medical Center in Houston, Texas, encompasses 740 acres and 42 member institutions where residents must learn to navigate, comprehend, and utilize the larger health care system as a whole.

ASSESSMENT AND THE ACCREDITATION COUNCIL FOR GRADUATE

MEDICAL EDUCATION LEARNING PORTFOLIO The ACGME not only has mandated the teaching of the six core competencies but also has stated that residents must be evaluated to ensure that they have acquired these necessary skills. There is little doubt that, in the future, these or similar core competencies will be used to assess practicing surgeons as well. Hence, the need to document the acquisition and maintenance of these competencies is important to all surgeons, not just those in training. Competence has been defined as "the ability to do something well measured against a standard, especially ability acquired through training." 78 Miller has described a model of competency that consists of four levels: "knows," "knows how," "shows how," and "performs." Residents, early in their training, would most likely attain the level of "knows" and "knows how." This would be comparable to a resident's understanding the pathology and clinical diagnosis of appendicitis and the appropriate treatment algorithms. The "shows how" level would be demonstrated by a resident who could demonstrate how to perform an appendectomy while being supervised by faculty on a simulator or animal model. The "performs" level is the competence level at which the surgeon could perform this operation without any supervision or assistance in a real-life clinical situation. The levels of competency are not based on postgraduate year but are based on the ability to specifically meet a defined objective set forth by a surgical curriculum. 79 The most pressing question is how to implement a competency-based curriculum and, perhaps even more of a challenge, how to assess the six core competencies. An assessment tool should ideally be reliable, valid, reproducible, and also practical. 80 The two most common evaluation tools in surgical programs have been the American Board of Surgery InTraining Examination (ABSITE) and the ward evaluation. The ABSITE is administered once a year and attempts to test the general medical knowledge and patient care knowledge of surgical trainees. A direct linear correlation has been described between the ABSITE score and the American Board of Surgery Qualifying Examination score, 81 which emphasizes the need to perform at an adequate level on the ABSITE. ABSITE scores also have been found to be higher in programs that have instituted mandatory reading programs and focused problem-based learning education programs.29,82 Overall, the ABSITE remains a tried and true method of assessing the basic medical knowledge of surgical trainees. The second method of evaluation has been the ward evaluation. These evaluations are typically performed at the end of the rotation and are subject to biases related to factors such as memory and the general impression of the surgery faculty of the given resident. These evaluations often consist of subjective terms that globally define the residents, for example, excellent, good, and very good. However, these ratings do not provide any objective data on competence. 83 Even though the ward evaluation provides general information on achievement of educational goals, the new ACGME mandates will require either revising these evaluations to make them more competence based or developing new methods for measuring outcomes. A number of programs have instituted novel evaluation tools to assess for competency in patient care and medical knowledge. The Operative Performance Rating System (OPRS) is an innovative tool used to assess the competence of patient care that was developed by Larson and colleagues. It is an Internet-based system for evaluating sentinel procedures performed by residents that assesses not only technical skills but also the intraoperative decision-making process. They found this to be a feasible and reliable method. The authors concluded that this may be a way to evaluate competence in patient care, track the development of surgical skills, identify problems early on, and certify competence in a particular procedure.84 Schell and Flynn described a web-based program for teaching and assessing medical knowledge and patient care. Residents were allowed to follow a self-paced curriculum by viewing a CD-ROM didactic lesson and participating in a minimally invasive skills laboratory to assess competency in the basics of minimally invasive surgery. They found that

residents showed significant improvement in their surgical skills, and the trainees described a high satisfaction with this program and felt that it should be an integral component of their education.10 The Objective Structured Assessment of Technical Skills (OSATS) test was developed at the University of Toronto to assess technical competency. The test is administered in stations that simulate tasks performed in the operating room, such as a small-bowel anastomosis, placement of a T tube, control of inferior vena cava hemorrhage, and so on. The participants are graded by a surgical evaluator who completes two standardized grading forms for each station. One grading form covers the specific steps and technical points of the station (i.e., correct suture, use of forceps, etc), whereas the second form is a global rating scale that evaluates the flow of operation and more subjective but important aspects of an operation. The authors concluded that this method has high reliability and construct validity for assessing competency in technical skills.85 Furthermore, the OSATS examination has been validated in a number of studies as accurately representing the technical skills of a surgical trainee when compared with performance in carrying out a procedure on a live patient. 86,87 Virtual simulators have also been used effectively to teach and assess surgical skills, medical knowledge, and practice-based learning and improvement in a controlled environment.12,88 Other competencies, such as communication and professionalism, may require a more interactive and direct means for true assessment. The methods most described in the literature involve standardized patients and the 360-degree evaluations. Yudkowsky and colleagues described a method to assess communication and interpersonal skills, patient care, and professionalism known as the Communication and Interpersonal Skills Objective Structured Clinical Assessment (CIS-OSCE) examination. This examination was administered to residents in multiple specialties at the University of Illinois at Chicago and consisted of resident interaction with standardized patients on various matters such as obtaining informed consent, relaying bad news, and discussing domestic violence. They found this method of evaluation to be valid and feasible. 50 The Patient Assessment and Management Examination (PAME) to access competencies such as patient care, communication and interpersonal skills, and professionalism has also been described. This examination consists of six stations with standardized patients. It entails an initial assessment, ordering and interpretation of test, discussion of the findings with the patient, and evaluation of a higher level of thinking with implementation of a treatment plan. These interactions are observed by a staff physician, which allows for direct assessment of competencies. 38,51 The 360-degree evaluation to assess communication and professionalism has been described for various specialties. This process involves evaluation of the resident by various people who have had interactions with the resident, including patients as well as nurses and other ancillary staff. The resident's ability to communicate effectively and behave in a professional manner is evaluated based on a scale. This method has been found to be a valid and reliable method to assess for the competencies; however, it can be difficult to carry out.89–91 Practice-based learning and systems-based practice have been assessed through existing conferences. Rosenfeld as well as Williams and Dunnington revised their morbidity and mortality conference to allow for assessment of practice-based learning by having residents fill out a practice-based learning log. This allowed staff to determine whether the residents were able to identify key issues and implement improved practice patterns. 20,38 Stiles and associates developed a competency-based morning report format and felt that this was an ideal environment in which to directly assess many of the core competencies, including systems-based practice and practice-based learning, through direct interactions with the residents. 23 In 2004, the Association of Program Directors and the ACS worked together to develop a web-based system to evaluate all of the core competencies at the end of residents' rotations. This evaluation system was studied throughout multiple institutions and found to be both a reliable and valid method to assess the core competencies. 92 In addition, the ACGME has developed a professional developmental tool called the ACGME Learning Portfolio. This portfolio is an interactive web-based

portfolio that allows residents to record, organize, and reflect back on their learning experiences. Residents, faculty, and program directors can use this portfolio as a tool to allow for constructive feedback, to monitor a resident's progress, and to identify areas of weakness. It will also enable program directors to evaluate the quality of their curriculums and isolate deficiencies that require improvement. 93 Both of these tools use the web for data collection and evaluation, which allows for centralization and ease in interpretation of the data, permits use of real-time data to identify strengths and weaknesses, and may allow programs to provide competency-based performance data for the RRC. The number of assessment tools for the core competencies continues to increase as programs learn from trial and error. Programs should continue to share their work through publications to identify programs with models of excellence that can be adopted at other institutions (see Table 1-2).

CONCLUSION The goal of the ACGME core competency mandate has been to ensure that patient care continues to improve into the twenty-first century with the development of benchmark programs and best educational practices. The goal of the modern surgical educator is to develop a better means to ensure that the material is properly taught and, even more importantly, truly learned. The defined core competencies provide an excellent framework for surgical education. This supplies an exciting foundation for the introduction of new educational initiatives and the development of novel educational programs through collaboration. These innovations should serve to move surgical education forward and allow for improved training of the surgeons of the future.

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Schwartz's Principles of Surgery > Part I. Basic Considerations > Chapter 2. Systemic Response to Injury and Metabolic Support >

KEY POINTS 1. Systemic inflammation is characterized by exaggerated immune responses to either a sterile or infectious process. The cause of inflammatory activation needs to be addressed to resolve the dysregulated immune state. 2. An understanding of the signaling mechanisms and pathways underlying systemic inflammation can help guide therapeutic interventions in injured and/or septic patients. 3. Management of such patients is optimized with the use of evidence-based and algorithm-driven therapy. 4. Nutritional assessments, whether clinical or laboratory guided, and intervention should be considered at an early juncture in all surgical and critically ill patients. 5. Excessive feeding should be avoided in an effort to limit complications, including ventilator dependency, aspiration events, and infections.

SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT: INTRODUCTION The immune system has developed to respond to and neutralize pathogenic micro-organisms as well as coordinate tissue repair. The inflammatory response to injury or infection involves cell signaling, cell migration, and mediator release. Minor host insults instigate a local inflammatory response that is transient and in most cases beneficial. Major host insults may propagate reactions that can become amplified, resulting in systemic inflammation and potentially detrimental responses. This topic is highly relevant because systemic inflammation is a central feature 1 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 increasing incidence of over 900,000 cases per year. Trauma is the leading cause of mortality and morbidity for individuals under 50 years of age. This chapter reviews the autonomic, cellular, and hormonal responses to injury. These facets of the inflammatory response to injury and infection are discussed in reference to the specific response being considered.

SYSTEMIC INFLAMMATORY RESPONSE SYNDROME The systemic inflammatory response syndrome (SIRS) is characterized by a sequence of host phenotypic and metabolic responses to systemic inflammation that includes changes in heart rate, respiratory rate, blood pressure, temperature regulation, and immune cell activation (Table 21). The systemic inflammatory response includes two general phases: (1) an acute proinflammatory state resulting from innate immune system recognition of ligands, and (2) an anti-inflammatory phase that may serve to modulate the proinflammatory phase. Under normal circumstances, these coordinated responses direct a return to homeostasis2 (Fig. 2-1). Table 2-1 Clinical Spectrum of Infection and Systemic Inflammatory Response Syndrome (SIRS) Term

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 Pa CO2

White blood cell count 12,000/ L or Sepsis

32 mmHg or mechanical ventilation

4000/ L or 10% band forms

Identifiable source of infection + SIRS

Severe sepsis Sepsis + organ dysfunction Septic shock

Sepsis + cardiovascular collapse (requiring vasopressor support)

Pa CO2 = partial pressure of arterial carbon dioxide. Fig. 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 20:437, 1996. With kind permission from Springer Science + Business Media.)

CENTRAL NERVOUS SYSTEM REGULATION OF INFLAMMATION Afferent Signals to the Brain The central nervous system (CNS) plays a key role in orchestrating the inflammatory response. The CNS influences multiple organs through both neurohormonal and endocrine signals. Injury or infection signals are recognized by the CNS through afferent signal pathways (Fig. 2-2). The CNS may respond to peripheral inflammatory stimuli through both circulatory and neuronal pathways. Inflammatory mediators activate CNS receptors and establish phenotypic responses such as fever and anorexia. The vagus nerve has been described as highly influential in mediating afferent

sensory input to the CNS.3 Fig. 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 420:853, 2002. Copyright © 2002.)

Cholinergic Anti-Inflammatory Pathways The vagus nerve exerts several homeostatic influences, including enhancing gut motility, reducing heart rate, and regulating inflammation. Central to this pathway is the understanding of neurally controlled anti-inflammatory pathways of the vagus nerve. Parasympathetic nervous system activity transmits vagus nerve efferent signals primarily through the neurotransmitter acetylcholine. This neurally mediated anti-inflammatory pathway allows for a rapid response to inflammatory stimuli and also for the potential regulation of early proinflammatory mediator release, specifically tumor necrosis factor (TNF). 4 Vagus nerve activity in the presence of systemic inflammation may inhibit cytokine activity and reduce injury from disease processes such as pancreatitis, ischemia and reperfusion, and hemorrhagic shock. This activity is primarily mediated through nicotinic acetylcholine receptors on immune mediator cells such as tissue macrophages. Furthermore, enhanced inflammatory profiles are

observed after vagotomy, during stress conditions. 4 Experimental trials have studied this pathway to develop therapeutic interventions. Specifically, nicotine, which also activates nicotinic acetylcholine receptors on immune cells, has been shown to reduce cytokine release after endotoxemia in animal models. 5

HORMONAL RESPONSE TO INJURY Hormone Signaling Pathways Hormones are chemical signals that are released to modulate the function of target cells. Humans release hormones in several chemical categories, including polypeptides (e.g., cytokines, glucagon, and insulin), amino acids (e.g., epinephrine, serotonin, and histamine), and fatty acids (e.g., glucocorticoids, prostaglandins, and leukotrienes). Hormone receptors are present on or within the target cells and allow signal transduction to progress intracellularly mostly through three major pathways: (1) receptor kinases such as insulin and insulin-like growth factor (IGF) receptors, (2) guanine nucleotide-binding or G-protein receptors such as neurotransmitter and prostaglandin receptors, and (3) ligandgated ion channels that permit ion transport when activated. On activation, the signal is then amplified through the action of secondary signaling molecules. Intracellular signaling leads to downstream effects such as protein synthesis and further mediator release. Protein synthesis is mediated through intracellular receptor binding either by hormone ligands or through subsequently released secondary signaling molecules. These, together with the targeted DNA sequences, activate transcription. The prototype of the intracellular hormone receptor is the glucocorticoid receptor (Fig. 2-3). This receptor is regulated by the stress-induced protein known as heat shock protein (HSP), which maintains the glucocorticoid receptor in the cytosol; however, on ligand binding, HSP is released, and the receptor-ligand complex is transported to the nucleus for DNA transcription. 6 Fig. 2-3.

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. Virtually every hormone of the hypothalamic-pituitary-adrenal axis influences the physiologic response to injury and stress (Table 2-2), but some with direct influence on the inflammatory response or immediate clinical impact are highlighted here. Table 2-2 Hormones Regulated by the Hypothalamus, Pituitary, and Autonomic System Hypothalamic Regulation Corticotropin-releasing hormone Thyrotropin-releasing hormone Growth hormone–releasing hormone Luteinizing hormone–releasing hormone 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

Adrenocorticotropic Hormone Adrenocorticotropic hormone (ACTH) is a polypeptide hormone released by the anterior pituitary gland. ACTH binds with receptors in the zona fasciculata of the adrenal gland, which mediate intracellular signaling and subsequent cortisol release. ACTH release follows circadian rhythms in healthy humans; however, during times of stress this diurnal pattern becomes blunted because ACTH release is elevated in proportion to the severity of injury. Several important stimuli for ACTH release are present in the injured patient, including corticotropin-releasing hormone, pain,

anxiety, vasopressin, angiotensin II, cholecystokinin, vasoactive intestinal polypeptide, catecholamines, and proinflammatory cytokines. Within the zona fasciculata of the adrenal gland, ACTH signaling activates intracellular pathways that lead to glucocorticoid production (Fig. 2-4). Conditions of excess ACTH stimulation result in adrenocortical hypertrophy. 7 Fig. 2-4.

Steroid synthesis from cholesterol. Adrenocorticotropic hormone (ACTH) is a principal regulator of steroid synthesis. The end products are mineralocorticoids, glucocorticoids, and sex steroids.

Cortisol and Glucocorticoids Cortisol is a glucocorticoid steroid hormone released by the adrenal cortex in response to ACTH. Cortisol release is increased during times of stress and may be chronically elevated in certain disease processes. For example, burn-injured patients may exhibit elevated levels for 4 weeks. Metabolically, cortisol potentiates the actions of glucagon and epinephrine that manifest as hyperglycemia. Cortisol acts on liver enzymes by decreasing glycogenesis, while increasing gluconeogenesis. In skeletal muscle, cortisol facilitates the breakdown of protein and amino acids, and mediates the release of lactate. Subsequently, these substrates are used by the liver for gluconeogenesis. In adipose tissue cortisol stimulates the release of free fatty acids, triglycerides, and glycerol to increase circulating energy stores. Wound healing also is impaired, because cortisol reduces transforming growth factor beta (TGF- ) and insulin-like growth factor I (IGF-I) in the wound. This effect can be partially ameliorated by the administration of vitamin A. 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. Laboratory findings in adrenal insufficiency include hypoglycemia from decreased gluconeogenesis, hyponatremia from impaired renal tubular sodium resorption, and hyperkalemia from diminished kaliuresis. Diagnostic tests include baseline cortisol levels and ACTH-stimulated cortisol levels, both of which are lower than normal during adrenal insufficiency. Treatment strategies are controversial; however, they include low-dose steroid supplementation.8 Glucocorticoids have immunosuppressive properties that have been used when needed, as in organ transplantation. Immunologic changes associated with glucocorticoid administration include thymic involution, depressed cell-mediated immune responses reflected by decreases in Tkiller and natural killer cell function, T-lymphocyte blastogenesis, mixed lymphocyte responsiveness, graft-versus-host reactions, and delayed hypersensitivity responses. In addition glucocorticoids inhibit leukocyte migration to sites of inflammation by inhibiting the expression of adhesion molecules. In monocytes, glucocorticoids inhibit intracellular killing while maintaining chemotactic and phagocytic properties. Glucocorticoids inhibit neutrophil superoxide reactivity, suppress chemotaxis, and normalize apoptosis signaling mechanisms but maintain neutrophil phagocytic function. In clinical settings manifested by hypoperfusion, such as septic shock, trauma, and coronary artery bypass grafting, glucocorticoid administration is associated with attenuation of the inflammatory response.

Macrophage Migration–Inhibiting Factor Macrophage migration–inhibiting factor (MIF) is a neurohormone that is stored and secreted by the anterior pituitary and by intracellular pools within macrophages. MIF is a counterregulatory mediator that potentially reverses the anti-inflammatory effects of cortisol. During times of stress, hypercortisolemia, and host immunosuppression, MIF may modulate the inflammatory response by inhibiting the immunosuppressive effect of cortisol on immunocytes and thereby increasing their activity against foreign pathogens. 9

Growth Hormones and Insulin-Like Growth Factors 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 secondarily through the enhanced hepatic synthesis of IGF-I. IGF circulates primarily bound to various IGF-binding proteins and also has anabolic effects, including increased protein synthesis and lipogenesis. 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. Critical illness is associated with an acquired GH resistance and contributes to decreased levels of IGF. This effect in part mediates the overall catabolic phenotype manifested during critical illness. In addition, GH enhances phagocytic activity of immunocytes through increased lysosomal superoxide production. GH also increases the proliferation of T-cell populations.10 Exogenous GH administration has been studied in critically ill patients and may be associated with worse outcomes, including increased mortality, prolonged ventilator dependence, and increased susceptibility to infection.11 The mechanisms through which GH is associated with these outcomes are unclear, although GH-induced insulin resistance and hyperglycemia may contribute.

Catecholamines Catecholamines are hormones secreted by the chromaffin cells of the adrenal medulla and function as neurotransmitters in the CNS. The most common catecholamines are epinephrine, norepinephrine, and dopamine, which have metabolic, immunomodulatory, and vasoactive effects. After severe injury, plasma catecholamine levels are increased threefold to fourfold, with elevations lasting 24 to 48 hours before returning toward baseline levels. Catecholamines act on both alpha and beta receptors, which are widely distributed on several cell types, including vascular endothelial cells, immunocytes, myocytes, adipose tissue, and hepatocytes. Epinephrine has been shown to induce a catabolic state and hyperglycemia through

hepatic gluconeogenesis and glycogenolysis as well as by peripheral lipolysis and proteolysis. In addition epinephrine promotes insulin resistance in skeletal muscle. Catecholamines also increase the secretion of thyroid hormone, parathyroid hormones, and renin, but inhibit the release of aldosterone. Epinephrine also has immunomodulatory properties mediated primarily through the activation of beta 2 receptors on immunocytes. Epinephrine has been shown to inhibit the release of inflammatory cytokines, including TNF, interleukin-1, and interleukin-6, while also enhancing the release of the anti-inflammatory mediator interleukin-10. 12 Similar to cortisol, epinephrine increases leukocyte demargination with resultant neutrophilia and lymphocytosis. The immunomodulatory sequelae of catecholamines in patients during septic shock have yet to be clearly elucidated. Catecholamines exert several hemodynamic effects, including increased cardiac oxygen demand, vasoconstriction, and increased cardiac output. Catecholamines are used to treat systemic hypotension during septic shock. Because of the increased cardiac stress induced by catecholamines, however, cardioprotective strategies, including beta blockade for patients undergoing surgery, have shown significant benefit in reducing cardiacrelated deaths.

Aldosterone Aldosterone is a mineralocorticoid released by the zona glomerulosa of the adrenal cortex. Aldosterone increases intravascular volume by acting on the renal mineralocorticoid receptor of the distal convoluted tubules to retain sodium and eliminate potassium and hydrogen ions. Aldosterone secretion is stimulated by ACTH, angiotensin II, decreased intravascular volume, and hyperkalemia. Aldosterone deficiency is manifested by hypotension and hyperkalemia, whereas aldosterone excess is manifested by edema, hypertension, hypokalemia, and metabolic alkalosis.

Insulin Hyperglycemia and insulin resistance are hallmarks of critical illness due to the catabolic effects of circulating mediators, including catecholamines, cortisol, glucagon, and growth hormone. Insulin is secreted by the islets of Langerhans in the pancreas. Insulin mediates an overall host anabolic state through hepatic glycogenesis and glycolysis, peripheral glucose uptake, lipogenesis, and protein synthesis. 13 Hyperglycemia during critical illness has immunosuppressive effects, including glycosylation of immunoglobulins and decreased phagocytosis and respiratory burst of monocytes, and thus is associated with an increased risk for infection. 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, caution should be exercised to avoid the deleterious sequelae of hypoglycemia from overaggressive glycemic control.14 The ideal blood glucose range within which to maintain critically ill patients and avoid hypoglycemia has yet to be determined.

ACUTE PHASE PROTEINS Acute phase proteins are a class of proteins produced by the liver that manifest either increased or decreased plasma concentration in response to inflammatory stimuli such as traumatic injury and infection. Specifically, C-reactive protein has been studied as a marker of proinflammatory response in many clinical settings, including appendicitis, vasculitis, and ulcerative colitis. Importantly, C-reactive protein levels do not show diurnal variations and are not modulated by feeding. Acute phase protein levels may be unreliable as an index of inflammation in the setting of hepatic insufficiency.

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, including cell migration, DNA replication, cell turnover, and immunocyte proliferation (Table 2-3). When

functioning locally at the site of injury and infection, cytokines mediate the eradication of invading micro-organisms 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). Table 2-3 Cytokines and Their Sources Cytokine Source

Comment

TNF

Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and catabolism

Macrophages/monocytes Kupffer cells Neutrophils NK cells Astrocytes Endothelial cells T lymphocytes Adrenal cortical cells Adipocytes Keratinocytes Osteoblasts Mast cells Dendritic cells

IL-1

Macrophages/monocytes B and T lymphocytes

Two forms (IL-1 and IL-1 ); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior hypothalamus; promotes -endorphin release from pituitary; half-life <6 min

NK cells Endothelial cells Epithelial cells Keratinocytes Fibroblasts Osteoblasts Dendritic cells Astrocytes Adrenal cortical cells Megakaryocytes Platelets Neutrophils Neuronal cells IL-2

T lymphocytes

IL-3

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

Macrophages Eosinophils Mast cells IL-4

T lymphocytes

Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response;

Mast cells

downregulates TNF, IL-1, IL-6, IL-8

Basophils Macrophages B lymphocytes Eosinophils Stromal cells IL-5

T lymphocytes

Promotes eosinophil proliferation and airway inflammation

Eosinophils Mast cells Basophils IL-6

Macrophages B lymphocytes

Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs activated neutrophil survival

Neutrophils Basophils Mast cells Fibroblasts Endothelial cells Astrocytes Synovial cells Adipocytes Osteoblasts Megakaryocytes Chromaffin cells Keratinocytes IL-8

Macrophages/monocytes

Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes

T lymphocytes Basophils Mast cells Epithelial cells Platelets IL-10

T lymphocytes

Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models

B lymphocytes Macrophages Basophils Mast cells Keratinocytes IL-12

Macrophages/monocytes Neutrophils Keratinocytes Dendritic cells

Promotes T H 1 differentiation; synergistic activity with IL-2

B lymphocytes IL-13

T lymphocytes

Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation

IL-15

Macrophages/monocytes

Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections

Epithelial cells IL-18

Macrophages Kupffer cells

Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac deaths

Keratinocytes Adrenal cortical cells Osteoblasts IFN-

T lymphocytes

Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS

NK cells Macrophages GM-CSF

T lymphocytes

Promotes wound healing and inflammation through activation of leukocytes

Fibroblasts Endothelial cells Stromal cells IL-21

T lymphocytes

Preferentially secreted by T H 2 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; T H 1 = helper T cell subtype 1; T H 2 = helper T cell subtype 2; TNF = tumor necrosis factor. Anti-inflammatory cytokines also are released, at least in part as an opposing influence to the proinflammatory cascade. These anti-inflammatory mediators also may result in immunocyte dysfunction and host immunosuppression. Cytokine signaling after an inflammatory stimulus is manifested by a fluctuating and counterregulated balance of opposing influences and should not be oversimplified into dichotomic proinflammatory and anti-inflammatory responses.2

Heat Shock Proteins Heat shock proteins (HSPs) are a group of intracellular proteins that are increasingly expressed during times of stress, such as burn injury, inflammation, and infection. HSPs participate in many physiologic processes, including protein folding and protein targeting. The formation of HSPs requires gene induction by the heat shock transcription factor. HSPs bind both autologous and foreign proteins and thereby function as intracellular chaperones for ligands such as bacterial DNA and endotoxin. HSPs are presumed to protect cells from the deleterious effects of traumatic stress15 and, when released by damaged cells, alert the immune system of the tissue damage.

Reactive Oxygen Species Reactive oxygen species (ROS) 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 the oxidation of unsaturated fatty acids within cell membranes. Oxygen radicals are produced as a by-product of oxygen metabolism as well as by anaerobic processes. Potent oxygen radicals include oxygen, superoxide, hydrogen peroxide, and hydroxyl radicals. The main areas of ROS production include mitochondrial electron transport, peroxisomal

fatty acid metabolism, cytochrome P-450 reactions, and the respiratory burst of phagocytic cells. Host cells are protected from the damaging effects of ROS through the activity of endogenous antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase. Under normal physiologic conditions ROS are balanced by antioxidative enzymes. During times of stress or ischemia, however, enzymatic clearance mechanisms are consumed, and on restoration of perfusion, the unbalanced production of ROS leads to reperfusion injury. 16

Eicosanoids Eicosanoids are derived primarily by oxidation of the membrane phospholipid arachidonic acid (eicosatetraenoic acid) and are composed of subgroups, including prostaglandins, prostacyclins, hydroxyeicosatetraenoic acids (HETEs), thromboxanes, and leukotrienes. The synthesis of arachidonic acid from phospholipids requires the enzymatic activation of phospholipase A2 (Fig. 2-5). Products of the COX pathway include all of the prostaglandins and thromboxanes. The lipoxygenase pathway generates leukotrienes and HETE. Eicosanoids are not stored within cells but are instead generated rapidly in response to many stimuli, including hypoxic injury, direct tissue injury, endotoxin (lipopolysaccharide, or LPS), norepinephrine, vasopressin, angiotensin II, bradykinin, serotonin, acetylcholine, cytokines, and histamine. Eicosanoid pathway activation also leads to the formation of the anti-inflammatory compound lipoxin, which inhibits chemotaxis and nuclear factor B (NF- B) activation. Glucocorticoids, NSAIDs, and leukotriene inhibitors block the end products of eicosanoid pathways. Fig. 2-5.

Schematic diagram of arachidonic acid metabolism. LT = leukotriene; PG = prostaglandin; TXA2 = thromboxane A 2 . Eicosanoids have a broad range of physiologic roles, including neurotransmission, vasomotor regulation, and immune cell regulation (Table 2-4). Eicosanoids mostly generate a proinflammatory response with deleterious host effects and are associated with acute lung injury, pancreatitis, and renal failure. Leukotrienes are potent mediators of capillary leakage as well as leukocyte adherence, neutrophil activation, bronchoconstriction,

and vasoconstriction. Experimental models of sepsis have shown a benefit to inhibiting eicosanoid production. However, human sepsis trials have failed to show a mortality benefit using NSAIDs. 17 Table 2-4 Systemic Stimulatory and Inhibitory Actions of Eicosanoids Organ/Function

Stimulator

Inhibitor

Glucose-stimulated insulin secretion

12-HPETE

PGE2

Glucagon secretion

PGD2 , PGE2

Pancreas

Liver Glucagon-stimulated glucose production PGE2 Fat Hormone-stimulated lipolysis

PGE2

Bone Resorption

PGE2 , PGE-m, 6-K-PGE1 , PGF 1 , PGI2

Pituitary Prolactin

PGE1

Luteinizing hormone

PGE1 , PGE2 , 5-HETE

Thyroid-stimulating hormone

PGA1 , PGB1 , PGE1 , PGE1

Growth hormone

PGE1

Parathyroid Parathyroid hormone

PGE2

PGF 2

Lung Bronchoconstriction

PGF 2

TXA2 , LTC 4 , LTD 4 , LTE4

PGE2

Kidney Stimulation of renin secretion

PGE2 , PGI2

Gastrointestinal system Cytoprotective effect

PGE2

Immune response Suppression of lymphocyte activity

PGE2

Hematologic system Platelet aggregation

TXA2

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 PGE 2 ); TXA2 = thromboxane A 2 . Eicosanoids also have several recognized metabolic effects. Cyclooxygenase pathway products inhibit pancreatic

-cell release of insulin, whereas

lipoxygenase pathway products stimulate

-cell activity. Prostaglandins such as prostaglandin E2 can inhibit gluconeogenesis through the binding

of hepatic receptors and also can inhibit hormone-stimulated lipolysis.18

Fatty Acid Metabolites Fatty acid metabolites function as inflammatory mediators and as such have significant roles in the inflammatory response. As previously discussed, eicosanoids participate in inflammatory signaling; however, dietary omega-3 and omega-6 fatty acids also influence inflammation. Eicosanoids are produced primarily through two major pathways: (1) with arachidonic acid (omega-6 fatty acid) as substrate and (2) eicosapentaenoic acid (omega-3 fatty acid) as substrate. Many lipid preparations are soy based and are primarily composed of omega-6 fatty acids. Nutritional supplementation with either omega-6 or omega-3 fatty acid can significantly modulate the inflammatory response, because omega-6 substrate is associated with increased downstream mediator production. Omega-3 fatty acids have specific anti-inflammatory effects, including inhibition of NF- B activity, TNF release from hepatic Kupffer cells, as well as leukocyte adhesion and migration. The anti-inflammatory effects of omega-3 fatty acids on chronic autoimmune diseases such as rheumatoid arthritis, psoriasis, and lupus have been documented in both animals and humans. In experimental models of sepsis, omega-3 fatty acids inhibit inflammation, ameliorate weight loss, increase small-bowel perfusion, and may increase gut barrier protection. In human studies, omega-3 supplementation is associated with decreased production of TNF, interleukin-1 , and interleukin-6 by endotoxin-stimulated monocytes. In a study of surgical patients, preoperative supplementation with omega-3 fatty acid was associated with reduced need for mechanical ventilation, decreased hospital length of stay, and decreased mortality with a good safety profile. 19

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 activated by stimuli such as Hageman factor, trypsin, plasmin, factor XI, glass surfaces, kaolin, and collagen to produce the serine protease kallikrein, which subsequently plays a role in the coagulation cascade. High molecular weight kininogen is produced by the liver and is metabolized by kallikrein to form bradykinin. Kinins 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. Decreased renal perfusion leads to activation of the renin-angiotensin-aldosterone system, which acts on the nephron to actively resorb sodium and subsequently increase intravascular volume. 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. 20

Serotonin Serotonin is a monoamine neurotransmitter (5-hydroxytryptamine) derived from tryptophan. Serotonin is synthesized by neurons in the CNS as well as by enterochromaffin cells of the GI tract and platelets. This neurotransmitter stimulates vasoconstriction, bronchoconstriction, and platelet aggregation. Serotonin also increases cardiac inotropy and chronotropy through nonadrenergic cyclic adenosine monophosphate (cAMP) pathways. Serotonin receptors are located in the CNS, GI tract, and monocytes.21 Ex vivo study has shown that serotonin receptor blockade is associated with decreased production of TNF and interleukin-1 in endotoxin-treated monocytes. Serotonin is released at sites of injury, primarily by platelets; however, its role in inflammatory modulation has yet to be clearly defined.

Histamine

Histamine is synthesized by the decarboxylation of the amino acid histidine. Histamine is either rapidly released or stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets. There are four histamine receptor (H) subtypes with varying physiologic roles. H 1 binding mediates vasodilation, bronchoconstriction, intestinal motility, and myocardial contractility. H 2 binding stimulates gastric parietal cell acid secretion. H 3 is an autoreceptor found on presynaptic histamine-containing nerve endings and leads to downregulation of histamine release. H 4 is expressed primarily in bone marrow, eosinophils, and mast cells. H 4 binding interactions have not been fully delineated but have been associated with eosinophil and mast cell chemotaxis. Increased histamine release has been documented in hemorrhagic shock, trauma, thermal injury, endotoxemia, and sepsis. 22

CYTOKINE RESPONSE TO INJURY Tumor Necrosis Factor Tumor necrosis factor alpha (TNF) 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 macrophages, monocytes, and T cells, which are abundant in peritoneum and splanchnic tissues. Although the circulating half-life of TNF is brief, the activity of TNF elicits many metabolic and immunomodulatory activities. TNF stimulates muscle breakdown and cachexia through increased catabolism, insulin resistance, and redistribution of amino acids to hepatic circulation as fuel substrates. In addition, 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.23 Tumor necrosis factor receptors (TNFRs) are composed of two subtypes: TNFR-1 and TNFR-2. TNFR-1 is ubiquitously expressed in most tissues and, on ligand binding, mediates apoptosis through proteolytic caspases. TNFR-2 is expressed primarily on immunocytes and, on ligand binding, leads to NF- B activation and subsequent amplification of the inflammatory signal. TNFRs exist in both transmembrane and soluble form. In response to inflammatory stimuli such as injury and infection, TNFRs are proteolytically cleaved from cell membranes and are readily detectable in soluble form. This may represent a mechanism of inflammatory regulation, because soluble TNFRs maintain their affinity for TNF and thereby compete with and limit the activation of transmembrane TNFR.24

Interleukin-1 Interleukin-1 (IL-1) is represented by two active subtypes, IL-1 cellular contact. IL-1

and IL-1 . IL-1

is primarily membrane associated and functions through

is readily detectable in soluble form and mediates an inflammatory sequence similar to that of TNF. IL-1 is primarily

synthesized by monocytes, macrophages, endothelial cells, fibroblasts, and epidermal cells. IL-1 is released in response to inflammatory stimuli, including cytokines (TNF, IL-2, interferon- [IFN- ]) and foreign pathogens, and requires the formation of the inflammasome in the cell for processing and release. High doses of either IL-1 or TNF are associated with profound hemodynamic compromise. Interestingly, low doses of both IL-1 and TNF combined elicit hemodynamic events similar to those elicited by high doses of either mediator, which suggests a synergistic effect. IL-1 is an endogenous pyrogen because it acts on the hypothalamus by stimulating prostaglandin activity and thereby mediates a febrile response. IL-1 is autoregulated by endogenous IL-1 receptor antagonists, which are released in response to inflammatory stimuli and compete with IL-1 at receptor binding sites. 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. 25

Interleukin-2 Interleukin-2 (IL-2) is upregulated in response to IL-1 and is primarily a promoter of T-lymphocyte proliferation and differentiation,

immunoglobulin production, and gut barrier integrity. IL-2 binds to IL-2 receptors, which are expressed on leukocytes. 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. 26

Interleukin-4 Interleukin-4 (IL-4) is released by activated helper T cells and stimulates the differentiation of T cells, and also stimulates T-cell proliferation and B-cell activation. It is also important in antibody-mediated immunity and in antigen presentation. IL-4 induces class switching of differentiating B lymphocytes to produce predominantly immunoglobulin G4 and immunoglobulin E, which are important immunoglobulins in allergic and antihelmintic responses. IL-4 has anti-inflammatory effects on macrophages, exhibited by an attenuated response to proinflammatory mediators such as IL-1, TNF, interleukin-6, and interleukin-8. In addition, IL-4 appears to increase macrophage susceptibility to the anti-inflammatory effects of glucocorticoids.

Interleukin-6 Interleukin-6 (IL-6) release by macrophages is stimulated by inflammatory mediators such as endotoxin, TNF, and IL-1. IL-6 is increasingly expressed during times of stress, as in septic shock. After injury, IL-6 levels in the circulation are detectable by 60 minutes, peak between 4 and 6 hours, and can persist for as long as 10 days. Plasma levels of IL-6 are proportional to the degree of injury during surgery. Interestingly, IL-6 has counterregulatory effects on the inflammatory cascade through the inhibition of TNF and IL-1. IL-6 also promotes the release of soluble tumor necrosis factor receptors and IL-1 receptor antagonists, and stimulates the release of cortisol. High plasma IL-6 levels have been associated with mortality during intra-abdominal sepsis. 27

Interleukin-8 Interleukin-8 (IL-8) is synthesized by macrophages as well as other cell lines such as endothelial cells. Critical illness as manifested during sepsis is a potent stimulus for IL-8 expression. IL-8 stimulates the release of IFN- and functions as a potent chemoattractant for neutrophils. Elevated plasma IL-8 also has been associated with disease severity and end organ dysfunction during sepsis. 28

Interleukin-10 Interleukin-10 (IL-10) is an anti-inflammatory cytokine synthesized primarily by monocytes; however, it is also released by other lymphocytes. IL-10 is increasingly expressed during times of systemic inflammation, and its release is specifically enhanced by TNF and IL-1. IL-10 inhibits the secretion of proinflammatory cytokines, including TNF and IL-1, partly through the downregulation of NF- B and thereby functions as a negative feedback regulator of the inflammatory cascade. Experimental 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.29

Interleukin-12 Interleukin-12 (IL-12) has been described as a regulator of cell mediated immunity. IL-12 is released by activated phagocytes, including monocytes, macrophages, neutrophils, and dendritic cells, and is increasingly expressed during endotoxemia and sepsis. IL-12 stimulates lymphocytes to increase secretion of IFN- with the costimulus of interleukin-18 and also stimulates natural killer cell cytotoxicity and helper T cell differentiation. 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- 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. Despite evidence of both proinflammatory and anti-inflammatory pathway activation, most evidence suggests that IL-12 contributes to an overall proinflammatory response. 30

Interleukin-13 Interleukin-13 (IL-13) exerts many of the same immunomodulatory effects as does IL-4. IL-13 inhibits monocyte release of TNF, IL-1, IL-6, and IL-8, while increasing the secretion of IL-1R antagonist. However, unlike IL4, IL-13 has no identifiable effect on T lymphocytes and only has influence on selected B-lymphocyte populations. Increased IL-13 expression is observed during septic shock and mediates neutropenia, monocytopenia, and leukopenia. In addition, IL-13 inhibits leukocyte interaction with activated endothelial surfaces. Similar to IL-4 and IL-10, IL13 has a net anti-inflammatory effect. 31

Interleukin-15 Interleukin-15 (IL-15) is synthesized in many cell types, including macrophages and skeletal muscle after endotoxin administration. IL-15 stimulates natural killer cell activation as well as B-cell and T-cell proliferation and thus functions as a regulator of cellular immunity. IL-15 has immunomodulatory effects similar to those of IL-2, in part due to shared receptor subunits. Furthermore, IL-15 acts as a potent inhibitor of lymphocyte apoptosis by enhancing the expression of antiapoptotic molecules such as Bcl-2.32

Interleukin-18 Interleukin-18 (IL-18), formerly IFN- –inducing factor, is synthesized primarily by macrophages. IL-18 and its receptor complex are members of the IL-1 superfamily. As with IL-1, macrophages release IL-18 in response to inflammatory stimuli, including endotoxin, TNF, IL-1, and IL-6. IL18 level also is elevated during sepsis. IL-18 activates NF- B through an Myeloid differentiation primary response gene (88) (MyD88)-dependent pathway with subsequent proinflammatory mediator release. IL-18 regulation is in part mediated through IL-18–binding protein (IL-18BP). This molecule is not a soluble receptor isoform but rather a specific endogenous antagonist. IL-18 also mediates hepatotoxicity associated with Fas ligand and TNF. The viral skin pathogen molluscum contagiosum secretes an IL-18BP–like protein, which neutralizes IL-18 and thereby inhibits the inflammatory response. IL-18 and IL-12 act synergistically to release IFN- from T cells. In a murine model of systemic inflammation, IL-18 neutralization reduced lethal endotoxemia. IL-18 signaling also is associated with increased expression of intercellular adhesion molecule-1. Interestingly, in a murine model of systemic inflammation, a reversal of left ventricular dysfunction was observed with IL-18 blockade, which suggests that IL-18 may contribute to the hemodynamic compromise during septic shock.33

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 two major subtypes based on receptor specificity and sequence homology. Type I interferons include IFN- , IFN- , and IFN- , which are structurally related and bind to a common receptor, IFN-

receptor. 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 MHC expression. IFN-

and IFN-

also enhance immune

responses by increasing the cytotoxicity of natural killer cells both in culture and in vivo. In murine models, the absence of IFN-

receptor results

in greater susceptibility to viral infection as well as diminished LPS-induced lethality. Furthermore, type I interferons have also been studied as therapeutic agents in hepatitis C and relapsing multiple sclerosis.

Many of the physiologic effects observed with increased levels of IL-12 and IL-18 are mediated through IFN- . IFN- is a type II interferon secreted by T lymphocytes, natural killer cells, and antigen-presenting cells in response to bacterial antigens, IL-2, IL-12, and IL-18. IFNstimulates the release of IL-12 and IL-18. Negative regulators of IFN- include IL4, IL-10, and glucocorticoids. IFN- binding with a cognate receptor activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, leading to subsequent induction of biologic responses. Macrophages stimulated by IFN- demonstrate enhanced phagocytosis and microbial killing, and increased release of oxygen radicals, partly through a nicotinamide adenosine dinucleotide phosphate–dependent phagocyte oxidase. IFN- mediates macrophage stimulation and thus may contribute to acute lung injury after major surgery or trauma. Diminished IFN- level, as seen in knockout mice, is associated with increased susceptibility to both viral and bacterial pathogens. IFN- regulates trafficking of immunocytes to sites of inflammation via upregulation !"#$%& '(()'#('*(+",%-.-/"& * 01*%"1*23#%2"45"6789:";<6=>/"&'#) ?$'.%"1*!@'&&'( )5"?) (%1*"A9'@?$'"'*2"A94%('B"'*2"'2$%+1 *"& @%#3@%+ (e.g., intercellular adhesion molecule-1, vascular cell adhesion molecule-1). In addition, IFN- promotes differentiation of T cells to the helper T cell subtype 1 and also enhances B-cell isotype switching to immunoglobulin G. 34

Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-macrophage colony-stimulating factor (GM-CSF), as the name suggests, upregulates both granulocyte and monocyte cell lines from hematopoietic bone marrow stem cells. GM-CSF plasma levels are low to undetectable but rapidly increase in response to inflammatory stimuli such as TNF. GM-CSF inhibits both monocyte and neutrophil apoptosis and enhances macrophage cytokine release in response to inflammatory stimuli. GM-CSF also potentiates the release of neutrophil superoxide as well as the cytotoxicity of monocytes. Administration of GM-CSF has proven beneficial during the treatment of fungal infections in immunocompromised patients. GM-CSF may potentiate acute lung injury during critical illness, because GM-CSF blockade has been found to be associated with decreased alveolar macrophage activity and NF- B intensity. This growth factor is effective in promoting the maturation and recruitment of functional leukocytes necessary for normal inflammatory cytokine responses and also may be effective in wound healing.35

High Mobility Group Box 1 High mobility group box 1 (HMGB1) is a DNA transcription factor that facilitates the binding of regulatory protein complexes to DNA. HMGB1 is actively secreted by macrophages, natural killer cells, and enterocytes. Endotoxin, TNF, and IFN- promote the release of HMGB1, and in a murine model of intraperitoneal sepsis, increased circulating HMGB1 was associated with increased mortality. HMGB1 also appears to have cytokine-like activities, because it promotes the release of TNF from monocytes. Interestingly, elevation of plasma HMGB1 levels after experimental induction of endotoxemia is delayed relative to that of other inflammatory mediators, with levels peaking at 16 hours and remaining elevated beyond 30 hours. This response contrasts with that of acute inflammatory mediators such as TNF, which peaks at 1 to 2 hours and becomes undetectable by 12 hours. Furthermore, HMGB1 blockade is associated with decreased mortality even when initiated 4 to 24 hours after the inflammatory stimulus. 36 HMGB1 is passively released by necrotic cells. Thus, HMGB1 alone or in combination with other molecules may contribute to the regulation of inflammation after tissue injury. Receptors for HMGB1 are receptors for advanced glycation end products and toll-like receptor 4. Binding leads to the proinflammatory response through the activation of NF- B. Clinical trials have demonstrated increased plasma HMGB1 during systemic inflammation, as in sepsis, hemorrhagic shock, pancreatitis, myocardial infarction, and major surgery.

CELLULAR RESPONSE TO INJURY Gene Expression and Regulation Many genes are regulated at the point of DNA transcription and thus influence whether messenger RNA (mRNA) and its subsequent product are expressed (Fig. 2-6). These mRNA transcripts are also regulated by modulation 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; (c) and the addition of a polyadenylated tail, which adds a noncoding sequence to the mRNA, effectively increasing the half-life of the transcript. Once out of the nucleus, the mRNA can be inactivated or translated to form proteins. Many protein products are also further modified for specific function or trafficking. Fig. 2-6.

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. 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. During systemic inflammation, transcription factors are highly important, because regulation of cytokine gene expression may have profound effects on the clinical phenotype.

CELL SIGNALING PATHWAYS G-Protein Receptors G-protein receptors (GPRs) are a large family of transmembrane receptors. They bind a multitude of ligands (e.g., epinephrine, bradykinin, leukotriene) and are involved in signal transduction during the inflammatory response. Extracellular ligands bind to GPR, which result in a conformational change and activation of associated proteins. The two major second messengers of the G-protein pathway are (1) cAMP, and (2) calcium, released from the endoplasmic reticulum (Fig. 2-7). Increased intracellular cAMP can activate gene transcription through the activity of intracellular signal transducers such as protein kinase A. Increased intracellular calcium can activate the intracellular signal transducer phospholipase C with further subsequent downstream effects. GPR binding also can promote the activity of protein kinase C, which can subsequently stimulate NF- B as well as other transcription factors. Fig. 2-7.

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 (IP 3 ) is to induce release of calcium from the endoplasmic reticulum (ER). cAMP = cyclic adenosine triphosphate.

Ligand-Gated Ion Channels Ligand-gated ion channels (LGICs) are transmembrane receptors that allow the rapid influx of ions (e.g., sodium, calcium, potassium, chloride) and are central to the signal transduction of neurotransmitters. On ligand binding LGICs effectively convert a chemical signal into an electrical signal. The prototypical LGIC is the nicotinic acetylcholine receptor (Fig. 2-8). Fig. 2-8.

Ligand-gated ion channels convert chemical signals into electrical signals, inducing a change in cell membrane potential. On activation of the channel, millions of ions per second influx into the cell. These channels are composed of many subunits, and the nicotinic acetylcholine receptor is one such example.

Receptor Tyrosine Kinases Receptor tyrosine kinases (RTKs) are transmembrane receptors that are involved in cell signaling for several growth factors, including plateletderived growth factor, insulin-like growth factor, epidermal growth factor, and vascular endothelial growth factor. On ligand binding, RTKs dimerize with adjacent receptors, undergo autophosphorylation, and recruit secondary signaling molecules (e.g., phospholipase C) (Fig. 2-9). Activation of RTK is important for gene transcription as well as cell proliferation and may have influence in the development of many types of cancer. Fig. 2-9.

The receptor tyrosine kinase requires dimerization of monomeric units. These receptors possess intrinsic enzymatic activity that requires multiple autophosphorylation steps to recruit and activate intracellular signaling molecules. ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate.

Janus Kinase/Signal Transducer and Activator of Transcription Signaling The Janus kinases (JAKs) represent a family of tyrosine kinases that mediate signal transduction of several cytokines, including IFN- , IL-6, IL10, IL-12, and IL-13. JAKs bind to cytokines, and on ligand binding and dimerization, activated JAKs recruit and phosphorylate signal transducer and activator of transcription (STAT) molecules (Fig. 2-10). Activated STAT proteins further dimerize and translocate into the nucleus and modulate the transcription of target genes. Interestingly, STAT-DNA binding can be observed within minutes of cytokine binding. The JAK/STAT system is a rapid pathway for membrane to nucleus signal transduction. The JAK/STAT pathway is inhibited by the action of phosphatase, the export of STATs from the nucleus, as well the interaction of antagonistic proteins. 37 Fig. 2-10.

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.

Suppressors of Cytokine Signaling Suppressor of cytokine signaling (SOCS) molecules are a group of cytokine-induced proteins that function as a negative feedback loop by downregulating the JAK/STAT pathway. SOCSs exert an inhibitory effect partly by binding with JAK and thus competing with STAT. A deficiency of SOCS activity may render a cell hypersensitive to certain stimuli, such as inflammatory cytokines and growth hormones. Interestingly, in a murine model, SOCS knockout resulted in a lethal phenotype in part because of unregulated interferon- signaling. An example of this pathway is highlighted by an attenuated IL-6 response in macrophages via suppressor of cytokine signaling 3 (SOCS-3) inhibition of signal transducer and activator of transcription 3 (STAT3). 38

Mitogen-Activated Protein Kinases Pathways mediated through mitogen-activated protein kinase (MAPK) contribute to inflammatory signaling and regulation of cell proliferation and cell death (Fig. 2-11). MAPK pathways involve sequential stages of mediator phosphorylation resulting in the activation of downstream effectors,

including c-Jun N-terminal kinase (JNK), extracellular signal regulated protein kinase (ERK), and p38 kinase, with subsequent gene modulation. Dephosphorylation of MAPK pathway mediators inhibit their function. Activated JNK phosphorylates c-Jun, which dimerizes to form the transcription factor activated protein 1. The protein MAP/ERK kinase kinase (MEKK) has several functions, including protein kinase and ubiquitin ligase, and also has been shown to downregulate MAPK pathways. JNK is activated by TNF and IL-1 and is a regulator of apoptosis. Pharmacologic blockade of JNK was associated with decreased pulmonary injury and TNF and IL-1 secretion in an ischemia/reperfusion model. The p38 kinase is activated in response to endotoxin, viruses, IL-1, IL-2, IL-7, IL-17, IL-18, and TNF. The p38 also plays a role in immunocyte development, because p38 inactivation is a critical step in the differentiation of thymic T cells. These MAPK isoforms do not function independently but rather exhibit significant counteraction and cosignaling, which can influence the inflammatory response. 39 Fig. 2-11.

The mitogen-activated protein kinase (MAPK) signaling pathway requires multiple phosphorylation steps. Ras, Raf, and Mos are examples of the MAPK kinase kinase (MAPKKK) and are upstream molecules. Well-characterized downstream kinases are extracellular signal regulated kinases 1 and 2 (ERK 1/2), c-Jun N-terminal kinases (JNKs) or stress-activated protein kinases (SAPKs), and p38 MAPKs that target specific gene transcription sites in the nucleus. ATF2 = activating transcription factor 2; MAPKK = mitogen-activated protein kinase kinase; MEF2 = myocyteenhancing factor 2; P = phosphate.

Nuclear Factor B Nuclear factor B (NF- B) is a transcription factor that has a central role in regulating the gene products expressed after inflammatory stimuli (Fig. 2-12). NF- B is composed of two smaller polypeptides, p50 and p65. NF- B resides in the cytosol in the resting state primarily through the inhibitory binding of inhibitor of B (I- B). 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- B and subsequent release of NF- B. On release, NF- B travels to the nucleus

and promotes gene expression. NF- B also stimulates the gene expression for I- B, which results in negative feedback regulation. In clinical appendicitis, for example, increased NF- B 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. 40 Fig. 2-12.

Inhibitor of B (I- B) binding to the p50-p65 subunits of nuclear factor B (NF- B) inactivates the molecule. Ligand binding to the receptor activates a series of downstream signaling molecules, of which I- B kinase is one. The phosphorylated NF- B complex further undergoes ubiquitinization and proteosome degradation of I- B, activating NF- B, which translocates into the nucleus. Rapid resynthesis of I- B is one method of inactivating the p50-p65 complex. IL-1 = interleukin-1; P = phosphate; TNF = tumor necrosis factor.

Toll-Like Receptors and CD14 The innate immune system responds to pathogen-associated molecular patterns (PAMPs) such as microbial antigens and LPS. Toll-like receptors (TLRs) are a group of pattern recognition receptors activated by PAMPs that function as effectors of the innate immune system and belong to the IL-1 superfamily. Immunocyte recognition of LPS is mediated primarily by TLR4. LPS-binding proteins chaperone LPS to the CD14/TLR4 complex, which sets into effect cellular mechanisms that activate MAPK, NF- B, and cytokine gene expression (Fig. 2-13). In contrast to TLR4, TLR2 recognizes PAMPs from gram-positive bacteria, including lipoproteins, lipopeptides, peptidoglycans, and phenol-soluble modulin from Staphylococcus species. Interestingly, loss-of-function single nucleotide polymorphisms of TLR are associated with an increased risk of infection in susceptible critically ill patients.41 As multiligand receptors, TLRs also bind damage-associated molecular pattern molecules (DAMPs), which are endogenous cellular products released during times of stress or injury. DAMPs include products such as HMGB1, heat shock proteins, and hyaluronic acid. Innate immune activation by DAMPs stimulates the recruitment of inflammatory cells to the site of injury and also mediates proinflammatory signaling.42 Fig. 2-13.

Lipopolysaccharide (LPS) recognition by immune cells is primarily by the toll-like receptor-4 (TLR4)/CD14/MD-2 complex. LPS is transported by LPS-binding protein (LBP) to the cell surface complex. Other cell surface LPS sensors include ion-gated channels, CD11b/CD18, and macrophage scavenger receptors. MAPK = mitogen-activated protein kinase; NF- B = nuclear factor B.

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. Conversely, cell necrosis results in a disorganized sequence of intracellular molecular releases 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 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. 2-14). 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). Fig. 2-14.

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 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 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 B (NF- B) 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- B and c-Jun activation. TRAF2 also recruits additional proteins that are antiapoptotic, known as inhibitor of apoptosis proteins (IAPs). DED = death effector domain; I- B = inhibitor of B; I- B/NF- B = inactive complex of NF- B that becomes activated when the I- B portion is cleaved; JNK = c-Jun N-terminal kinase; MEKK1 = mitogen-activated protein/extracellular regulatory protein kinase kinase kinase-1; NIK = NF- B–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, 1999, p 365. With kind permission from Springer Science + Business Media.) 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- 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, GM-CSF, and IFN. 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. 28

CELL-MEDIATED INFLAMMATORY RESPONSE Platelets Platelets are nonnucleated structures containing both mitochondria and mediators of coagulation and inflammatory signaling. Platelets are derived from bone marrow megakaryocytes. Platelets are critically important in the hemostatic response and are activated by several factors, including exposed collagen. Activated platelets at the site of injury release inflammatory mediators that serve as the principal chemoattractant for neutrophils and monocytes. The migration of platelets and neutrophils through the vascular endothelium occurs within 3 hours of injury and is enhanced by serotonin release, platelet-activating factor, and prostaglandin E2 . Platelets are an important source of eicosanoids and vasoactive mediators. A hallmark of the septic response includes thrombocytopenia; however, the mechanism is unclear and likely multifactorial. Pharmaceutical agents such as NSAIDs inhibit platelet function through the blockade of COX. 43

Lymphocytes and T-Cell Immunity Lymphocytes are circulating immune cells composed primarily of B cells, T cells, and natural killer cells. As mediators of adaptive immunity, T lymphocytes are recruited to sites of injury. Helper T lymphocytes are broadly categorized into two groups: T H 1 and T H 2. T H 1 cells favor cellular immune responses and secrete IFN- , IL-2, and IL-12, whereas T H 2 cells favor humoral responses and produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. T H 1 activation is paramount in the defense against bacterial pathogens; however, during critical illness induced by severe trauma or sepsis, there appears to be a predominance of T H 2 over T H 1 cytokine responses, which may exacerbate immune dysregulation through amplified cytokine signaling (Fig. 2-15). In burn injury, T regulatory cells are associated with T-cell suppression via the release of transforming growth factor beta (TGF- ), which can downregulate T-cell function. Nutritional supplementation may confer a benefit in T-cell responses, because arginine is essential for T-cell proliferation and receptor function.44 Fig. 2-15.

Specific immunity mediated by helper T lymphocytes subtype 1 (TH 1) and subtype 2 (TH 2) after injury. A T H 1 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 T H 2 response from naïve helper T cells is associated with injuries of greater magnitude and is not as effective against microbial infections. A T H 2 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 T H 1 response. Interferon- (IFN- ) is a known inhibitor of the T H 2 response. Although not cytokines, glucocorticoids are potent stimulants of a T H 2 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 127:117, 2000. Copyright Elsevier.)

Eosinophils Eosinophils are immunocytes whose primary functions are antihelmintic. Eosinophils are found mostly in tissues such as the lung and GI 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 reactive oxygen species, histamine, and peroxidase.45

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. 46

Monocytes Monocytes are mononuclear phagocytes that circulate in the bloodstream and can differentiate into macrophages, osteoclasts, and dendritic cells

on migrating into tissues. Macrophages are the main effector cells of the immune response to infection and injury, primarily through mechanisms that include phagocytosis of microbial pathogens, release of inflammatory mediators, and clearance of apoptotic cells. In humans, downregulation of monocyte and neutrophil 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. 47

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). On activation by inflammatory stimuli, including TNF, IL-1, and microbial pathogens, neutrophils are able to phagocytose, release lytic enzymes, and generate large amounts of toxic reactive oxygen species. 48

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 2-5). Prolonged and unremitting neutrophil activation and mediator release can lead to tissue injury through the production of toxic oxygen metabolites and lysosomal enzymes that degrade tissue basal membranes, cause microvascular thrombosis, and activate myeloperoxidases. In response to inflammatory stimuli, including chemokines, thrombin, IL-1, histamine, and TNF, vascular endothelium increases surface expression of the adhesion molecule P-selectin, which is observable in 10 to 20 minutes and mediates neutrophil rolling (Fig. 216). After 2 hours, however, cell surface expression favors E-selectin expression. L-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) are responsible for over 85% of monocyte-to-monocyte and monocyte-to-endothelium adhesion activity. Endothelial selectins interact with leukocyte selectins (PSGL-1, L-selectin) to mediate leukocyte rolling, which allows targeted immunocyte migration. Also important are secondary leukocyteleukocyte 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.49 Table 2-5 Molecules that Mediate Leukocyte-Endothelial Adhesion, Categorized by Family Adhesion Molecule

Action

Origin

Inducers of Expression

Target Cells

Selectins L-selectin

Fast rolling

Leukocytes

Native

Endothelium, platelets, eosinophils

P-selectin

Slow rolling

Platelets and endothelium

Thrombin, histamine

Neutrophils, monocytes

E-selectin

Very slow rolling

Endothelium

Cytokines

Neutrophils, monocytes, lymphocytes

ICAM-1

Firm adhesion/transmigration

Endothelium, leukocytes, fibroblasts, epithelium

Cytokines

Leukocytes

ICAM-2

Firm adhesion

Endothelium, platelets

Native

Leukocytes

VCAM-1

Firm adhesion/transmigration

Endothelium

Cytokines

Monocytes, lymphocytes

PECAM-1

Adhesion/transmigration

Endothelium, platelets, leukocytes

Native

Endothelium, platelets, leukocytes

Firm adhesion/transmigration

Leukocytes

Leukocyte activation

Endothelium

Neutrophils, monocytes, natural killer cells

Leukocyte activation

Endothelium

Adhesion

Neutrophils, monocytes, natural killer cells

Leukocyte activation

Endothelium

Firm adhesion/transmigration

Lymphocytes, monocytes

Leukocyte activation

Monocytes, endothelium, epithelium

Immunoglobulins

2 -(CD18)

Integrins CD18/11a

CD18/11b (Mac- Firm 1) adhesion/transmigration CD18/11c 1 -(CD29)

Integrins VLA-4

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. Fig. 2-16.

Simplified sequence of selectin-mediated neutrophil-endothelium 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 m/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 m/s) is predominantly mediated by P-selectins. The slowest rolling (3 to 10 m/s) before arrest is predominantly mediated by E-selectins, with contribution from P-selectins. ARREST (firm adhesion) leading to transmigration is mediated by -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 27:2050, 1999.)

Nitric Oxide Nitric oxide (NO) was initially known as endothelium-derived relaxing factor due to its effect on vascular smooth muscle and has important functions in both physiologic and pathologic control of vascular tone. Normal vascular smooth muscle relaxation is maintained by a constant output of NO and subsequent activation of soluble quanylyl cyclase. NO also can reduce microthrombosis by reducing platelet adhesion and aggregation (Fig. 2-17). NO easily traverses cell membranes and has a short half-life of a few seconds and is oxidized into nitrate and nitrite. NO is constitutively expressed by endothelial cells; however, inducible NO synthase, which is normally not expressed, is upregulated in response to inflammatory stimuli, which increases NO production. Increased NO is detectable in septic shock and in response to TNF, IL-1, IL-2, and hemorrhage. NO mediates hypotension observed during septic shock; however, a clinical trial of a nonselective NOS inhibitor showed increased

organ dysfunction and mortality.50 Fig. 2-17.

Endothelial interaction with smooth muscle cells and with intraluminal platelets. Prostacyclin (prostaglandin I 2 , 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.

Prostacyclin Prostacyclin is a member of the eicosanoid family and is primarily produced by endothelial cells. Prostacyclin is an effective vasodilator and also inhibits platelet aggregation. During systemic inflammation, endothelial prostacyclin expression is impaired, and thus the endothelium favors a more procoagulant profile. Prostacyclin therapy during sepsis has been shown to reduce the levels of cytokines, growth factors, and adhesion molecules through a cAMP-dependent pathway. In clinical trials, prostacyclin infusion is associated with increased cardiac output, splanchnic blood flow, and oxygen delivery and consumption with no significant decrease in mean arterial pressure. However, further study is required before the widespread use of prostacyclin is recommended. 51

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, TGF- , 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 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 endothelin 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. In addition, increased plasma ET concentration correlates with the severity of injury after major trauma or major surgical procedures, and in patients with cardiogenic or septic shock.52

Platelet-Activating Factor Another endothelium-derived product is platelet-activating factor (PAF), a natural phospholipid constituent of cell membranes that is minimally expressed under normal physiologic conditions. During acute inflammation, PAF is released by neutrophils, platelets, mast cells, and monocytes, and is expressed at the outer leaflet of endothelial cells. PAF can further activate neutrophils and platelets, and increase vascular permeability. Antagonists to PAF receptors have been experimentally shown to mitigate the effects of ischemia and reperfusion injury. Human sepsis is associated with a reduction in levels of PAF-acetylhydrolase, which is the endogenous inhibitor of PAF. Indeed, PAF-acetylhydrolase administration in patients with severe sepsis has yielded some reduction in multiple organ dysfunction and mortality.53

Atrial Natriuretic Peptides Atrial natriuretic peptides (ANPs) 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. They induce vasodilation as well as fluid and electrolyte excretion. ANPs are potent inhibitors of aldosterone secretion and prevent reabsorption of sodium. There is some experimental evidence to suggest that ANP can reverse acute renal failure or early acute tubular necrosis.

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 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. 2-18). 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. Fig. 2-18.

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 with permission from Cahill GF: Starvation in man. N Engl J Med 282:668, 1970. Copyright © Massachusetts Medical Society. All rights reserved.)

In the healthy adult, principal sources of fuel during short-term fasting (<5 days) are derived from muscle protein and body fat, with fat being the most abundant source of energy (Table 2-6). 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). Table 2-6 A. Body Fuel Reserves in a 70-kg Man A. Component

Mass (kg) Energy (kcal) Days Available

Water and minerals 49

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. Energy Equivalent of Substrate Oxidation B. Substrate O 2 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

During fasting, a healthy 70-kg adult will utilize 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. Glucagon, norepinephrine, vasopressin, and angiotensin II can promote the utilization of glycogen stores (glycogenolysis) during fasting. Although glucagon, epinephrine, and cortisol directly promote gluconeogenesis, epinephrine 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. 2-19). Fig. 2-19.

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.

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. 54 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. 220). 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. Fig. 2-20.

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 with permission from Cahill GF: Starvation in man. N Engl J Med 282:668, 1970. Copyright © Massachusetts Medical Society. All rights reserved.) Enhanced deamination of amino acids for gluconeogenesis during starvation consequently increases renal excretion of 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.

Metabolism after Injury Injuries or infections induce unique neuroendocrine and immunologic responses that differentiate injury metabolism from that of unstressed fasting (Fig. 2-21). 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. 2-22). 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.55 Fig. 2-21.

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.

Fig. 2-22.

Influence of injury severity on resting metabolism (resting energy expenditure, or REE). The shaded area indicates normal REE. (Adapted with permission from Long CL 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 3:452, 1979.)

LIPID METABOLISM AFTER INJURY 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 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 which potentiate lipolysis include adrenocorticotropic hormone (ACTH), catecholamines, thyroid hormone, cortisol, glucagon, growth hormone release, reduction in insulin levels, and increased sympathetic stimulus. 56

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 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. 2-23). Long-chain 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. 57 Trauma or sepsis suppresses lipoprotein lipase activity in both adipose tissue and muscle, presumably mediated by TNF. Fig. 2-23.

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.

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, growth hormone, and glucagon) on triglyceride lipase through a cAMP pathway (Fig. 2-24). 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. Fig. 2-24.

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-3phosphate 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.

Free fatty acids absorbed by cells conjugate with acyl-CoA 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. 2-25). 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. 58 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. Fig. 2-25.

Free fatty acids (FFAs) in the cells form fatty acyl coenzyme 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 reformed. 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. 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 adenosine triphosphate (ATP) molecules, carbon dioxide, and water. Excess acetyl-CoA 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 acetyl-CoA toward hepatic ketogenesis. A number of extrahepatic 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 and 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-6-phosphate. 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. 2-26). Fig. 2-26.

Simplified schema of glucose catabolism through the pentose monophosphate pathway or by breakdown into pyruvate. Glucose-6-phosphate becomes an important "crossroad" for glucose metabolism. 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 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 severalfold above baseline. This may occur in part due to reduced skeletal muscle pyruvate dehydrogenase activity after injury, which diminishes the conversion of pyruvate to acetyl-CoA 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.59 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 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. =@5# .%*"+( )%+"C1($1*"+0%@%('@"&3+#@%+"#'*"4%"& 41@1D%2"45"%?1*%?$)1*%"'#(1E'(1 *" !"4%('F'2)%*%).1#")%#%?( )+/"=GH941*21*."?) (%1*+";=9 proteins), which subsequently activates the second messenger, cAMP. The cAMP activates phosphorylase kinase, which in turn leads to conversion of glycogen to glucose-1-phosphate. Phosphorylase kinase also can be activated by the second messenger, calcium, through the breakdown of phosphatidylinositol phosphate, which is the case in vasopressin-mediated hepatic glycogenolysis. 60

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 2-7) and the Na + /glucose secondary active transport system (SGLT), which transports glucose molecules against concentration gradients by active transport. Table 2-7 Human Facilitated Diffusion Glucose Transporter (GLUT) Family Type

Amino Acids

Major Expression Sites

GLUT1 492

Placenta, brain, kidney, colon

GLUT2 524

Liver, pancreatic

GLUT3 496

Brain, testis

GLUT4 509

Skeletal muscle, heart muscle, brown and white fat

GLUT5 501

Small intestine, sperm

-cells, kidney, small intestine

Five functional human GLUTs have been cloned since 1985. GLUT1 is the transporter in human erythrocytes. It is expressed on several other tissues, but little is found in the liver and skeletal muscle. Importantly, it is a constitutive part of the endothelium in the blood-brain barrier. GLUT2 is predominantly expressed in the sinusoidal membranes of liver, renal tubules, enterocytes, and insulin-secreting

-cells of the pancreas.

GLUT2 is important for rapid export of glucose resulting from gluconeogenesis. GLUT3 is highly expressed in neuronal tissue of the brain, the kidney, and placenta, but GLUT3 mRNA has been detected in almost every human tissue. GLUT4 is significant to human metabolism because it is the primary glucose transporter of insulin-sensitive tissues, adipose tissue, and skeletal and cardiac muscle. These transporters are usually packaged as intracellular vesicles, but insulin induces rapid translocation of these vesicles to the cell surface. GLUT4 function has important implications in the physiology of patients with insulin-resistant diabetes. 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. 61 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. 62 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. 2-27). 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. Fig. 2-27.

The effect of injury severity on nitrogen wasting. (Adapted with permission from Long CL 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 3:452, 1979.) Activation of the ubiquitin-proteosome 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 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. It is imprecise to rely on any single or fixed combination of the aforementioned 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 metabolic processes, core temperature maintenance, 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. 60 However, the use of indirect calorimetry, particularly in the critically ill patient, is labor intensive and often leads to overestimation of caloric requirements. Basal energy expenditure (BEE) may also be estimated using the Harris-Benedict equations:

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 2-8). 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. Table 2-8 Caloric Adjustments above Basal Energy Expenditure (BEE) in Hypermetabolic Conditions 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

The second objective of nutritional support is to meet the substrate requirements for protein synthesis. An appropriate nonproteincalorie: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.64

Vitamins and Minerals The requirements for vitamins and essential trace minerals usually can be met easily in the average patient with an 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. 65 Laboratory models have long demonstrated that luminal nutrient contact reduces intestinal mucosal atrophy compared with parenteral or no nutritional support. Studies comparing postoperative enteral and parenteral nutrition in patients undergoing gastrointestinal surgery have demonstrated reduced infectious complications and acute phase protein production in those !%2"45"($%"%*(%)'@") 3(%-"I%("?) +?%#(1E%@5")'*2 &1D%2"+(321%+" !"?'(1%*(+"C1($"'2%J3'(%"*3()1(1 *'@"+('(3+";'@43&1*"KL".M2N>"3*2%). 1*. 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. 66 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. 67 At the other extreme, 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. The exception has been in studies of patients with closed-head injury, in which 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. The early initiation of enteral feeding in burn patients, while sensible and supported by retrospective analysis, is an empiric practice supported by limited prospective trials. Recommendations for instituting early enteral nutrition in surgical patients with moderate malnutrition (albumin level of 2.9 to 3.5 g/dL) can only be made by inference due to a lack of data directly pertaining to this population. For these patients, it is prudent to offer enteral nutrition based on measured energy expenditure of the recovering patient, or if complications arise that may alter the anticipated course of recovery (e.g., anastomotic leaks, return to surgery, sepsis, or failure to wean from the ventilator). 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. Collectively, the data support the use of early enteral nutritional support after major trauma and in patients who are anticipated to have prolonged recovery after surgery. Healthy patients without malnutrition 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 in patients with poorer preoperative nutritional reserves. 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 closed-head 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, but low-residue formulations may be preferred. Enteral feeding should also be offered to patients with short-bowel syndrome or clinical malabsorption, but necessary calories, essential minerals, and vitamins should be supplemented using parenteral modalities.

Enteral Formulas 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 such as lactose. In patients with malabsorption, such as in inflammatory bowel diseases, absorption may be improved by provision of dipeptides, tripeptides, and MCTs. However, MCTs are deficient in essential fatty acids, which necessitates supplementation with some LCTs. Factors that influence the choice of enteral formula 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.

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, an important fuel for colonocytes. There are no contraindications for using fiber-containing formulas in critically ill patients.

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, branched-chain amino acids, omega-3 fatty acids, nucleotides, and beta carotene.68 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. 69 The addition of amino acids to these formulas generally doubles the amount of protein (nitrogen) found in standard formula; however, their cost can be prohibitive. 70

CALORIE-DENSE FORMULAS The primary distinction of calorie-dense 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.

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.

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 nonprotein-calorie: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. 71 The use of 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 predisposed them to additional morbidity and mortality.72

ACCESS FOR ENTERAL NUTRITIONAL 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 2-9.73 Table 2-9 Options for Enteral Feeding Access Access Option

Comments

Nasogastric tube

Short-term use only; aspiration risks; nasopharyngeal trauma; frequent dislodgment

Nasoduodenal/nasojejunal Short-term use; lower aspiration risks in jejunum; placement challenges (radiographic assistance often necessary) tube 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

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, but access past the pylorus requires greater effort to accomplish. 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. 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 is 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. 74

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 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. 75 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. 76 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 2-10). 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. Table 2-10 Incidence of Septic Morbidity in Parenterally and Enterally Fed Trauma Patients Blunt Trauma

Penetrating Trauma

Total

Complication

TEN n = 48 TPN n = 44 TEN n = 38 TPN n = 48 TEN n = 44 TPN n = 84

Abdominal abscess

2

1

2

6

4

7

Pneumonia

4

10

1

2

5

12

Wound infection

2

3

1

3

3

Bacteremia

1

4

1

1

5

Urinary tract

1

1

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%

TEN = total enteral nutrition; TPN = total parenteral nutrition. 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 216(2):172–183, 1992.

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 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. 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 which 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 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 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 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. 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.

INTRAVENOUS ACCESS METHODS 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 long-term 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 considered, but is rare when proper pharmacy protocols have been followed. This problem occurs more frequently in patients with systemic sepsis and in many cases is due to hematogenous seeding of the catheter with bacteria.77 One of the earliest signs of systemic sepsis 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. 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. It is prudent to delay reinserting the catheter

by 12 to 24 hours, especially if bacteremia is present.78 Other complications related to catheter placement include the development of pneumothorax, hemothorax, hydrothorax, subclavian artery injury, thoracic duct injury, cardiac arrhythmia, air embolism, catheter embolism, and cardiac perforation with tamponade. All of these complications may be avoided by strict adherence to proper techniques. The use of multilumen catheters may be associated with a slightly increased risk of infection. This is most likely associated with greater catheter manipulation and intensive use. The rate of catheter infection is highest for those placed in the femoral vein, lower for those in the jugular vein, and lowest for those in the subclavian vein. When catheters are indwelling for <3 days, infection risks are negligible. If indwelling time is 3 to 7 days, the infection risk is 3 to 5%. Indwelling times of >7 days are associated with a catheter infection risk of 5 to 10%. Strict adherence to barrier precautions also reduces the rate of infection.

Metabolic Complications Hyperglycemia may develop with normal rates of infusion in patients with impaired glucose tolerance or in any patient if the hypertonic solutions are administered too rapidly. This is a particularly common complication in patients with latent diabetes and in patients subjected to severe surgical stress or trauma. Treatment of the condition consists of volume replacement with correction of electrolyte abnormalities and the administration of insulin. This complication can be avoided with careful attention to daily fluid balance and frequent monitoring of blood glucose levels and serum electrolytes. Increasing experience has emphasized the importance of not overfeeding the parenterally nourished patient. This is particularly true for the depleted patient in whom excess calorie infusion may result in carbon dioxide retention and respiratory insufficiency. In addition, excess feeding also has been related to the development of hepatic steatosis or marked glycogen deposition in selected patients. Cholestasis and formation of gallstones are common in patients receiving long-term parenteral nutrition. Mild but transient abnormalities of serum transaminase, alkaline phosphatase, and bilirubin levels occur in many parenterally nourished patients. Failure of the liver enzymes to plateau or return to normal over 7 to 14 days should suggest another etiology.

Intestinal Atrophy Lack of intestinal stimulation is associated with intestinal mucosal atrophy, diminished villous height, bacterial overgrowth, reduced lymphoid tissue size, reduced immunoglobulin A 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.

SPECIAL FORMULATIONS Glutamine and Arginine 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 source toward the visceral organs and tumors, respectively. These situations create, at least experimentally, a glutamine-depleted 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. Advanced methods of detecting glutamine traffic in patients with gastrointestinal cancer have not demonstrated more sequestration of glutamine in tumors than in normal intestine. There are data demonstrating decreased dependency on TPN in severe cases of short-bowel syndrome when glutamine therapy with modified diets and growth hormones are used. However, in patients with milder forms of short-bowel syndrome and better nutritional status, glutamine supplementation did not lead to appreciable enhancement in intestinal absorption. 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 evidence in support of these phenomena in human subjects remains inconclusive. 79 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. 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.

Omega-3 Fatty Acids The provision of omega-3 polyunsaturated fatty acids (canola oil or fish oil) displaces omega-6 fatty acids in cell membranes, which theoretically reduces the proinflammatory response from prostaglandin production. 80

Nucleotides RNA supplementation in solutions is purported, at least experimentally, to increase cell proliferation, provide building blocks for DNA synthesis, and improve helper T cell function.

NUTRITION-INDUCED INFLAMMATORY MODULATION Studies have demonstrated that the mode of nutritional supplementation, either enteral or parenteral, may influence stress-induced inflammatory responses. Intravenously fed subjects demonstrate a heightened response to proinflammatory stimuli such as endotoxin. Enteral feedings have been regarded as the feeding mode of choice when possible, and although advantages have been suggested, including improved GI barrier function, the mechanisms through which enteral feedings mediate efficacious effects have yet to be fully determined. Providing further insight into the benefit of enteral feedings, Luyer and colleagues have demonstrated that enteral fat maintains both afferent and efferent vagal pathway signaling via intestinal cholecystokinin receptor activation. They observed that consumption of a high-density fat meal before stress induced by hemorrhage resulted in reduced systemic inflammation and improved outcome. 81 Thus, enteral nutrients may act as agonists for endogenous neuroendocrine anti-inflammatory pathways (Fig. 2-28). 82 Fig. 2-28.

Vagal afferent system senses peripheral inflammatory focus and also responses to intestinal luminal substrates, in this case enteral lipid signaling via cholecystokinin receptors (CCK-r). Efferent vagal signals limit proinflammatory cytokine production via activation of cholinergic nicotinic receptors on visceral immune cells. Clinical conditions that disrupt the integrity of this circuit may enhance inflammatory responses. Ach = acetylcholine; CCK = cholecystokinin; IL-6 = interleukin-6; TLR = toll-like receptor; TNF = tumor necrosis factor. (Adapted with permission from Luyer MD, et al. Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 202:1023, 2005. By copyright permission of The Rockefeller University Press.)

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Schwartz's Principles of Surgery > Part I. Basic Considerations > Chapter 3. Fluid and Electrolyte Management of the Surgical Patient >

KEY POINTS 1. Proper management of fluid and electrolytes facilitates crucial homeostasis that allows cardiovascular perfusion, organ system function, and cellular mechanisms to respond to surgical illness. 2. 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. 3. Alterations in the concentration of serum sodium have profound effects on cellular function due to water shifts between the intracellular and extracellular spaces. 4. Different rates of compensation between respiratory and metabolic components of acid-base homeostasis require frequent laboratory reassessment during therapy. 5. Most acute surgical illnesses are accompanied by some degree of volume loss or redistribution. Consequently, isotonic fluid administration is the most common initial IV fluid strategy, while attention is being given to alterations in concentration and composition. 6. Although active investigation continues, alternative resuscitation fluids have limited clinical utility, other than the correction of specific electrolyte abnormalities. 7. Some surgical patients with neurologic illness, malnutrition, acute renal failure, or cancer require special attention to welldefined, disease-specific abnormalities in fluid and electrolyte status.

FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENT: 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 treatments, common metabolic derangements, and alternative 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 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 60% of total body weight is TBW, 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% 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. 31). The extracellular fluids (ECF), plasma and interstitial fluid, together comprise about one third of the TBW and the intracellular compartment the remaining two thirds. The extracellular water comprises 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. Fig. 3-1.

Functional body fluid compartments. TBW = total body water.

Composition of Fluid Compartments

The normal chemical composition of the body fluid compartments is shown in Fig. 3-2. The ECF compartment is balanced between sodium, the principal cation, and chloride and bicarbonate, the principal anions. The intracellular fluid compartment is comprised primarily of the cations potassium and magnesium, and the anions phosphate and proteins. The concentration gradient between compartments is maintained by adenosine triphosphate–driven sodium-potassium pumps located with the cell membranes. The composition of the plasma and interstitial fluid differs only slightly in ionic composition. The slightly higher protein content (organic anions) 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. Fig. 3-2.

Chemical composition of body fluid compartments.

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 (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:

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 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):

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 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 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. Table 3-1 Water Exchange (60- to 80-kg Man) Routes

Average Daily Volume (mL) Minimal (mL) Maximal (mL)

H 2 O gain:

Sensible: Oral fluids

800–1500

1500/h

Solid foods

500–700

1500

Water of oxidation 250

125

800

Water of solution

500

Urine

800–1500

300

1400/h

Intestinal

0–250

2500/h

Insensible:

H 2 O loss:

Sensible:

Sweat

4000/h

600

600

1500

Insensible: Lungs and skin

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 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. Table 3-2 Signs and Symptoms of Volume Disturbances System

Volume Deficit

Generalized Weight loss

Cardiac

Volume Excess Weight gain

Decreased skin turgor

Peripheral edema

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

Table 3-3 Composition of GI Secretions Type of Secretion Volume (mL/24 h) Na (mEq/L) K (mEq/L) Cl (mEq/L) HCO – (mEq/L) 3

Stomach

1000–2000

60–90

10–30

100–130

Small intestine

2000–3000

120–140

5–10

90–120

30–40

Colon

60

30

40

Pancreas

600–800

135–145

5–10

70–90

95–115

Bile

300–800

135–145

5–10

90–110

30–40

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 32). 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. 3 Additionally, the hypothalamus is stimulated to secrete vasopressin, which increases water reabsorption in the kidneys. 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 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 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 lowsodium 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. Fig. 3-3.

Evaluation of sodium abnormalities. ADH = antidiuretic hormone; SIADH = syndrome of inappropriate secretion of antidiuretic hormone. 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:

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. Table 3-4 Clinical Manifestations of Abnormalities in Serum Sodium Level Body System

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 significant increases in intracranial pressure

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

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 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 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 x 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.

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 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. Table 3-5 Etiology of Potassium Abnormalities

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 Hypokalemia Inadequate intake Dietary, potassium-free intravenous fluids, potassium-deficient TPN Excessive potassium excretion Hyperaldosteronism Medications GI losses Direct loss of potassium from GI fluid (diarrhea) Renal loss of potassium (gastric fluid, either as vomiting or high nasogastric output)

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 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. Table 3-6 Clinical Manifestations of Abnormalities in Potassium, Magnesium, and Calcium Levels Increased Serum Levels 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

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:

Additionally, drugs such as amphotericin, aminoglycosides, foscarnet, 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).

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:

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 osteoclastic 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.

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.

Hyperphosphatemia Hyperphosphatemia can be due to 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 phosphorus-containing 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.

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 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.

Hypomagnesemia Magnesium depletion is a common problem 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 hydrogen-sensitive 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. The predicted compensatory changes in response to metabolic or respiratory derangements are listed in Table 3-7.18 If the predicted change in pH is exceeded, then a mixed acid-base abnormality may be present (Table 3-8). Table 3-7 Predicted Changes in Acid-Base Disorders Disorder

Predicted Change

Metabolic Metabolic acidosis

Pco2 = 1.5 x HCO3 – + 8

Metabolic alkalosis

Pco2 = 0.7 x HCO3 – + 21

Respiratory Acute respiratory acidosis

pH = (Pco 2 – 40) x 0.008

Chronic respiratory acidosis

pH = (Pco 2 – 40) x 0.003

Acute respiratory alkalosis

pH = (40 – Pco2 ) x 0.008

Chronic respiratory alkalosis

pH = (40 – Pco2 ) x 0.017

P CO2 = partial pressure of carbon dioxide. Table 3-8 Respiratory and Metabolic Components of Acid-Base Disorders Acute Uncompensated

Chronic (Partially Compensated)

Type of AcidBase Disorder

pH PCO2 (Respiratory Component)

Plasma HCO3 –a (Metabolic Component)

Respiratory acidosis

N

Respiratory alkalosis

N

Metabolic acidosis

N

Metabolic alkalosis

N

a

pH PCO2 (Respiratory Plasma HCO –a 3 Component) (Metabolic Component)

?

Measured as standard bicarbonate, whole blood buffer base, CO2 content, or CO2 combining power. The base excess value

is positive when the standard bicarbonate is above normal and negative when the standard bicarbonate is below normal. N = normal; P CO2 = partial pressure of carbon dioxide.

METABOLIC DERANGEMENTS

Metabolic Acidosis Metabolic acidosis results from an increased intake of acids, an increased generation of acids, or an 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. Table 3-9 Etiology of Metabolic Acidosis Increased Anion Gap Metabolic Acidosis Exogenous acid ingestion Ethylene glycol Salicylate Methanol Endogenous acid production Ketoacidosis Lactic acidosis Renal insufficiency Normal Anion Gap Acid administration (HCl) Loss of bicarbonate GI losses (diarrhea, fistulas) Ureterosigmoidoscopy Renal tubular acidosis

Carbonic anhydrase inhibitor

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

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: -Hydroxybutyrate and acetoacetate in ketoacidosis Lactate in lactic acidosis Organic acids in renal insufficiency 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. The administration of bicarbonate for the treatment of metabolic acidosis is controversial, because it is not clear that acidosis is deleterious.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 either 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 if the loss of bicarbonate has a renal cause, the urinary [NH 4 + ] can be measured. A low urinary [NH 4 + ] 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 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, hypokalemic, and 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, 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 3-10 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)

RESPIRATORY DERANGEMENTS Under normal circumstances blood P CO2 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. 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

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.

FLUID AND ELECTROLYTE THERAPY Parenteral Solutions 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 Table 3-12 Electrolyte Solutions for Parenteral Administration Electrolyte Composition (mEq/L) Solution

Na CL

K HCO – 3

Ca Mg mOsm

Extracellular fluid

142 103 4 27

5

Lactated Ringer's

130 109 4 28

3

0.9% Sodium chloride

154 154

308

D 5 0.45% Sodium chloride

77

407

77

D5W

3

280–310 273

253

3% Sodium chloride

513 513

1026

D 5 = 5% dextrose; D5W = 5% dextrose in water. 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.

Alternative Resuscitative Fluids 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 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 also have been concerns of increased bleeding, because hypertonic saline is an arteriolar vasodilator. A meta-analysis of the results of prospective randomized controlled trials in trauma patients suggests that hypertonic saline may be no better than standardof-care isotonic saline. 26 In subgroup analysis, however, patients with shock and concomitant closed head injury did demonstrate benefit. Table 3-13 Alternative Resuscitative Fluids Solution

Molecular Weight Osmolality (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. 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 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 neutrophilmediated 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 in recipients of kidneys procured from brain-dead donors. 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

Correction of Life-Threatening Electrolyte Abnormalities38 SODIUM

Hypernatremia Treatment of hypernatremia usually consists of 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 1 / 4 normal saline, or enterally administered water. The formula used to estimate the amount of water required to correct hypernatremia is as follows:

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.

Hyponatremia Most cases of hyponatremia can be treated by free water restriction and, if severe, the administration of sodium. In patients !"#$%&'()*$'+%)*$,-%."!&%/$01(2"&()"!.$#12&%)"'+(!)$3&+0$%&"$&..-'$-%"!*$"#+$0+'-($0&3!-($*+4+*$!0$567$(89:;<$=, 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. Magnetic resonance imaging may assist in 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 cationexchange resin such as Kayexalate that binds potassium in exchange for sodium. It can be administered either 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 to 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. Table 3-14 Treatment of Symptomatic Hyperkalemia 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 Shift potassium Glucose 1 ampule of D 50 and regular insulin 5–10 units IV

Bicarbonate 1 ampule IV Counteract cardiac effects Calcium gluconate 5–10 mL of 10% solution D 50 = 50% dextrose.

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. Table 3-15 Electrolyte Replacement Therapy Protocol Potassium Serum potassium level <4.0 mEq/L: Asymptomatic, tolerating enteral nutrition: KCl 40 mEq per enteral access x 1 dose Asymptomatic, not tolerating enteral nutrition: KCl 20 mEq IV q2h x 2 doses Symptomatic: KCl 20 mEq IV q1h x 4 doses Recheck potassium level 2 h after end of infusion; if <3.5 mEq/L and asymptomatic, replace as per above protocol 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 x 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 x 1 d, then 0.5 mEq/kg in normal saline 250 mL infused IV over 24 h x 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 Calcium Normalized 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 x 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: KPHO 4 or NaPO4 0.15 mmol/kg IV over 6 h x 1 dose

Recheck phosphate level in 3 d Phosphate level <1.0 mg/dL: Tolerating enteral nutrition: KPHO 4 or NaPO4 0.25 mmol/kg over 6 h x 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: KPHO 4 or NaPO4 0.25 mmol/kg (LBW) over 6 h x 1 dose; recheck phosphate level 4 h after end of infusion; if <2.5 mg/dL, then KPHO 4 or NaPO4 0.15 mmol/kg (LBW) IV over 6 h x 1 dose

3 mmol KPHO 4 = 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.

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. 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 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 to 10 kg

Give 100 mL/kg per day

For the next 10 to 20 kg Give an additional 50 mL/kg per day For weight >20 kg

Give an additional 20 mL/kg per day

For example, a 60-kg female would receive a total of 2100 mL of fluid daily: 1000 mL for the first 10 kg of body weight (10 kg x 100 mL/kg per day), 500 mL for the next 20 kg (10 kg x 50 mL/kg per day), and 80 mL for the last 40 kg (40 kg x 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 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 pre-existing 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 ( 1 / 2 to 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 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/hr of a balanced salt solution to support homeostasis. The addition of albumin or other colloid-containing 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 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 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 disease. 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 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.

DIABETES INSIPIDUS Diabetes insipidus (DI) is a disorder of 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 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 SC every 6 to 8 hours. However, serum electrolytes and osmolality should be monitored to avoid excess vasopressin administration with resulting iatrogenic SIADH.

CEREBRAL SALT WASHING 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, at 20 kcal/kg per day, 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.

Acute Renal Failure Patients 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, normalization of sodium, potassium, and bicarbonate levels may be best achieved using continuous therapy.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. 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, duration 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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Schwartz's Principles of Surgery > Part I. Basic Considerations > Chapter 4. Hemostasis, Surgical Bleeding, and Transfusion >

KEY POINTS 1. 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. 2. The need for massive transfusion should be anticipated and guidelines should be in place to provide the simultaneous administration of blood, plasma, and platelets. 3. The acute coagulopathy of trauma results from a combination of activation of protein C and fibrinolysis. It is distinct from disseminated intravascular coagulation, is present on arrival to the emergency department, and is associated with an increase in mortality.

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. Fig. 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.

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 A 2 (TXA 2 ) is produced locally at the site of 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 (5hydroxytryptamine) released during platelet aggregation are potent vasoconstrictors. Lastly, bradykinin and fibrinopeptides, which are involved in the coagulation scheme, also are 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 Platelets are anucleate fragments of megakaryocytes. The normal circulating number of platelets ranges between 150,000 and 400,000/ L. Up to 30% of circulating platelets may be sequestered in the spleen. If not consumed in a clotting reaction, 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. 42). 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's factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand's disease. The vWF binds to glycoprotein I/IX/V on the platelet membrane. After 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. Fig. 4-2.

Schematic of platelet activation and thrombus function. ADP = adenosine diphosphate.

Arachidonic acid released from the platelet membranes is converted by COX to prostaglandin G 2 (PGG 2 ) and then to prostaglandin H 2 (PGH 2 ), 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 COX is irreversibly inhibited by aspirin and reversibly blocked by NSAIDs but is not affected by COX-2 inhibitors. In the second wave of platelet aggregation, a release reaction occurs in which several substances, including ADP, Ca 2+ , serotonin, TXA2 , and

-granule proteins are discharged. Fibrinogen is a required cofactor for this process, acting as a bridge

for the glycoprotein 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

-granule, stabilizes

fibrinogen binding to the activated platelet surface and strengthens the platelet-platelet interactions. Platelet factor 4 (PF4) and

-thromboglobulin also are secreted during the release reaction. PF4 is a potent heparin antagonist. The second wave of

platelet aggregation is inhibited by aspirin and NSAIDs, 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 thrombin (factor IIa) (Fig. 4-3) 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. Fig. 4-3.

Schematic of the coagulation system. HMW = high molecular weight.

Coagulation Under physiologic conditions, hemostasis is accomplished by a complex sequence of interactions between platelets, the endothelium, and multiple circulating or membrane-bound coagulation factors. As shown in Fig. 4-3, the coagulation cascade typically has been depicted as two intersecting pathways. The intrinsic pathway begins with factor XII and through a cascade

of enzymatic reactions activates factors XI, IX, and VII in sequence. In the intrinsic pathway all of the components leading ultimately to fibrin clot formation are intrinsic to the circulating plasma and no surface is required to initiate the process. In contrast, the extrinsic pathway requires exposure of tissue factor on the surface of the injured vessel wall to initiate the arm of the cascade beginning with factor VII. The two arms of the coagulation cascade merge to a common pathway at factor X, and activation proceeds in sequence of factors II (prothrombin) and I (fibrinogen). Clot formation occurs after proteolytic conversion of fibrinogen to fibrin. One convenient feature of depicting the coagulation cascade with two merging arms is that commonly used laboratory tests segregate abnormalities of clotting to one of the two arms (Table 4-1). An elevated activated partial thromboplastin time (aPTT) is associated with abnormal function of the intrinsic arm of the cascade, whereas an elevated prothrombin time (PT) is associated with the extrinsic arm. Vitamin K deficiency and warfarin use affect factors II, VII, IX, and X. Fibrinogen levels usually need to be <50 mg/dL to cause prolongation of the PT and aPTT. Recently, efforts have been made to present the coagulation cascade in a more physiologically relevant format. The primary physiologic pathway for coagulation is initiated by the exposure of subendothelial tissue factor when the luminal surface of a vessel is injured. Propagation of the clotting reaction then ensues with a sequence of four enzymatic reactions, each of which involves a proteolytic enzyme that generates the next enzyme in the cascade by cleavage of a proenzyme and a phospholipid surface, such as a platelet membrane. Each reaction requires a helper protein. Factor VIIa binds to tissue factor on exposure of the latter molecule through injury to the vascular wall. The tissue factor VIIa complex catalyzes the activation of factor X to factor Xa. The reaction takes place on the phospholipid surface of activated platelets. This complex is four orders of magnitude more active at converting factor X than is factor VIIa alone and also activates factor IX to factor IXa. Factor Xa, together with factor Va and Ca 2+ and phospholipid, comprises the prothrombinase complex that converts prothrombin to thrombin. Thrombin has multiple functions in the clotting process, including conversion of fibrinogen to fibrin and activation of factors V, VII, VIII, XI, and XIII, as well as activation of platelets. Table 4-1 Coagulation Factors Tested by the PT and the aPTT PT

aPTT

VII

XII

X

High molecular weight kininogen

V

Prekallikrein

II (prothrombin)

XI

Fibrinogen

IX VIII X V II Fibrinogen

aPTT = activated partial thromboplastin time; PT = prothrombin time. Factor VIIIa combines with factor IXa to form the intrinsic factor complex, which is responsible for the bulk of the conversion of factor X to Xa. This intrinsic complex (VIIIa-IXa) is approximately 50 times more effective at catalyzing factor X activation than is the extrinsic (tissue factor VIIa) complex and five to six orders of magnitude more effective than is factor IXa alone.

Factor Xa combines with factor Va, also on the activated platelet membrane surface, to form the prothrombinase complex, which is responsible for converting prothrombin to thrombin. As with the VIIIa-IXa complex, the prothrombinase is significantly more effective at catalyzing its substrate than is factor Xa 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. The coagulation system is exquisitely regulated. In addition to clot formation that must occur to prevent bleeding at the time of vascular injury, two related processes must exist to prevent propagation of the clot beyond the site of injury. First, there is a feedback inhibition on the coagulation cascade, which deactivates the enzyme complexes leading to thrombin formation. Second, mechanisms of fibrinolysis allow for breakdown of the fibrin clot and subsequent repair of the injured vessel with deposition of connective tissue. Tissue factor pathway inhibitor (TFPI) blocks the extrinsic tissue factor–VIIa complex, eliminating this catalyst's production of factors Xa and IXa. Antithrombin III effectively neutralizes all of the procoagulant serine proteases and only weakly inhibits the tissue factor–VIIa complex. The primary effect is to halt the production of thrombin. A third major mechanism of inhibition of thrombin formation is the protein C system. On its formation, thrombin binds to thrombomodulin and activates protein C to activated protein C (APC), which then forms a complex with its cofactor, protein S, on a phospholipid surface. The APC–protein S complex cleaves factors Va and VIIIa so they are no longer able to participate in the formation of tissue factor–VIIa or prothrombinase complexes. Of interest is an inherited form of factor V that carries a genetic mutation, called factor V Leiden, that is resistant to cleavage by APC and thus remains active (procoagulant). Patients with factor V Leiden are predisposed to venous thromboembolic events. As a result of the three systems described earlier, feedback inhibition of thrombin formation exists at upstream, intermediate, and downstream portions of the coagulation cascade to "turn off" thrombin formation once the procoagulant sequence is initially activated. The same thrombin-thrombomodulin complex that leads to formation of APC also activates TAFI. In addition to stabilizing the clot, removal of the terminal lysine on the fibrin molecule by TAFI renders the clot more susceptible to lysis by plasmin. 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. Tissue plasminogen activator (tPA) is made by the endothelium and other cells of the vascular wall and is the main circulating form of this family of enzymes. The 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. Because of the complex nature of hemostasis, potential interference in the process can occur at many levels. Platelet number or function can be insufficient to adequately support coagulation. Alternatively, abnormalities in the clotting factors may underlie an abnormality of hemostasis, either from an intrinsic defect in one of the factors or as the result of pharmacotherapy.

Fibrinolysis During the wound-healing process, the fibrin clot undergoes clot lysis, which permits restoration of blood flow. The main enzyme, plasmin, degrades the fibrin mesh at various places, which leads to the production of circulating fragments that are

cleared by other proteases or by the kidney and liver. Fibrinolysis is initiated at the same time as the clotting mechanism under the influence of circulating kinases, tissue activators, and kallikrein, which are present in many organs, including the vascular endothelium. Fibrin is degraded by plasmin, a serine protease derived from the proenzyme plasminogen. Plasminogen may be converted by one of several plasminogen activators, including tPA and uPA. The tPA is synthesized by endothelial cells and released by the cells on thrombin stimulation as single-chain tPA. This is then cleaved by plasmin to form two-chain tPA. Bradykinin, a potent endothelium-dependent vasodilator cleaved from high molecular weight kininogen by kallikrein, causes contraction of nonvascular smooth muscle, increases vascular permeability, and enhances 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 it cleaves fibrin, somewhat less efficiently, and it also will degrade fibrinogen. Fully cross-linked fibrin is also a relatively poor substrate for plasmin. Plasminogen activation may be initiated by activation of factor XII, which leads to the generation of kallikrein from prekallikrein and cleavage of high molecular weight kininogen by kallikrein. Several characteristics of the enzymatic reactions ensure that fibrinolysis occurs at a controlled rate and preferentially at the site of clot formation. The tPA activates plasminogen more efficiently when it is bound to fibrin, so that plasmin is formed selectively on the clot. Plasmin is inhibited by

2 -antiplasmin,

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 also is inhibited by

2 -antiplasmin

and

circulating tPA or urokinase. Clot lysis yields fibrin degradation products, including E-nodules and D-dimers. The 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. Presence of D-dimers in the circulation may be a marker of thrombosis or other conditions in which a significant activation of the fibrinolytic system is present. The final inhibitor for the fibrinolytic system is TAFI, a procarboxypeptidase that is activated by the thrombin-thrombomodulin complex. The active enzyme removes lysine residues from fibrin that are essential for binding plasminogen. The sequence of fibrin formation and its dissolution by plasmin is presented in schematic form in Fig. 4-4. Fig. 4-4.

Schematic of fibrin formation and dissolution. FBP = fibrin breakdown product; FPA = fibrinopeptide A.

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 <1% of normal are considered severe disease, factor levels between 1 and 5% moderately severe, and levels of 5 to 30% mild disease. Patients with severe hemophilia have severe spontaneous bleeds, frequently into joints, which leads to crippling arthropathies. Intramuscular hematomas, retroperitoneal hematomas, and GI, genitourinary, and retropharyngeal bleeding are added clinical sequelae seen with severe disease. Intracranial bleeding and bleeding from the tongue or lingual frenulum may be life-threatening with severe disease. Patients with moderately severe hemophilia have less spontaneous bleeding but are likely to bleed severely after trauma or surgery. Those with mild disease do not bleed spontaneously and frequently have only minor bleeding after major trauma or surgery. Because platelet function is normal in individuals with hemophilia, patients may not bleed immediately after an injury or minor surgery because 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 generally is recommended for patients who are both HIV and hepatitis C virus seronegative. For factor IX replacement, the preferred products are recombinant or high-purity factor IX, because of the risk of thrombosis with the intermediate factor IX (prothrombin complex) concentrates. Intermediate factor IX concentrates contain varying amounts of factors II, VII, and X and are reported to induce thrombosis when used in high doses. Furthermore, the cost of concentrates increases with the specific activity of factor VIII or factor IX. Up to 20% of hemophiliac patients with factor VIII deficiency develop inhibitors. Some patients have low titers of the inhibitors and can be treated with higher dosages of factor VIII to achieve the desired plasma level. For patients with high titers of inhibitors alternate treatments must be used. These include porcine factor VIII, prothrombin complex concentrates, activated prothrombin complex concentrates, and recombinant factor VIIa. Factor VII is the most effective but must be given every 2 hours in situations with active bleeding and can be very expensive. Recombinant factor VIIa may be useful in factor IX–deficient patients with inhibitors. Additionally -aminocaproic acid, or Amicar, an inhibitor of fibrinolysis, is frequently a useful adjunct to factor VIII or IX or desmopressin acetate (DDAVP) in treatment of bleeding in patients with hemophilia. Excess -aminocaproic acid can lead to thrombosis, so the drug should be used with caution.

VON WILLEBRAND'S DISEASE von Willebrand's disease (vWD), the most common congenital bleeding disorder, is characterized by low levels of factor VIII. It is an autosomal dominant disorder, and the primary defect is a low level of 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 (i.e., 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. One treatment for vWD is an

intermediate-purity factor VIII concentrate such as Humate-P that contains vWF as well as factor VIII. The second treatment strategy is desmopressin acetate, which raises endogenous vWF levels by triggering release of the factor from endothelial cells. Desmopressin acetate is used once a day because time is needed for synthesis of new stores of vWF within the endothelial cells. Historically, patients with type I disease have been found to respond well to desmopressin acetate. Type II patients may respond, depending on the particular defect. Type III patients are usually unresponsive.

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. Spontaneous bleeding is rare, but bleeding may occur after surgery, trauma, or invasive procedures. Patients with factor XI deficiency who present with bleeding or for whom surgery is planned and who are known to have bled previously are treated 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. Recombinant factor VIIa treatment has been used successfully in children with severe factor XI deficiency who require major operations such as open heart surgery. 1 Desmopressin acetate also may be useful in the prevention of surgical bleeding in these patients.

DEFICIENCY OF FACTORS II (PROTHROMBIN), V, AND X Inherited deficiencies of factors II, V, and X are rare. These deficiencies are inherited in an autosomal recessive pattern. Significant bleeding is encountered in homozygotes with <1% of normal activity. In any of these deficiencies, bleeding is treated with FFP. As with factor XI, FFP contains 1 unit of activity of each per milliliter. However, factor V activity is decreased because of its inherit instability. The half-life of prothrombin (factor II) is long (approximately 72 hours) and only approximately 25% of the 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 also are lacking the factor V normally present in platelets and may need platelet transfusions as well as FFP.

FACTOR VII DEFICIENCY Inherited factor VII deficiency is a rare autosomal recessive disorder. Clinical bleeding can widely vary and does not always correlate with the level of factor VII coagulant activity in plasma. Bleeding is uncommon unless the level is <3%. The most common bleeding manifestations are easy bruising and mucosal bleeding, particularly epistaxis or oral mucosal bleeding. Postoperative bleeding is also common, reported in 30% of surgical procedures in such patients.2 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 deficiency, originally recognized by François Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis. 3 The male:female ratio is 1:1. Although acquired factor XIII 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. 4 Bleeding typically is 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 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 1918.5 Bleeding in thrombasthenic patients must be treated with platelet transfusions. The Bernard-Soulier syndrome, caused by a defect in the glycoprotein Ib/IX/V receptor for vWF, is necessary for platelet adhesion to the subendothelium. Transfusion of normal platelets is required to treat 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), Ca 2+ , and inorganic phosphate] and

-granules. Dense granule deficiency is the most

prevalent of these. It may be an isolated defect or occur with 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. An isolated defect of the

-granules is known as gray platelet syndrome because of the appearance of the platelets

on Wright's stain preparations. A few patients have been reported who have decreased numbers of both dense and

-

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 desmopressin acetate. It is likely that the high levels of vWF in the plasma after desmopressin acetate administration somehow compensate for the intrinsic platelet defect. With more severe bleeding, platelet transfusion is required.

ACQUIRED HEMOSTATIC DEFECTS Platelet Abnormalities Acquired abnormalities of platelets 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 those caused by leukemia, myelodysplastic syndrome, severe vitamin B12 or folate deficiency, chemotherapeutic drug use, radiation therapy, 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 used. The etiology of both qualitative and quantitative defects is reviewed in Table 4-2. Table 4-2 Etiology of Platelet Disorders A. Quantitative disorders 1. Failure of production: related to impairment of bone marrow function a. Leukemia b. Myeloproliferative disorders c. Vitamin B12 or folate deficiency d. Chemotherapy or radiation therapy

e. Acute alcohol intoxication f. Viral infections 2. Decreased survival a. Immune-mediated disorders 1) Idiopathic thrombocytopenia 2) Heparin-induced thrombocytopenia 3) Autoimmune disorders or B-cell malignancies 4) Secondary thrombocytopenia b. Disseminated intravascular coagulation c. Disorders related to platelet thrombi 1) Thrombocytopenic purpura 2) Hemolytic uremic syndrome 3. Sequestration a. Portal hypertension b. Sarcoid c. Lymphoma d. Gaucher's disease B. Qualitative disorders 1. Massive transfusion 2. Therapeutic administration of platelet inhibitors 3. Disease states a. Myeloproliferative disorders b. Monoclonal gammopathies c. Liver disease

QUANTITATIVE DEFECTS Failure of platelet production can occur when bone marrow production of platelets is affected by marrow-related disease such as leukemia or myelodysplasia, vitamin B12 or folate deficiencies, chemotherapy or radiation therapy, acute alcohol intoxication, or viral illnesses. Shortened platelet survival is seen in immune thrombocytopenia, disseminated intravascular coagulation, and 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 infection) or use of certain 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, IV gamma globulin, or anti-D immunoglobulin in patients who are Rh-positive. Effects of both gamma globulin and anti-D immunoglobulin are rapid in onset. Platelet transfusions usually are not needed unless central nervous system bleeding or active bleeding from other sites occurs. Survival of the transfused platelets is usually short. Primary immune thrombocytopenia also is known as idiopathic thrombocytopenic purpura (ITP). In children it is usually acute

and short lived, and typically follows a viral illness. In contrast, ITP in adults is gradual in onset, chronic, 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.6 Management options are summarized in Table 4-3. Treatment of druginduced immune thrombocytopenia may simply entail withdrawal of the offending drug, but administration of corticosteroids, gamma globulin, and anti-D immunoglobulin may hasten recovery of the count. Table 4-3 Management of Idiopathic Thrombocytopenic Purpura (ITP) in Adults First Line a. Corticosteroids: The majority of patients respond, but only a few long term. b. IV immunoglobulin: Indicated with clinical bleeding, along with platelet transfusion, and when condition is steroid unresponsive. Response is rapid but transient. c. Anti-D immunoglobulin: Active only in Rh-positive patients before splenectomy. Response is transient. Second Line a. Splenectomy: Open or laparoscopic. Criteria include severe thrombocytopenia, high risk of bleeding, and continued need for steroids. Treatment failure may be due to retained accessory splenic tissue. Third Line a. Patients for whom first- and second-line therapies fail are considered to have chronic ITP. The objective in this subset of patients is to maintain the platelet count >20–30 x 10 9 /L and to minimize side effects of medications. b. Rituximab, an anti-CD20 monoclonal antibody: Acts by eliminating B cells. c. Alternative medications producing mixed results and a limited response: Danazol, cyclosporine A, dapsone, azathioprine, and vinca alkaloids. d. Thrombopoietic agents: A new class of drugs for patients with impaired production of platelets rather than accelerated destruction of platelets. Second-generation drugs still in clinical trials include AMG531 and eltrombopag.

Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia. It is an immunologic disorder in which antibodies against PF4 formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis. 7 The platelet count typically begins to fall 5 to 7 days after 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 <100,000/ L or if it drops by 50% from baseline in a patient receiving heparin. Although HIT is more common with full-dose unfractionated heparin (1 to 3%), it also can occur with prophylactic doses or with low molecular weight heparins. Interestingly, approximately 17% of patients receiving unfractionated heparin and 8% of those receiving low molecular weight heparin develop antibodies against PF4, yet a much smaller percentage develop thrombocytopenia and even fewer clinical HIT.8 In addition to the mild to moderate thrombocytopenia, this disorder is characterized by a high incidence of thrombosis, which 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 or an enzyme-linked immunosorbent assay (ELISA). The serotonin release assay is highly specific but not sensitive, so that a positive test result supports the diagnosis but a negative result does not exclude HIT.7 On the other hand, the ELISA has a low specificity, so although a positive ELISA result confirms the presence of anti–heparin-PF4, it does not help in the diagnosis of clinical HIT. A negative ELISA result, however, essentially rules out HIT.

The initial treatment of suspected HIT is to stop heparin and begin an alternative anticoagulant. Stopping heparin without adding another anticoagulant is not adequate to prevent thrombosis in this setting. Alternative anticoagulants are primarily thrombin inhibitors. Those available in the United States are lepirudin, argatroban, and bivalirudin. In Canada and Europe, danaparoid also is available. Danaparoid is a heparinoid that has approximately 20% cross reactivity with HIT antibodies in vitro but a much lower cross reactivity in vivo. Because of warfarin's early induction of a hypercoagulable state, only once full anticoagulation with an alternative agent has been accomplished and the platelet count has begun to recover should warfarin be instituted. There 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, which leads to activation. These large molecules result from inhibition of a metalloproteinase enzyme, ADAMTS13, which cleaves the large vWF molecules. 9 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. The most effective treatment for TTP is plasmapheresis, although plasma infusion also has been attempted. A recent study comparing these two modalities reported a higher relapse rate and a higher mortality with plasma infusions. Platelet transfusions are contraindicated. 10 Additionally, rituximab, a monoclonal antibody against the CD20 protein on B lymphocytes, has shown promise as an immunomodulatory therapy directed against acquired TTP, which in the majority of cases is autoimmune mediated. 11 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 usually is 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), and immunosuppressive agents (such as cyclosporine and tacrolimus). Discontinuation of the involved drug is the mainstay of therapy. Plasmapheresis frequently is 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 sequestration 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 receiving 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 and replacement with product deficient in platelets. Thrombocytopenia may also be induced by heparin administration in patients with cardiac and vascular disorders, 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 on the extent and cause of platelet reduction. A count of >50,000/ L generally requires no specific therapy. Prophylactic platelet administration has now become part of massive transfusion protocols. Platelets also are administered preoperatively to rapidly increase the platelet count in surgical patients with underlying thrombocytopenia. One unit of platelet concentrate contains approximately 5.5 x 10 10 platelets and would be expected to increase the circulating platelet count by approximately 10,000/ L in the average 70-kg person. Fever, infection, hepatosplenomegaly, and the presence of antiplatelet alloantibodies decrease the effectiveness of platelet transfusions. In patients whose thrombocytopenia is refractory to standard platelet transfusion, the use of human leukocyte antigen (HLA)–compatible platelets coupled with special processors has proved effective.

QUALITATIVE PLATELET DEFECTS Impaired platelet function often accompanies thrombocytopenia. Impaired ADP-stimulated aggregation occurs with massive transfusion (>10 units of packed red blood cells). Uremia may be associated with increased bleeding time and impaired aggregation and can be corrected by hemodialysis or peritoneal dialysis. Defective aggregation and platelet secretion can occur in patients with thrombocythemia, polycythemia vera, or myelofibrosis. Drugs that interfere with platelet function by design include aspirin, clopidogrel, dipyridamole, and the glycoprotein IIb/IIIa inhibitors. Both aspirin and clopidogrel irreversibly inhibit platelet function, clopidogrel through selective irreversible inhibition of ADP-induced platelet aggregation and aspirin 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 taking aspirin and/or clopidogrel. The general recommendation is that, for each, a period of approximately 7 days is required from the time the drug is stopped until an elective procedure can be performed. 12 Timing of urgent and emergent surgeries is even more unclear. Preoperative platelet transfusions may be beneficial, but again there are no good data to guide their administration. The problem is that accurate tests of platelet function are lacking. Other disorders associated with abnormal platelet function include uremia, myeloproliferative disorders, monoclonal gammopathies, and liver disease. In the surgical patient, platelet dysfunction of uremia often can be corrected by dialysis or the administration of desmopressin acetate. Platelet transfusion may not be helpful if the patient is uremic when the platelets are given. 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 The official definition of disseminated intravascular coagulation (DIC), as put forth by the Scientific Subcommittee on DIC of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (SSC/ISTH), is that "DIC is an acquired syndrome characterized by the intravascular activation of coagulation with the loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction." 13 Excessive thrombin generation leads to microthrombus formation, followed by consumption and depletion of coagulation factors and platelets, which leads to the classic picture of diffuse bleeding. The presence of an

underlying condition that predisposes a patient to DIC is required for the diagnosis. Specific injuries include central nervous system injuries with embolization of brain matter, fractures with embolization of bone marrow, and amniotic fluid embolization. Embolized materials are potent thromboplastins that activate the DIC cascade. 14 Additional causes include malignancy, organ injury (such as severe pancreatitis), liver failure, certain vascular abnormalities (such as large aneurysms), snakebites, illicit drugs, transfusion reactions, transplant rejection, and sepsis. 13 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. 14 The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut and colleagues, who showed that administration of activated protein C was particularly effective in septic patients with DIC. 15 The diagnosis of DIC is made on the basis of an inciting cause with associated thrombocytopenia, prolongation of the PT, low fibrinogen level, and elevated levels of fibrin markers (fibrin degradation products, D-dimer, soluble fibrin monomers). A scoring system developed by the SSC/ISTH assigns a score between 0 and 1 to the measured value on each of these laboratory tests; a score of 5 or greater is considered to be overt DIC. 16 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 using FFP, which generally is sufficient to correct the hypofibrinogenemia, although cryoprecipitate and platelet concentrates also may be needed. Because microthrombi are generated during DIC, heparin therapy has been proposed. Most studies, however, have shown that heparin is not helpful in acute forms of DIC but may be indicated for purpura fulminans or venous thromboembolism.

PRIMARY FIBRINOLYSIS An acquired hypofibrinogenic state in the surgical patient also can be a result of pathologic fibrinolysis. This may occur in patients after 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. The synthetic amino acid -aminocaproic acid interferes with fibrinolysis by inhibiting plasminogen activation.

Myeloproliferative Diseases Polycythemia, particularly with marked thrombocytosis, presents a major surgical risk. In such patients, operations should be considered only for the most grave surgical emergencies. If possible, the operation should be deferred until medical management has restored normal blood volume, hematocrit level, and platelet count. Spontaneous thrombosis is a complication of polycythemia vera 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. Myeloid metaplasia frequently represents part of the natural history of polycythemia vera. Approximately 50% of patients with myeloid metaplasia are postpolycythemic. Abnormalities in platelet aggregation and release have been demonstrated in these patients. Thrombocytosis can be reduced by the administration of hydroxyurea or anagrelide. Elective surgical procedures should be delayed until the institution of appropriate treatment. Ideally, the hematocrit level should be kept below 48% and the platelet count under 400,000/ L. When an emergency procedure is required, phlebotomy and blood replacement with lactated Ringer's solution may be beneficial.

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 4-4). The most common coagulation abnormalities associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolongation of the PT and increase in the International Normalized Ratio (INR). 17 Thrombocytopenia in patients with liver disease typically is related to hypersplenism, reduced production of thrombopoietin, and immune-mediated destruction of platelets. As noted earlier, in patients with hypersplenism the total body platelet mass is basically normal, but an abnormally high proportion of the platelets are found in the enlarged spleen. Less bleeding is seen than would be anticipated from the platelet count, because some of the sequestered platelets can be released into 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 cirrhotic patients, especially those with hepatitis C and primary biliary cirrhosis.18 Before any therapy to ameliorate thrombocytopenia is initiated, 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 is administration of interleukin-11, a cytokine that stimulates proliferation of hematopoietic stem cells and megakaryocyte progenitors. 16 Most studies using interleukin-11 have been in patients with cancer, although some evidence exists that it may be beneficial in cirrhotic patients as well. Significant side effects limit its usefulness.19 A less well accepted option is splenectomy or splenic embolization to reduce hypersplenism. Not only are there risks associated with these techniques, but reduced splenic blood flow can reduce portal vein flow with subsequent portal vein thrombosis. Results are mixed after transjugular intrahepatic portosystemic shunt (TIPS). Therefore, treatment of thrombocytopenia should not be the primary indication for a TIPS procedure. Table 4-4 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

Decreased production or increased destruction of coagulation factors as well as a vitamin K deficiency can contribute to a prolonged PT and increased 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, abnormalities in laboratory results may mimic those of DIC. Elevated D-dimer levels have been reported to increase the risk of variceal bleeding. 20 The absorption of vitamin K is dependent on bile production. Therefore, patients with liver disease who have impaired bile production, such as those with cholestatic disease, may be at risk for vitamin K deficiency. As with thrombocytopenia, correction of coagulopathy should be reserved for treatment of active bleeding and prophylaxis for invasive procedures and surgery. Coagulopathy caused by liver disease is most often treated with FFP, but because the

coagulopathy generally is not a result of decreased levels of factor V, complete correction usually is not possible. If the fibrinogen level is <100 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.

Coagulopathy of Trauma Traditionally recognized causes of traumatic coagulopathy include acidosis, hypothermia, and dilution of coagulation factors. However, a significant proportion of trauma patients arrive at the emergency department coagulopathic, and this early coagulopathy is associated with a significant increase in mortality.21,22 Brohi and colleagues 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.23 As shown in Fig. 4-5, hypoperfusion causes activation of thrombomodulin on the surface of endothelial cells. Circulating thrombin complexes with thrombomodulin. This complex not only induces an anticoagulant state through activation of protein C but also enhances fibrinolysis by deinhibition of tPA through the consumption of plasminogen activator inhibitor 1. Fig. 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. Lastly, the thrombin-thrombomodulin complex limits the availability of thrombin to cleave fibrinogen to fibrin, which may explain why injured patients rarely have low levels of fibrinogen.

Acquired Coagulation Inhibition Among the most common acquired disorder of coagulation inhibition is the antiphospholipid syndrome (APLS), in which the lupus anticoagulant and anticardiolipin antibodies are present. These antibodies may be associated with either venous or arterial thrombosis, or both. In fact, patients who show recurrent thrombosis should be evaluated for APLS. The presence of antiphospholipid antibodies is very common in patients with systemic lupus erythematosus but also may be seen in association with rheumatoid arthritis and Sjögren's syndrome. There are also individuals who have no autoimmune disorders but develop transient antibodies in response to infections or who develop drug-induced APLS. The hallmark of APLS is a prolonged aPTT in vitro but an increased risk of thrombosis in vivo. 24

Paraprotein Disorders Paraprotein disorders are characterized by production of an abnormal globulin or fibrinogen that interferes with clotting or platelet function. This may be an immunoglobulin M in Waldenström's macroglobulinemia, an immunoglobulin G or immunoglobulin A in multiple myeloma, a cryoglobulin in liver disease (especially hepatitis C) or autoimmune diseases, or a cryofibrinogen. Chemotherapy usually is effective in lowering the level of paraproteins in macroglobulinemia and myeloma, although for rapid removal before surgery, plasmapheresis may be needed. Cryoglobulins and cryofibrinogens are usually removed by plasmapheresis.

Anticoagulation and Bleeding Spontaneous bleeding can be a complication of anticoagulant therapy with either heparin, warfarin, low molecular weight heparins, or factor Xa inhibitors. The risk of spontaneous bleeding related to heparin administration is reduced when a continuous infusion technique is used. Therapeutic anticoagulation is more reliably achieved with a low molecular weight heparin. Laboratory testing is not routinely used to monitor dosing of these agents, which makes them attractive options for outpatient anticoagulation. If monitoring is needed for low molecular weight heparins (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 embolism, and recurrent myocardial infarction, as well as in patients with prosthetic heart valves and prosthetic implants.25–27 Due to the interaction of the P-450 system, the anticoagulant effect of the warfarin is reduced (e.g., higher dosage is required) in patients receiving barbiturates as well as in patients with diets low in vitamin K. Warfarin requirements also may be increased in patients taking contraceptives or estrogen-containing compounds, corticosteroids, or adrenocorticotropic hormone. A number of medications can alter warfarin requirements (Table 4-5). Table 4-5 Medications That Can Alter Warfarin Dosing Warfarin effect Warfarin requirements Warfarin effect Warfarin requirements

Barbiturates, oral contraceptives, estrogen-containing compounds, corticosteroids, adrenocorticotropic hormone

Phenylbutazone, clofibrate, anabolic steroids, L -thyroxine, glucagons, amiodarone, quinidine, cephalosporins

Bleeding complications are frequent in patients taking anticoagulants. Examples include hematuria, soft tissue bleeding, intracerebral bleeding, skin necrosis, and abdominal bleeding. Bleeding into the abdominal cavity is by far the most common complication of warfarin therapy and may be either intraperitoneal, extraperitoneal, or retroperitoneal. 28–30 An intramural bowel hematoma is the most common cause of abdominal pain in patients receiving anticoagulation therapy.31–33 Fortunately, most intramural bowel hematomas respond to nonoperative treatment. Bleeding secondary to anticoagulation therapy is also not an uncommon cause of 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 one of the first symptoms of an underlying tumor may be bleeding in a patient who is receiving anticoagulation therapy. Surgical intervention may prove necessary in patients receiving anticoagulation therapy. Increasing experience suggests that surgical treatment can be undertaken without discontinuing the anticoagulant program, depending on the procedure being performed. 34 Furthermore, the risk of thrombotic complications may be increased when anticoagulation therapy is discontinued abruptly. When the aPTT is <1.3 times the control value in a patient receiving heparin or when the INR is <1.5 in a patient taking 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; this applies, in particular, to circumstances in which even minor bleeding can cause great morbidity, such as procedures involving the central nervous system or the eye. Emergency operations are occasionally necessary in patients who have been receiving heparin. The first step for these patients is to discontinue heparin. For more rapid reversal of anticoagulation, use of protamine sulfate is effective. However, significant adverse reactions may be encountered when administering protamine, especially in patients with severe fish allergies. 35,36 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 a patient undergoing elective surgery who is receiving coumarin-derivative therapy sufficient to effect anticoagulation, the drug can be discontinued several days before the operation and the prothrombin concentration then checked (a level >50% is considered safe).37 Rapid reversal of anticoagulation can be accomplished with FFP in an 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) are a result of hepatocellular dysfunction, vitamin K administration is ineffective. For patients who were taking warfarin preoperatively and are at high risk for thrombosis, low molecular weight heparin should be administered while the INR is decreasing and should be restarted at prophylactic dosages as soon as possible after surgery. The perioperative management of patients receiving long-term oral anticoagulation therapy is an increasingly common problem. Firm evidence-based guidelines regarding which patients require perioperative "bridging" anticoagulation and the most effective way to bridge are lacking. IV unfractionated heparin and SC low molecular weight heparin in therapeutic dosages reduce the risk of venous thromboembolism but have not been proven to reduce the risk of arterial thromboembolism. 38 Bridging anticoagulation involves discontinuation of oral anticoagulation before surgery and the use of IV or SC agents for several days before and (sometimes) after surgery. Most studies have shown that preoperative bridging is associated with an acceptably low postoperative bleeding rate (1.8 to 5.8%). Not unexpectedly, the risk of bleeding can be substantially higher for procedures associated with intraoperative and postoperative bleeding.

CARDIOPULMONARY BYPASS The predisposing factors that are associated with excessive bleeding are prolonged perfusion times, prior use of oral

anticoagulants or antiplatelet drugs, cyanotic heart disease, and hypothermia. Two factors triggering excessive bleeding associated with cardiopulmonary bypass are excessive fibrinolysis and platelet function defects, with the latter being more important. The laboratory evaluation of patients with cardiopulmonary bypass hemorrhage should include INR, aPTT, complete blood count, platelet count, peripheral blood smear examination, and measurement of fibrin degradation products. The management entails empiric administration of platelets, and if hyperheparinemia is believed to be the major factor, 25% of the calculated dose of protamine should be administered and repeated every 30 to 60 minutes until the bleeding ceases. If there is laboratory evidence of excess fibrinolysis, -aminocaproic acid can be given at an initial dose of 5 to 10 g followed by 1 to 2 g/h until bleeding ceases. Aprotinin, a protease inhibitor that acts as an antifibrinolytic agent, has been shown to reduce transfusion requirements associated with cardiac surgery and orthotopic liver transplantation.39 Desmopressin acetate, which stimulates release of factor VIII from endothelial cells, also may be effective in reducing blood loss during cardiac surgery. Laboratory evidence of heparin-induced thrombocytopenia (HIT) often is found after cardiopulmonary bypass; however, clinically significant HIT is rare unless the patient has had previous heparin exposure or heparin continues to be administered in the postoperative period.

LOCAL HEMOSTASIS Significant surgical bleeding usually is 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 halting bleeding is digital pressure. When pressure is applied to an artery proximal to an area of bleeding, profuse bleeding may be reduced so that more definitive action is permitted. Application of an extremity tourniquet that occludes a major vessel proximal to the bleeding site and the Pringle maneuver for liver bleeding are good examples. Direct digital pressure over a bleeding site often is effective and has the advantage of being less traumatic than a hemostatic clamp. Even an "atraumatic" vascular clamp results in damage to the intimal wall of a blood vessel. When a small vessel is transected, a simple ligature is sufficient. For large arteries with pulsation, a transfixion suture to prevent slipping is indicated. All sutures represent foreign material, and selection is based on their intrinsic characteristics and the state of the wound. Direct pressure applied by packs affords the best method of controlling diffuse bleeding from large areas, such as in the trauma situation. Bleeding from cut bone can be controlled by packing bone wax on the raw surface to achieve pressure. The Harmonic scalpel is an instrument that cuts and coagulates tissue via vibration at 55 kHz. The device converts electrical energy into mechanical motion. The motion of the blade causes collagen molecules within the tissue to become denatured, forming a coagulum. No significant electrical current flows through the patient. The instrument has proved advantageous in performing thyroidectomy, hemorrhoidectomy, and transsection of the short gastric veins during splenectomy, and in transecting hepatic parenchyma.40–42

Thermal Agents Heat achieves hemostasis by denaturation of protein that results in coagulation of large areas of tissue. With cautery, heat is transmitted from the instrument by conduction directly to the tissue. When electrocautery is used, heating occurs by

induction from an alternating current source. 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 burns outside the operative field and prevents the 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. Certain anesthetic agents (diethyl ether, divinyl ether, ethyl chloride, ethylene, and cyclopropane) cannot be used with electrocautery because of the hazard of explosion. Use of 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 100mA range have successfully controlled diffuse bleeding from raw surfaces, as has argon gas.

Topical Hemostatic Agents Topical hemostatic agents play an important role in common or complex general surgical procedures. These agents can be classified based on their mechanism of action and include physical or mechanical, caustic, biologic, and physiologic agents. Some agents induce protein coagulation and precipitation that results in occlusion of small cutaneous vessels, whereas others take advantage of later stages in the coagulation cascade, activating biologic responses to bleeding. 43 The ideal topical hemostatic agent has significant hemostatic action, shows minimal tissue reactivity, is nonantigenic, biodegrades in vivo, provides ease of sterilization, is low in cost, and can be tailored to specific needs.44 Table 4-6 reviews only some of the commonly used products on the market. Table 4-6 Common Hemostatic Agents Hemostatic Agent

Manufacturer

Cost

Comments

Baxter

$1500 per 6 Disseminated intravascular coagulation may result from intravascular pack/5 mL exposure. Solution soaked in gauze or injected over wound bed, forming attachment. $56– 60/5000– 10,000 vial

Thrombin Products Floseal

Thrombostat Parke-Davis

ThrombinJMI

King $285/10,000 Pharmaceuticals units

Fibrin Sealant Tisseel

Baxter

$135/2 mL

Crosseal

Johnson & Johnson

$100–150/1 mL

Gelfoam

Pfizer

$90/1 g

Surgifoam

Johnson & Johnson

$8– 14/gelatin square

Useful in skin grafts or anticoagulated patients. Crosseal contains no aprotinin, reduces anaphylaxis risk.

Gelatin Agents Forms hydrated meshwork to promote clotting. Can swell. May cause granulomatous reaction.

Thrombin-derivative products direct the conversion of fibrinogen to fibrin, aiding in clot formation. Thrombin takes advantage

of natural physiologic processes, thereby avoiding foreign body or inflammatory reactions, and the wound bed is not disturbed.44 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. Fibrin sealants are prepared from cryoprecipitate (homologous or synthetic) and have the advantage of not promoting inflammation or tissue necrosis. 45 The sealant is administered using a dual syringe compartment system. In one compartment is fibrinogen, factor XIII, fibronectin, and fibrinolysis inhibitors. The second compartment contains thrombin and calcium chloride.46 The use of fibrin glue is particularly helpful in patients who have received heparin or who have deficiencies in coagulation (e.g., hemophilia or von Willebrand's disease). 47–49 Purified gelatin solution can be prepared into several vehicles, including powders, sponges or foams, and sheets or films. 43 Gelatin is hygroscopic, absorbing many times its weight in water or liquid. It is effectively metabolized and degraded by proteinases in the wound bed over a period of 4 to 6 weeks.43 Gelfoam provides effective hemostasis for operative fields with diffuse small-vessel oozing. 50 Thrombin may be applied to this vehicle to boost hemostasis. Gelatin is relatively inexpensive, readily available, pliable, and easy to handle. Although relatively inert, the implanted gelatin can serve as a nidus for infection.44 These agents are not a substitute for meticulous surgical technique. The advantages and disadvantages of each agent must be weighed in selecting the correct agent to control bleeding. In general, the minimum amount of each topical hemostatic agent should be used to minimize toxic effects and adverse reactions, interference with wound healing, and procedural cost.

TRANSFUSION Background Human blood replacement therapy was accepted in the late nineteenth century. This was followed by the introduction of blood grouping by Dr. Karl Landsteiner, who identified the major A, B, and O groups in 1900. In 1939 Dr. Philip Levine and Dr. Rufus Stetson 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 goal-directed component therapy began to take prominence. This change in practice was made possible by the development of improved collection strategies, testing for infection, 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 donors' red blood cells and recipients' sera (the major cross-match) is performed. Rh-negative recipients should receive transfusions only of Rhnegative 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 childbearing 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 4 or more units of Onegative blood, because there is a significant increase in the risk of hemolysis. In patients with clinically significant levels of 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 transfused multiple times 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 blood if their hemoglobin concentration exceeds 11 g/dL or if the hematocrit is >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. Administration of recombinant human erythropoietin accelerates generation of red blood cells and allows for more frequent harvesting of blood.

BANKED WHOLE BLOOD Banked whole blood, once the gold standard, is rarely available. The shelf life is now around 6 weeks. At least 70% of the transfused erythrocytes remain in the circulation for 24 hours after transfusion and are viable. The age of red cells may play a significant role in the inflammatory response and incidence of multiple organ failure. The changes in the red blood cells that occur during storage include reduction of intracellular ADP and 2,3-diphosphoglycerate, which alters the oxygen dissociation curve of hemoglobin and results in a decrease in oxygen transport. Although all clotting factors are relatively stable in banked blood except for factors V and VIII, banked blood progressively becomes acidotic with elevated levels of lactate, potassium, and ammonia. The hemolysis that occurs during storage is insignificant.

FRESH WHOLE BLOOD Fresh whole blood refers to blood that is administered within 24 hours of its donation. Advances in testing for infectious disease now make fresh whole blood another option. Recent evidence has shown that the use of fresh whole blood may improve outcomes in patients with trauma-associated coagulopathy in the combat situation, 51 and a civilian study will soon be under way. An advantage to the use of fresh whole blood is that it provides greater coagulation activity than equal units of component therapy.

PACKED RED BLOOD CELLS AND FROZEN RED BLOOD CELLS Packed red blood cells are the product of choice for most clinical situations. Concentrated suspensions of red blood cells can be prepared by removing most of the supernatant plasma after centrifugation. This preparation reduces, but does not eliminate, reaction caused by plasma components. It also reduces the amount of sodium, potassium, lactic acid, and citrate administered. Frozen red blood cells are not available for use in emergencies. They are used for patients who are known to have been previously sensitized. By freezing red blood cells viability is theoretically improved, and the ATP and 2,3diphosphoglycerate concentrations are maintained. Little clinical outcome data are available to substantiate these findings.

LEUKOCYTE-REDUCED AND LEUKOCYTE-REDUCED/WASHED RED BLOOD CELLS Leukocyte-reduced and leukocyte-reduced/washed red blood cell products are prepared by filtration that removes approximately 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, nonhemolytic transfusion reactions (fever and/or rigors), alloimmunization to HLA class I antigens, and platelet transfusion refractoriness as well as cytomegalovirus transmission. In most western nations, it is the standard red blood cell transfusion

product. Opponents of universal leukoreduction believe that the additional costs associated with this process are not justified because they are of the opinion that transfused allogenic white blood cells have no significant immunomodulatory effects. 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-analysis have not provided convincing evidence either way, 52,53 although a large Canadian retrospective study suggests a decrease in mortality and infections when leukocyte-reduced red blood cells are used.54

PLATELET CONCENTRATES The indications for platelet transfusion include thrombocytopenia caused by massive blood loss and replacement with platelet-poor products, thrombocytopenia caused by inadequate platelet 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 provoke allergic reactions similar to those !"#$%&'(&')**%&+,!-#."#/*-0&12$,!3$"+/ &)$4$)#&*.&3)!+$)$+#&,$! 2$%&!.+$,&+2$,!3(&!,$&/-&+2$&,!-5$&*.&678777&+*&9778777:;<0 However, there is a growing body of information suggesting that platelet transfusion thresholds can safely be lowered in patients who have no signs of hemostatic deficiency and who have no history of poor tolerance to low platelet counts. Prevention of HLA alloimmunization can be achieved by leukocyte reduction through filtration. In rare cases, such as in patients who have become alloimmunized through previous transfusion or patients who are refractory from sensitization through prior pregnancies, HLA-matched platelets can be used.

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. However, FFP carries infectious risks similar to those of other component therapies. FFP has come to the forefront with the inception of damage control resuscitation in patients with trauma-associated coagulopathy. In an effort to increase the shelf life and avoid the need for refrigeration, lyophilized plasma is being tested. Preliminary animal studies suggest that this process preserves the beneficial effects of FFP. 55

CONCENTRATES AND RECOMBINANT DNA TECHNOLOGY Technologic advancements have made the majority of clotting factors and albumin readily available as concentrates. These products are readily obtainable and carry no inherent infectious risks as do other component therapies.

HUMAN POLYMERIZED HEMOGLOBIN (POLYHEME) Human polymerized hemoglobin (PolyHeme) is a universally compatible, immediately available, disease-free, oxygencarrying resuscitative fluid that has been successfully used in massively bleeding patients when red blood cells were not transfused. Advantages of an artificial oxygen carrier include the absence of blood-type antigens (no cross-match needed) and viral infections and long-term stability, which allows prolonged periods of storage. Disadvantages include shorter half-life in the bloodstream and the potential to increase cardiovascular complications. This product has not yet been approved for use in patients.

Indications for Replacement of Blood and Its Elements GENERAL INDICATIONS

Improvement in Oxygen-Carrying Capacity

Oxygen-carrying capacity is primarily a function of the red blood cells. Thus, transfusion of red blood cells should augment oxygen-carrying capacity. Additionally, hemoglobin is fundamental to 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 the storage of blood. The decrease in 2,3-diphosphoglycerate and p50 impair oxygen offloading, and deformation of the red cells impairs microcirculatory perfusion. 56

Treatment of Anemia: Transfusion Trigger A 1988 National Institutes of Health Consensus Report challenged the dictum that a hemoglobin value of <10 g/dL or a hematocrit level of <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 use of a restrictive transfusion threshold with use of 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 Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 20 or less and patients 55 years or younger actually had a lower mortality.57 Despite these results, little has changed in transfusion practice. Critically ill patients frequently receive transfusions, with the hemoglobin level at which transfusion is initiated approaching 9 g/dL in a large observational study. 58 One unresolved issue related to transfusion triggers is the safety of maintaining a hemoglobin level 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 literature favors a restrictive transfusion trigger for patients with acute coronary syndrome without ST elevation, and many report worse outcomes in those patients receiving transfusions. Patients with acute myocardial infarctions with ST elevation may, however, benefit from receiving red blood cell transfusions for anemia. 56,58 Clearly, further investigation is warranted.

Volume Replacement The most common indication for blood transfusion in surgical patients is the replenishment of the blood volume, a deficit of which is difficult to evaluate. Measurements of hemoglobin levels or hematocrit are frequently used to assess blood loss. These measurements can be misleading in the face of acute loss, because the levels can be normal in spite of severely contracted blood volume. Both the amount and the rate of bleeding are factors in the development of signs and symptoms of blood loss. 56 A healthy adult can lose up to 15% of total blood volume (class I hemorrhage or up to 750 mL) with only minor effects on the circulation. Loss of 15 to 30% of blood volume (class II hemorrhage or 750 to 1500 mL) is associated with tachycardia and decreased pulse pressure but, importantly, a normal blood pressure. Loss of 30 to 40% (class III hemorrhage or 1500 to 2000 mL) results in tachycardia, tachypnea, hypotension, oliguria, and changes in mental status. Class IV hemorrhage is loss of >40% of blood volume and is considered life-threatening. Loss of blood in the operating room can be 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 of up to 20% of total blood volume can be replaced with crystalloid solution. Blood loss above this amount may require the addition of packed red blood cells and, in the case of massive transfusion, the addition of FFP (detailed later in this chapter). Transfusion of platelets and/or FFP may be indicated in specific patients before or during an operative

procedure (Table 4-7). Table 4-7 Replacement of Clotting Factors Factor

Normal Level

Life Span Fate during In Vivo Coagulation (HalfLife)

Level Required for Safe Hemostasis

Ideal Agent ACD Bank Blood [4°C (39.2°F)]

Ideal Agent for 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 36 h level

Consumed

5–20%

Labile (40% of normal level at 1 wk)

Fresh-frozen plasma; blood under 7 d

VII (proconvertin, serum 100% of normal 5 h prothrombin conversion level accelerator, stable factor)

Survives

5–30%

Stable

Bank blood; concentrated preparation

VIII (antihemophilic factor, antihemophilic globulin)

100% of normal 6–12 h level (50–150% of normal level)

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 24 h level

Survives

20–30%

Stable

Fresh-frozen plasma; bank blood; concentrated preparation

X (Stuart-Prower factor)

100% of normal 40 h level

Survives

15–20%

Stable

Bank blood; concentrated preparation

XI (plasma thromboplastin antecedent)

100% of normal Probably level 40–80 h

Survives

10%

Probably stable Bank blood

XII (Hageman factor)

100% of normal Unknown level

Survives

Deficit Stable produces no bleeding tendency

Replacement not required

XIII (fibrinase, fibrinstabilizing factor)

100% of normal 4–7 d level

Survives

Probably <1%

Stable

Bank blood

Platelets

150,000– 400,000/ L

Consumed

60,000– 100,000/ L

Very labile (40% of normal level at 20 h; 0 at 48 h)

Fresh blood or plasma; fresh platelet concentrate (not frozen plasma)

8–11 d

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, p 157. Copyright Elsevier.

DAMAGE CONTROL RESUSCITATION

Current resuscitation algorithms are based on the sequence of crystalloid followed by red blood cells and then plasma and platelet transfusions and have been in widespread use since the 1970s. 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.

Rationale In civilian trauma systems nearly half of all deaths occur before a patient reaches the hospital, and few of these deaths are preventable.59–61 Those patients who survive until arrival at 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. 21,22,62 Many of these patients receive a massive transfusion, generally defined as the administration of 10 or more units of packed red blood cells within 24 hours of admission. Although 25% of all trauma patients admitted receive a unit of blood early after admission, only a small percentage of patients receive a massive transfusion. In the military setting, however, the percentage of patients receiving a massive transfusion almost doubles.63

New Concepts in Resuscitation Strategies Standard advanced trauma life support guidelines start resuscitation with crystalloid, followed by packed red blood cells. 64 Only after liters of crystalloid have been transfused does transfusion of units of plasma or platelets begin. This conventional massive transfusion practice was based on a small uncontrolled retrospective study that used blood products containing increased amounts of plasma, which are no longer available. 65 More recently, multiple retrospective studies have suggested that this standard resuscitation practice exacerbates the initial coagulopathy of trauma, thus increasing mortality, whereas transfusing a higher ratio of plasma and platelets to red blood cells is associated with improved survival. 66,67 An example of an adult massive transfusion clinical guideline specifying the early use of component therapy is shown in Fig. 4-6. Specific recommendations for the administration of component therapy during a massive transfusion are shown in Table 4-8. Recent data suggest that plasma should be given earlier to patients who are significantly injured and massively transfused, because they arrive in the intensive care unit coagulopathic. 68 Fig. 4-6.

Adult transfusion clinical practice guidelines. ED = emergency department; CBC = complete blood count; INR = International Normalized Ratio; TEG = thromboelastography. Table 4-8 Component Therapy Administration during Massive Transfusion

Fresh-frozen plasma (FFP)

As soon as the need for massive transfusion is recognized. For every 6 units of red blood cells (RBCs), give 6 units of FFP (1:1 ratio).

Platelets

For every 6 units of RBCs and plasma, give one 6-pack of platelets. Six random-donor platelet packs = 1 apheresis platelet unit. Keep platelet counts >100,000 /L during active hemorrhage control.

Cryoprecipitate =.+$,&./,#+&>&"-/+#&*.&?@A#8& 2$ B&./',/-*5$-&)$4$)0&C.&D977&E5:%<8&5/4$&F7&"-/+#&*.& ,(*3,$ /3/+!+$&GF&5 fibrinogen). Repeat as needed, depending on fibrinogen level.

When one center modified its transfusion practice so that plasma was started when the first units of red cells were administered rather than waiting until after 6 units of red cells were transfused, a significant decrease in 30-day mortality was demonstrated. 69 This work documents the importance of starting increased amounts of plasma early and supports a 1:1 ratio of plasma to red cells in patients receiving massive transfusion. This is a shift from traditional resuscitation strategies that called for the early use of crystalloids followed by packed red cells and the administration of plasma only after large amounts of blood products were transfused or to treat the resultant coagulopathy. As noted earlier, this new strategy has been termed damage control resuscitation and represents an alternative to traditional resuscitation standards. The central tenet of DCR is transfusion of plasma and red blood cells in a 1:1 ratio, started within minutes of the patient's arrival to the emergency department. In Iraq and Afghanistan, DCR practices are demonstrating unprecedented success with improved overall survival. 70 Greater use of platelets recently has been added to the DCR approach, because survival is improved with their early and increased use. As an adjunct to DCR, recombinant activated factor VII is used by the military and many major civilian trauma centers. Retrospective studies in combat wounded reveals an association with decreased transfusions and improved 30-day survival. 71 However, some studies have reported increased thrombotic complications after administration of factor VII.72 To verify military and single-institution civilian data on DCR, a multicenter retrospective study of modern transfusion practices at 17 leading civilian trauma centers was recently completed.73 There was significant variation among centers, with plasma:platelet:red blood cell ratios varying from 1:1:1 to 0.3:0.1:1 and corresponding survival rates ranging from 71 to 41%. Centers using ratios approximating 1:1:1 demonstrated significantly fewer truncal hemorrhagic deaths and significantly lower 30-day mortality without a concomitant increase in multiple organ failure as a cause of death. A prospective observational study will soon commence to study the practice of the early use of plasma. Because only a small percentage of trauma patients require a massive transfusion and blood products in general are in short supply, attempts have been made to develop early prediction models. A comparison of results from both civilian and military studies is shown in Table 4-9.74–78 Although they are compelling, none of these algorithms has yet been prospectively validated. Table 4-9 Comparison of Massive Transfusion Prediction Studies Authors

Variables

ROC AUC Value

McLaughlin et al 73

SBP, HR, pH, Hct

0.839

Yücel et al 74

SBP, HR, BD, Hgb, male gender, + FAST, long bone/pelvic fracture 0.892

Moore et al 75

SBP, pH, ISS >25

0.804

Schreiber et al 76

H5'&D998&CI?&J9068&3$-$+,!+/-5&/-K",(

0.80

Wade et al 77

SBP, HR, pH, Hct

0.78

AUC = area under the curve; BD = base deficit; FAST = focused assessment by sonography in trauma; Hct = hematocrit; Hgb = hemoglobin level; HR = heart rate; INR = International Normalized Ratio; ISS = injury severity score; ROC = receiver operating characteristic; SBP = systolic blood pressure.

Complications of Transfusion (Table 4-10) Complications of transfusion are primarily related to blood-induced proinflammatory responses. Transfusion-related events are estimated to occur in approximately 10% of all transfusions, but <0.5% are serious. Transfusion-related deaths, although rare, do occur and are caused primarily by transfusion-related acute lung injury (16 to 22%), ABO hemolytic transfusion reactions (12 to 15%), and bacterial contamination of platelets (11 to 18%).79 Table 4-10 Transfusion-Related Complications Abbreviation Complication

Signs & Symptoms

Frequency

Mechanism

Prevention

NHTR

Febrile, nonhemolytic transfusion reaction

Fever

0.5–1.5% of transfusions

Preformed cytokines

Use leukocytereduced blood

Bacterial contamination

High fever, chills

<<0.05% of blood

Infusion of contaminated blood

Store platelets <5 d

Hemodynamic changes

0.05% of platelets

Soluble transfusion constituents

Provide antihistamine prophylaxis

Large volume of blood transfused into an older patient with CHF

Increase transfusion time

Host Ab to donor lymphocytes

DIC Emesis, diarrhea Hemoglobinuria Allergic reactions Rash, hives

0.1–0.3% of units

Itching TACO

Transfusionassociated circulatory overload

Pulmonary edema ? 1:200– 1:10,00 of transfused patients

Administer diuretics Minimize associated fluids

TRALI

Transfusionrelated acute lung injury

Acute (<6 h) hypoxemia Bilateral infiltrates ± Tachycardia, hypotension

Hemolytic reactions

Anti-HLA or anti-HNA Ab in Limit female transfused blood attacks circulatory donors and pulmonary leukocytes

Acute

Fever Hypotension

1:33,000– 1:1,500,000 units

DIC

Transfusion of ABO incompatible blood

Transfuse appropriately matched blood

Preformed IgM Ab to ABO Ag

Hemoglobinuria Hemoglobinemia Renal insufficiency Delayed (2–10 d)

Anemia Indirect hyperbilirubinemia

IgG mediated

Identify patient's Ag to prevent recurrence

Elevated haptoglobin level Positive result on direct Coombs' test 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.

NONHEMOLYTIC REACTIONS Febrile nonhemolytic reactions are defined as an increase in temperature [>1°C (1.8°F)] 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 causes. 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. Gram-negative organisms, especially Yersinia enterocolitica and Pseudomonas species, which are capable of growth at 4°C (39.2°F), are the most common cause. Most cases, however, are associated with the administration of platelets that are stored at 20°C (68°F) or even more commonly with apheresis platelets stored at room temperature. Bacterial contamination results in sepsis and death in up to 25% of patients.80 Clinical manifestations include systemic signs such as fever and chills, tachycardia, and hypotension, and GI symptoms (abdominal cramps, vomiting, and diarrhea). There also can be hemorrhagic manifestations such as hemoglobinemia, hemoglobinuria, and disseminated intravascular coagulation. If the diagnosis is suspected, the transfusion should be discontinued and the blood cultured. Emergency treatment includes administration of oxygen, adrenergic blocking agents, and antibiotics. Prevention includes avoidance of out-of-date platelets.

ALLERGIC REACTIONS Allergic reactions are relatively frequent, occurring in approximately 1% of all transfusions. Reactions usually are mild and consist of rash, urticaria, and fever occurring within 60 to 90 minutes of the start of the transfusion. In rare instances, anaphylactic shock develops. Allergic reactions are 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. Treatment and prophylaxis consist of the administration of antihistamines. In more serious cases, use of epinephrine or steroids may be indicated.

RESPIRATORY COMPLICATIONS

Respiratory compromise may be associated with transfusion-associated circulatory overload, 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 generally can be heard at the lung bases. Treatment consists of initiating diuresis, slowing the rate of blood administration, and minimizing delivery of fluids while blood products are being transfused. The syndrome of transfusion-related acute lung injury (TRALI) is defined as noncardiogenic pulmonary edema related to transfusion. 81 It can occur with the administration of any plasma-containing blood product. Symptoms are similar to those of circulatory overload with dyspnea and associated hypoxemia. However, TRALI is characterized as noncardiogenic and often is accompanied by fever, rigors, and bilateral pulmonary infiltrates on chest radiograph. It most commonly occurs within 1 to 2 hours after the onset of transfusion, but virtually always before 6 hours. The actual incidence is unknown, because most cases are not reported (or not diagnosed). The etiology is not well established, but TRALI is thought to be related to anti-HLA or anti–human neutrophil antigen antibodies in transfused blood that primes neutrophils in the pulmonary circulation. Multiparity of the donor is considered a major risk factor for the development of TRALI. In a recent study by Gajic and colleagues, critically ill patients who received high volumes of plasma had worsened gas exchange after transfusion of components from female but not male donors. 82 This association of TRALI with components from female donors has prompted the American Association of Blood Banks to propose the use of male-only donor plasma. Treatment of TRALI entails discontinuation of any transfusion, notification of the transfusion service, and provision of 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 are fatal in up to 6% of cases. Contributing factors include technical or clerical errors in the laboratory and administration of blood 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 activation of factor XII and complement by antibody-antigen complexes, which leads to initiation of the coagulation cascade. Finally, acute renal insufficiency results from the toxicity associated with free hemoglobin in the plasma, leading to 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 findings that show incompatibility of the donor and recipient blood. A positive Coombs' test result indicates the presence of transfused cells coated with patient antibody and is diagnostic. Delayed hemolytic transfusion reactions may also be manifested by fever and recurrent anemia. Jaundice and decreased haptoglobin levels usually occur, and low-grade hemoglobinemia and hemoglobinuria may be seen. The Coombs' test usually yields a positive result, 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 suspect 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.

TRANSMISSION OF DISEASE Among the diseases that have been transmitted by transfusion are malaria, Chagas' disease, brucellosis, and, very rarely, syphilis. 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 infection resembling infectious mononucleosis also has occurred. Transmission of hepatitis C virus and HIV-1 has been dramatically minimized by the introduction of better antibody and nucleic acid screening for these pathogens. The infection rate for these pathogens is now estimated to be <1 per 1,000,000 units transfused. Hepatitis B virus transmission may still occur in about 1 in 100,000 transfusions in nonimmune recipients. Hepatitis A virus is very rarely transmitted because there is no asymptomatic carrier state. 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) and drug use, and basic laboratory testing. Common screening laboratory testing includes platelet count, PT or INR, and aPTT. Platelet dysfunction can occur at either extreme of platelet count. The normal platelet count ranges from 150,000 to 400,000/ L. Platelet counts >1,000,000/ L may be associated with bleeding or thrombotic complications. Increased bleeding complications may be seen with major surgical procedures when the platelet count is <100,000/ L and with minor surgical procedures when counts are <50,000/ L. Spontaneous hemorrhage can occur when the count falls below 20,000/ L. 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 detection of 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, determination of 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:

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 factor Xa inhibitors and 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 so frequently as in the past. Several standard methods have been described; however, the Ivy bleeding time is most commonly used. It is determined by placing a sphygmomanometer on the upper arm and inflating it to 40 mmHg and then making a 5-mm stab incision on the flexor surface of the forearm. The time is measured to cessation of bleeding, and the upper limit of normal bleeding time with Ivy's test is 7 minutes. A template aids in administering the test uniformly and adds to the reproducibility of the results. An abnormal bleeding time suggests either 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 patients with vWD, primary platelet function disorders, or other platelet dysfunction disorders and patients who are taking aspirin. Additional medications may significantly impair hemostatic function, such as antiplatelet agents (clopidogrel and glycoprotein IIb/IIIa inhibitors), anticoagulant agents (hirudin, chondroitin sulfate, dermatan sulfate), and thrombolytic agents (streptokinase, tPA). If abnormal results on any of the coagulation studies cannot be explained by known medications, congenital abnormalities of coagulation or comorbid disease should be considered. Thromboelastography (TEG) was originally described by Hartert in 1948.83 Continuous improvements in this technique have made this test a valuable tool. TEG monitors hemostasis as a dynamic process rather than revealing isolated information as in conventional coagulation screens. 84 TEG measures the viscoelastic properties of blood as it is induced to clot in a lowshear environment (resembling sluggish venous flow). The patterns of change in shear elasticity allow the kinetics of clot formation and growth as well as the strength and stability of the formed clot to be determined. The strength and stability data provide information about the ability of the clot to perform the work of hemostasis, whereas the kinetic data determine the adequacy of quantitative factors available for clot formation. A sample of celite-activated whole blood is placed into a prewarmed cuvette. A suspended piston is then lowered into the cuvette, which is rotated through a 4.5-degree arc backwards and forwards. The normal clot goes through an 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 thromboelastogram. A strong clot, in contrast, will move the piston simultaneously and proportionally to the cuvette's movements, creating a thick thromboelastogram.85 The strength of a clot is graphically represented over time as a characteristic cigar-shaped figure (Fig. 4-7). There are five parameters of the TEG(r) tracing: R, k, alpha angle, MA, and MA60, all of which measure different stages of clot development. R is the time from the commencement of the test to the initial fibrin formation.

k is a measure of the time from the beginning of clot formation until the amplitude of the TEG tracing reaches 20 mm and represents the dynamics of clot formation. alpha angle is the angle between the line in the middle of the TEG(r) tracing and the line tangential to the developing body of the TEG(r) tracing. The alpha angle represents the acceleration (kinetics) of fibrin buildup and cross-linking. MA is the maximum amplitude and reflects the strength of the clot, which is dependent on the number and function of platelets and the clot's interaction with fibrin. MA60 is the rate of amplitude reduction 60 minutes after MA and represents the stability of the clot. Fig. 4-7.

Illustration of a thromboelastographic tracing. See text for explanation of parameters.

Examples of normal and abnormal TEG tracings are shown in Fig. 4-8. The usefulness of TEG has been sufficiently documented in general surgery, 86,87 cardiac surgery, 88 urologic surgery, 89 obstetrics,90 pediatrics, 91 and liver transplantation.92,93 It is the only test measuring all dynamic steps of clot formation until eventual clot lysis or retraction. Its role in evaluating coagulopathic patients is still being investigated. Fig. 4-8.

Examples of normal and abnormal thromboelastographic tracings. DIC = disseminated intravascular coagulation.

EVALUATION OF HEMOSTATIC RISK IN THE SURGICAL PATIENT Preoperative Evaluation of Hemostasis Several hematologic disorders may have an impact on the outcome of surgery. The more common clinical situations faced by the surgeon are pre-existing anemia and oral anticoagulation therapy. Assessment of bleeding risk should also be considered in patients with liver or renal dysfunction. When feasible, diagnostic evaluation of the patient with previously unrecognized anemia should be carried out before surgery, because certain types of anemia (particularly sickle cell disease and immune hemolytic anemias) may have implications for perioperative management. Hemoglobin levels below 7 or 8 g/dL appear to be associated with significantly more perioperative complications than higher levels. 94 Determination of the need for preoperative transfusion in an individual patient must consider factors other than the absolute hemoglobin level, including the presence of cardiopulmonary disease, the type of surgery, and the likelihood of surgical blood loss. Many patients have anemia postoperatively secondary to blood loss and hemodilution and do not necessarily require transfusion. The most important component of the bleeding risk assessment is a directed bleeding history. A detailed patient history can provide meaningful clues to the presence of a bleeding tendency, such as easy bruising or a family history of bleeding problems. Patients who are reliable historians and who reveal no suggestion of abnormal bleeding on directed bleeding history and physical examination are at very low risk for having an occult bleeding disorder. Laboratory tests of hemostatic

parameters in patients with low risk of bleeding are not required. When the directed bleeding history is unreliable or incomplete or when abnormal bleeding is suggested, a formal evaluation of hemostasis should be performed before surgery including measurement of the PT, the aPTT, and the platelet count.95

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 after 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 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 Pl(A1) 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 blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing 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. The pathogenesis of endotoxin-induced thrombocytopenia has been suggested to be related to lability of factor V, which appears necessary for this interaction. 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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Schwartz's Principles of Surgery > Part I. Basic Considerations > Chapter 5. Shock >

KEY POINTS 1. Shock is defined as a failure to meet the metabolic demands of cells and tissues and the consequences that ensue. 2. 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. 3. Physiologic responses to shock are based upon a series of afferent (sensing) signals and efferent responses that include neuroendocrine, metabolic, and immune/inflammatory signaling. 4. The mainstay of treatment of hemorrhagic/hypovolemic shock includes volume resuscitation with blood products and fluids. In the case of hemorrhagic shock, timely control of bleeding is essential and influences outcome. 5. Prevention of hypothermia, acidemia, and coagulopathy are essential in the management of patients in hemorrhagic shock. 6. 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. 7. 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.

EVOLUTION IN UNDERSTANDING SHOCK "Shock is the manifestation of the rude unhinging of the machinery of life."1 —Samuel V. Gross, 1872

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 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 and restoration of vascular volume and tissue perfusion.

Historical Background 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 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. 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 lead 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 [damageassociated 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. Table 5-1 Classification of Shock Hypovolemic Cardiogenic Septic (vasogenic) Neurogenic Traumatic Obstructive

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 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, that control of bleeding is the paramount priority), (c) volume resuscitation with red blood cells, plasma, and 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 decreased delivery of required metabolic substrates and inadequate removal of cellular waste products. This involves failure of oxidative metabolism that can involve defects of oxygen (O2 ) delivery, transport, and/or utilization. Current challenges include moving beyond fluid resuscitation based upon 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.

PATHOPHYSIOLOGY OF SHOCK Regardless of etiology, the initial physiologic responses in shock are driven by tissue hypoperfusion and the developing cellular energy deficit. This imbalance between cellular 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 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. Fig. 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.

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). Fig. 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.

Fig. 5-3.

Rat model of hemorrhagic shock through the phases of compensation, decompensation, and irreversibility. The percentages shown above the curve represent survival rates. (From Shah et al,10 with permission.)

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 peripheral perfusion and tissue O 2 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 O 2 tension, H + ion concentration, and carbon dioxide (CO 2 ) 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.

Efferent Signals 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 beta 1 -adrenergic receptors that increase heart rate and contractility in this attempt to increase cardiac output. Increased myocardial O 2 consumption occurs as a result of the increased workload; thus, myocardial O 2 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. Table 5-2 Hemodynamic Responses to Different Types of Shock Type of Shock Cardiac Index SVR Venous Capacitance CVP/PCWP Sv O 2

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; Sv O2 = mixed venous

oxygen saturation; SVR = systemic vascular resistance. Direct sympathetic stimulation of the peripheral circulation via the activation of alpha1 -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.

HORMONAL RESPONSE The stress response includes activation of the ANS as discussed above in the Afferent Signals secition, as well as activation of the hypothalamic-pituitary-adrenal axis. Shock stimulates the hypothalamus to release corticotropin-releasing 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, beta-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 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 GI tract to preserve perfusion of the myocardium and CNS. Flow in the capillary bed often 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. 13 Together, these mechanisms lead to diminished capillary perfusion that may persist after resuscitation. In hemorrhagic shock, correction of hemodynamic parameters and restoration of O 2 delivery generally leads to restoration of tissue O 2 consumption and tissue O 2 levels. In contrast, regional tissue dysoxia often persists in sepsis, despite similar restoration of hemodynamics and O 2 delivery. Whether this defect in O 2 extraction in sepsis is the result of heterogeneous impairment of the microcirculation (intraparenchymal shunting) or impaired tissue parenchymal cell oxidative phosphorylation and O 2 consumption by the mitochondria is not resolved. 14 Interesting data suggest that in sepsis the response to limit O 2 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.7,16 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 -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 O 2 as a final electron acceptor in the electron transport chain. As O 2 tension within a cell decreases, there is a decrease in oxidative phosphorylation, and the generation of ATP slows. When O 2 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

-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.

Cellular Hypoperfusion Hypoperfused cells and tissues experience what has been termed oxygen debt, a concept first proposed by Crowell in 1961.19 The O 2 debt is the deficit in tissue oxygenation over time that occurs during shock. When O 2 delivery is limited, O 2 consumption can be inadequate to match the metabolic needs of cellular respiration, creating a deficit in O 2 requirements at the cellular level. The measurement of O 2 deficit uses calculation of the difference between the estimated O 2 demand and the actual value obtained for O 2 consumption. Under normal circumstances, cells can "repay" the O 2 debt during reperfusion. The magnitude of the O 2 debt correlates with the severity and duration of hypoperfusion. Surrogate values for measuring O 2 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 O 2 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 shock-induced gene products, such as cytokines, have the ability to 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.

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 and restore hostmicrobe 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 peptides, 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. 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). Table 5-3 Endogenous Damage Associated Molecular Pattern Molecules Hyaluronan oligomers Heparan sulfate Extra domain A of fibronectin Heat shock proteins 60, 70, Gp96 Surfactant Protein A -Defensin 2 Fibrinogen Biglycan High mobility group box 1 Uric acid

Interleukin-1 S-100s Nucleolin

Fig. 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.

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 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. Fig. 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- !"!#$%&'()!*(%+,)!- .!/012!"!/,&&3&45'!)'%'6+,)327 (From Mollen et al,74 with permission.)

Cytokines 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. Table 5-4 Inflammatory Mediators of Shock Proinflammatory

Anti-Inflammatory

Interleukin-1 /

Interleukin-4

Interleukin-2

Interleukin-10

Interleukin-6

Interleukin-13

Interleukin-8

Prostaglandin E2

Interferon

TGF

TNF PAF PAF = platelet activating factor; TGF

= transforming growth factor beta; TNF = tumor necrosis factor.

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, as well as 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- ) 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. TNFof stimulation and return frequently to baseline levels within 4 hours. Release of TNF-

may be induced by bacteria or endotoxin, and leads

to the development of shock and hypoperfusion, most commonly observed in septic shock. Production of TNFother insults, such as hemorrhage and ischemia. TNFincrease in serum TNF-

levels peak within 90 minutes

also may be induced following

levels correlate with mortality in animal models of hemorrhage.23 In contrast, the

levels reported in trauma patients is far less than that seen in septic patients.24 Once released, TNF-

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-

contributes to the muscle protein breakdown and cachexia.

Interleukin-1 (IL-1) has actions that are similar to those of TNF- . IL-1 has a very short half-life (6 minutes) 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, glucorticoids, and

-endorphins. In conjunction with TNF- , 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- . 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 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 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, and enhance the expression and activity of complement, C-reactive protein, fibrinogen, haptoglobin, amyloid A, and alpha1-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, O 2 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

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.33 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 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 TNFARDS and MODS in trauma patients correlates with the intensity of complement

activation. 34

and IL-1. The development of

Complement and neutrophil activation may

correlate with mortality in multiply injured patients.

Neutrophils 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 leukocyte (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 O 2 species, lipidperoxidation products, proteolytic enzymes (elastase, cathepsin G), and vasoactive mediators (leukotrienes, eicosanoids, and plateletactivating 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. 35 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, the expression or breakdown of important proteins, or affect intracellular energy metabolism. Intracellular calcium (Ca 2+ ) homeostasis and regulation represents one such pathway. Intracellular Ca 2+ concentrations regulate many aspects of cellular metabolism; many important enzyme systems require Ca 2+ for full activity. Profound changes in intracellular Ca 2+ levels and Ca 2+ transport are seen in models of shock.36,37 Alterations in Ca 2+ 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. 38–40 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 O 2 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.41–44 Either through changes in these signaling pathways, changes in the activation of enzyme systems through Ca 2+ -mediated events, or direct conformational changes to oxygen-sensitive proteins, O 2 radicals also regulate the activity of a number of transcription factors that are important in gene expression, such as nuclear factor B, APETALA1, and hypoxia-inducible factor 1.45,46 It is therefore becoming increasingly clear that oxidant-mediated direct cell injury is merely one consequence of the production of O 2 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. 47 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. 48–50 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. 51,52

FORMS OF SHOCK 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 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 and 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 to 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 to 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 to bleeding (e.g., beta 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 upon an increasing rate of mortality below this pressure (Fig. 5-6). 53 Table 5-5 Classification of Hemorrhage Class Parameter

I

II

III

IV

Blood loss (mL)

<750

750–1500

1500–2000

>2000

Blood loss (%)

<15

15–30

30–40

>40

>100

>120

>140

Heart rate (bpm) <100 Blood pressure

Normal Orthostatic Hypotension Severe hypotension

CNS symptoms

Normal Anxious

Confused

Obtunded

bpm = beats per minute; CNS = central nervous system. Fig. 5-6.

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 upon an increasing rate of mortality below this pressure. Base deficit (BD) is also shown on this graph. ED = emergency department. (From Eastridge et al,53 with permission.)

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. 54 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.55 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 O 2 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. 5-7). 56 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 with transfusion requirements, the development of multiple organ failure, and death (Fig. 5-8). 57 Both base deficit and lactate correlate with the extent of shock and patient outcome, but interestingly do not firmly correlate with each other. 58–60 Evaluation of both values may be useful in trauma patients with hemorrhage. Fig. 5-7.

Progressive increases in serum lactate, muscle lactate, and liver lactate in a baboon model of hemorrhagic shock. (From Peitzman et al,8 with permission.)

Fig. 5-8.

From Lycan / Dr. MV

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 125:498, 1990. Copyright © 1990 American Medical Association. All rights reserved.) 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 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 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 that have sustained high-energy blunt trauma that are hemodynamically stable or that 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.

TREATMENT Control of ongoing hemorrhage is an essential component of the resuscitation of the patient in shock. As mentioned in Diagnosis above, 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 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) 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, continues into the operating room, and into the intensive care unit (ICU). Initial resuscitation is limited to keep SBP around 90 mmHg. This prevents renewed bleeding from recently clotted vessels. Resuscitation and intravascular volume resuscitation is accomplished with blood products and limited crystalloids, which is addressed 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 was rarely achievable 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, a 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 uncorrectable hypothermia, 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 all too 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 O 2 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/dL; 68,69 however, no prospective randomized trials have compared restrictive and liberal transfusion regimens in trauma patients with hemorrhagic shock. Fresh frozen plasma (FFP) should also be transfused in patients with massive bleeding or bleeding with increases in prothrombin or activated partial thromboplastin times 1.5 times greater than control. Civilian trauma data show that severity of coagulopathy early after ICU admission is predictive of mortality (Fig. 5-9). 70 Evolving data suggest more liberal transfusion of FFP in bleeding patients, but the clinical efficacy of FFP requires further investigation. Recent data collected from a U.S. Army combat support hospital in patients that received massive transfusion of packed red blood cells (>10 units in 24 hours) suggests that a high plasma to RBC ratio (1:1.4 units) was independently associated with improved survival (Fig. 5-10). 71 Platelets should be transfused in the bleeding patient to maintain counts above 50 x 10 9 /L. There is a potential role for other blood products, such as fibrinogen concentrate of cryoprecipitate, if bleeding is accompanied by a drop in fibrinogen levels to less than 1 g/L. Pharmacologic agents such as recombinant activated coagulation factor 7, and antifibrinolytic agents such as -aminocaproic acid, tranexamic acid (both are synthetic lysine analogues that are competitive inhibitors of plasmin and plasminogen), and aprotinin (protease inhibitor) may all have potential benefits in severe hemorrhage but require further investigation. Fig. 5-9.

The relationship between coagulopathy and mortality in trauma patients. Civilian trauma data show that severity of coagulopathy as determined by an increasing International Normalized Ratio (INR) early after intensive care unit (ICU) admission is predictive of mortality. (From Gonzalez et al,70 with permission.)

Fig. 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. (From Borgman et al,71 with permission.) 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. 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 acute respiratory distress syndrome (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.72,73 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.5,74 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 precipitate 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 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 O 2 debt, débridement of nonviable tissue, stabilization of bony injuries, and appropriate treatment of soft tissue injuries.

Septic Shock (Vasodilatory Shock) 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.75 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

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. 76 Sepsis accounts for 9.3% of deaths in the United States, as many yearly as MI. 77 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. 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.78 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. 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, broadspectrum antibiotic use should be minimized to reduce the development of resistant organisms and to avoid the potential complications of fungal overgrowth and antibiotic-associated colitis from overgrowth of Clostridium difficile. IV antibiotics will be insufficient to adequately treat the infectious episode in the settings of infected fluid collections, infected foreign bodies, and devitalized tissue. This situation is termed source control and involves 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. Occasionally, patients with septic shock will develop arterial resistance to catecholamines. Arginine vasopressin, a potent vasoconstrictor, is often efficacious in this setting. 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. 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 O 2 delivery, even to supranormal values), and optimization of mixed venous O 2 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 (Fig. 5-11). 78,79 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. 80 This approach involved adjustment of cardiac preload, afterload, and contractility to balance O 2 delivery with O 2 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 O 2 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. Goaldirected therapy allowed identification and treatment of these patients with insidious illness (global tissue hypoxia in the setting of normal vital signs). Fig. 5-11.

An algorithm for the treatment of patients presenting with sepsis syndrome. CVP = central venous pressure; ETI = ejective time index; HCT = hematocrit; MAP = mean arterial pressure; O 2 = oxygen; SaO2 = oxygen saturation; SBP = systolic blood pressure. (From Cinel et al,79 with permission.) 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.81 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.82 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 and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 mL/kg of predicted body weight and a plateau pressure of 30 cm of water or less. 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; 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. A recent study reported benefit from IV infusion of recombinant human activated protein C for severe sepsis. 83 Activated protein C is an endogenous protein that promotes fibrinolysis and inhibits thrombosis and inflammation. The authors conducted a randomized, prospective, multicenter trial assessing the efficacy of activated protein C in patients with systemic inflammation and organ failure due to acute infection. Treatment with activated protein C reduced the 28-day mortality rate from 31 to 25%; the reduction in relative risk of death was 19.4%. However, several follow-up studies have suggested that activated protein C may not improve mortality when patients are followed up to 6 months. 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 g orally once daily) vs. placebo for 1 week in patients with septic shock.84 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 intent to treat mortality or shock reversal.85 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/day 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 O 2 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). 86 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 inhospital mortality (i.e., 33% mortality with complete reperfusion, 50% mortality with incomplete reperfusion, and 85% mortality with absent reperfusion). 87 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). 86–88 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 volume decreases. An autopsy series of patients dying from cardiogenic shock have found damage to 40% of the left ventricle. 89 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. 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

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 O 2 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 O 2 demand at a time when myocardial O 2 supply may be limited. Acute heart failure may also result in fluid accumulation in the pulmonary microcirculatory bed, decreasing myocardial O 2 delivery even further.

DIAGNOSIS Rapid identification of the patient with pump failure and institution of corrective action are essential in preventing the ongoing spiral of decreased cardiac output from injury causing increased myocardial O 2 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 and establishing the presence of cardiac dysfunction are essential. Treatment of cardiac dysfunction includes maintenance of adequate oxygenation to ensure adequate myocardial O 2 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. 86 When profound cardiac dysfunction exists, inotropic support may be indicated to improve cardiac contractility and cardiac output. Dobutamine primarily stimulates cardiac beta 1 receptors to increase cardiac output but may also vasodilate peripheral vascular beds, lower total peripheral resistance, and lower systemic blood pressure through effects on beta 2 receptors. Ensuring adequate preload and intravascular volume is therefore essential prior to instituting therapy with dobutamine. Dopamine stimulates receptors (vasoconstriction),

1

receptors (cardiac

stimulation), and BETA 2 receptors (vasodilation), with its effects on beta 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 alpha and beta 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 O 2 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 intra-aortic balloon pump. 90 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 O 2 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 O 2 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 beta blockers to control heart rate and myocardial O 2 consumption, nitrates to promote coronary blood flow through vasodilation, and ACE inhibitors to reduce ACE-mediated vasoconstrictive effects that increase myocardial workload and myocardial O 2 consumption. Current guidelines of the American Heart Association recommend percutaneous transluminal coronary angiography for patients with cardiogenic shock, ST elevation, left bundle-branch block, and age less than 75 years. 91 Early definition of coronary anatomy and revascularization is the pivotal step in treatment of patients with cardiogenic shock from acute MI. 92 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 58), 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 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. 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.

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 above, 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 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 are 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 or 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").

Neurogenic Shock 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 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. Table 5-9 Causes of Neurogenic Shock Spinal cord trauma Spinal cord neoplasm Spinal/epidural anesthetic

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. 93 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.94 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 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 alpha 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 O 2 debt accumulate. Thus, the goal in the treatment of shock is restoration of adequate organ perfusion and tissue oxygenation. Resuscitation is complete when O 2 debt is repaid, tissue acidosis is corrected, and aerobic metabolism 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 O 2 saturation. 56,95 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 (lactic acidosis) longer than 12 hours were independent predictors of infection.96 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, O 2 delivery and consumption, lactate, and base deficit (Table 5-10). 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

Assessment of Endpoints in Resuscitation OXYGEN TRANSPORT Attaining supranormal O 2 transport variables has been proposed as a means to correct O 2 debt. Shoemaker and associates published the first randomized study examining supranormal O 2 consumption and delivery as endpoints in resuscitation. 97 The supranormal O 2 transport variables include O 2 delivery greater than 600 mL/min per square meter, cardiac index greater than 4.5 L/min per square meter, and O 2 consumption index greater than 170 mL/min per square meter. These authors reported a significant reduction in mortality in the patients achieving supranormal endpoints. More recent publications suggest that patients unable to increase O 2 delivery have a higher mortality, as opposed to it being a true benefit of the therapy.98–100 This observation strongly correlates with age of the patient, with older patients less able to generate supranormal O 2 delivery. Gattinoni and colleagues reported effects of hemodynamic therapy in critically ill patients on 10,726 patients in 56 ICUs.101 Seven hundred sixty-two patients met the predefined diagnostic categories and were assigned to one of three groups: control group, supranormal cardiac index group, and O 2 saturation group (with a goal of achieving normal venous O 2 saturation). The authors found that hemodynamic therapy aimed at reaching supranormal values for cardiac index or normal values for mixed venous O 2 saturation did not reduce morbidity or mortality among critically ill patients. In this paper's accompanying editorial, it was noted that failure to achieve both values is a relatively common problem, particularly among older or more severely ill patients. These results emphasize the importance of adequate volume replacement, maintenance of normal blood pressure, and the use of minor doses of inotropic drugs to maintain a normal cardiac output. In a recent paper from Shoemaker's group, supranormal values were achieved intentionally in 70% of the treatment group and spontaneously by 40% of the control group. 98 Mortality, incidence of organ failure and sepsis, and length of stay were no different between the treatment and control groups. Patients in each group who attained supranormal values had better outcomes than those who could not, and mortality was 30% in patients unable to reach supranormal values and 0% in patients with supranormal indices. Age younger than 40 years was the sole independent variable that predicted ability to reach these supraphysiologic endpoints. Thus, the evidence is insufficient to support the routine use of a strategy to maximize O 2 delivery in a group of unselected patients. Inability to repay O 2 debt is a predictor of mortality and organ failure; the probability of death has been directly correlated to the calculated O 2 debt in hemorrhagic shock. Direct measurement of the O 2 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 O 2 debt; serum lactate and base deficit have been shown to correlate with O 2 debt.

LACTATE Lactate is generated by conversion of pyruvate to lactate by lactate dehydrogenase in the setting of insufficient O 2 . 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 O 2 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.56 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 O 2 at 37°C (98.6°F) and 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 to 5 mmol/L), moderate (6 to 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.57 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.59 Persistently high base deficit is associated with abnormal O 2 utilization and higher mortality. Monitoring base deficit in the resuscitation of trauma patients assists in assessment of O 2 transport and efficacy of resuscitation. 58 Factors that may compromise the utility of the base deficit in estimating O 2 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 O 2 debt for its clinical relevance, accuracy, and availability.

GASTRIC TONOMETRY Lactate and base deficit indicate global tissue acidosis. Several authors have suggested that tissue-specific 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 O 2 delivery to the tissues. pHi is a good prognostic indicator; patients with normal pHi have better outcomes than those patients with pHi less than 7.3.102–104 Goal-directed 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. 105

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 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 O 2 supply to cytochrome a,a3 with mitochondrial O 2 consumption), thus demonstrating flow-independent mitochondrial oxidative dysfunction and the need for further resuscitation. Trauma patients with decoupled oxyhemoglobin and cytochrome a,a3 have redox dysfunction and have been shown to have a higher incidence of organ failure (89 vs. 13%).106,107

TISSUE PH, OXYGEN, AND CARBON DIOXIDE CONCENTRATION Tissue probes with optical sensors have been used to measure tissue pH and partial pressure of O 2 and CO2 in subcutaneous sites, muscle, and the bladder. These probes may use transcutaneous methodology with Clark electrodes or direct percutaneous probes. 108,109 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. 110 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. 111

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Schwartz's Principles of Surgery > Part I. Basic Considerations > Chapter 6. Surgical Infections >

KEY POINTS 1. 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. 2. Principles relevant to appropriate antibiotic prophylaxis for surgery: (a) select an agent with activity against common organisms at the site of surgery, (b) the initial dose of the antibiotic should be given within 30 minutes of incision, (c) antibiotics should be redosed every 1 to 2 half-lives during surgery to ensure adequate tissue levels, and (d) antibiotics should not be continued for more than 24 hours after surgery for routine prophylaxis. 3. 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. 4. 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. 5. When using antimicrobial agents for therapy of serious infection, several principles should be followed: (a) identify likely sources of infection, (b) choose an agent (or agents) that covers likely organisms for these sources, (c) remember that inadequate or delayed antibiotic therapy results in increased mortality, so it is important to begin therapy with broader coverage, (d) when possible, obtain cultures early and use results to tailor therapy, (e) if there is no infection identified after 3 days, strongly consider discontinuation of antibiotics, and (f) stop antibiotics after an appropriate course of therapy. 6. The keys to good outcomes in patients with necrotizing soft tissue infection are early recognition and appropriate débridement of infected tissue with repeated débridement until no further signs of infection are present. 7. 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.

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 before 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 due to the fact that 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 before 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 Despondent, he committed suicide in 1865 by intentionally cutting his finger during the autopsy of a woman who died of puerperal fever, presumably as the ultimate proof of his tenets. 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, Streptococcus, and 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 more than 50% of his patients undergoing amputation died due to 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 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 (then Prussia, now a part of Poland), 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 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, GI 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 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 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 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 end-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.

PATHOGENESIS OF INFECTION 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 sitespecific 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, 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. However, barrier function 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 surface, the skin harbors its own resident microflora that may block the attachment and invasion of noncommensal microbes. Microbes also are 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 GI tract, with vast numbers being found within the oropharynx and distal colorectum, although the specific organisms differ. One would suppose that the entire GI tract would be populated via those microbes found in the oropharynx, but this is not the case. This is because after ingestion, these organisms routinely are killed in the highly acidic, low-motility environment of the stomach during the initial phases of digestion. Thus, small numbers of microbes populate the gastric mucosa [approximately 10 2 to 10 3 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 10 5 to 10 8 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 colorectum, and approximately 10 11 to 10 12 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 (E. coli and other Enterobacteriaceae, E. faecalis and faecium, C. 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 provide the initial inoculum for infection should perforation of the GI tract occur. It is of great interest that only some of these microbial species predominate in established intra-abdominal infection. 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 such as microbes within peritoneal fluid are expunged from the abdominal cavity via specialized structures on the undersurface of the diaphragm. Concurrently, containment by the omentum, the so-called gatekeeper of the abdomen and intestinal ileus, serves to wall off infection. 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 (Ig, antibodies). 10 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. Macrophage cytokine synthesis is upregulated. Secretion of tumor necrosis factor alpha (TNF- ), of interleukins (IL)-1 , 6, and 8; and of interferon-gamma (INF- ) occurs within the tissue milieu, and, depending on the magnitude of the host defense response, the systemic circulation. 11 Concurrently, a counterregulatory response is initiated consisting of binding proteins (TNF-BP), cytokine receptor antagonists (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 (phagocytic vacuoles). Concurrently, the classic 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 infection (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 identification of microorganisms in host tissue or the bloodstream, plus an inflammatory response to their presence. 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 above comprise the systemic inflammatory response syndrome (SIRS). SIRS can be caused by a variety of disease processes, including pancreatitis, polytrauma, malignancy, and transfusion reaction, as well as infection (Fig. 6-1). Strict criteria for SIRS (tachycardia, tachypnea, fever, and elevated WBC count) have been broadened to include additional clinical indicators noted in Table 6-1.12 SIRS caused by infection is termed sepsis and is mediated by the production of a cascade of proinflammatory mediators produced in response to exposure to microbial products. These products include lipopolysaccharide (endotoxin) derived from gram-negative organisms; peptidoglycans and teichoic acids from gram-positive organisms; multiple cell wall components such as mannan from yeast and fungi; and many others. Patients have developed sepsis if they have met clinical criteria for SIRS and have evidence of a local or systemic source of infection. Fig. 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. Table 6-1 Criteria for Systemic Inflammatory Response Syndrome General variables Fever [core temp >38.3°C (100.9°F)] Hypothermia [core temp <36°C (96.8°F)] 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 mmHg, MAP <70, or SBP decrease >40 mmHg) S VO2 >70%

Cardiac index >3.5 L/min per square meter Organ dysfunction variables Arterial hypoxemia Acute oliguria Creatinine increase Coagulation abnormalities Ileus

Thrombocytopenia Hyperbilirubinemia Tissue perfusion variables Hyperlactatemia Decreased capillary filling bpm = beats per minute; MAP = mean arterial pressure; SBP = systolic blood pressure; s.d. = standard deviations; S VO2 = venous oxygen saturation; WBC = white blood cell count. Severe sepsis is characterized as sepsis (defined above) combined with the presence of new-onset organ failure. Severe sepsis is the most common cause of death in noncoronary critical care units, with a mortality rate of 51 cases/100,000 population per year in 2003.13 A number of organ dysfunction scoring systems have been described. 14–16 With 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 mmHg) 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 45 to 60%. 17,18 Clinicians dedicated to improving the treatment of sepsis have recently developed a new classification scheme for this entity.12 This scheme has borrowed from the tumor-node-metastasis staging scheme developed for oncology. The impetus for development of this scheme was 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. Although 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. 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). Current definitions using this system are listed in Table 6-2. Published trials using this classification system have confirmed the validity of this concept. 19 Further investigation is ongoing to evaluate the clinical utility of this scheme. Table 6-2 PIRO Classification Scheme Domain

Means of Classification

Predisposition

Premorbid illness that affects probability of survival (e.g., immunosuppression, age, genetics)

Insult (infection)

Type of infecting organisms, location of disease, intervention (source control)

Response

SIRS, other signs of sepsis, presence of shock, tissue markers (e.g., C-reactive protein, IL-6)

Organ dysfunction Organ dysfunction as a number of failing organs or composite score IL-6 = interleukin-6; SIRS = systemic inflammatory response syndrome.

MICROBIOLOGY OF INFECTIOUS AGENTS A partial list of common pathogens that cause infections in surgical patients is provided in Table 6-3. Table 6-3 Common Pathogens in Surgical Patients Gram-positive aerobic cocci Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Streptococcus pneumoniae Enterococcus faecium, E. faecalis 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. parapsilosis, C. krusei Coccidioides immitis Cryptococcus neoformans Histoplasma capsulatum Mucor/Rhizopus Viruses Cytomegalovirus Epstein-Barr virus Hepatitis A, B, C viruses Herpes simplex virus HIV Varicella-zoster virus

Bacteria 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 gram-negative bacteria stain red. Bacteria are

classified based upon 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 E. 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 E. coli, Klebsiella pneumoniae, Serratia marcescens, and Enterobacter, Citrobacter, and Acinetobacter spp. Other gram-negative bacilli of note include Pseudomonas spp., including P. 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 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 above, large numbers of anaerobes contribute to the microflora of the oropharynx and colorectum. 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 often was required for severe pulmonary disease, now an increasingly uncommon occurrence in developed countries. This organism and other related organisms (M. aviumintracellulare 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 before final identification, although 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, 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 vs. 37°C (77 vs. 98.6°F)]. Fungi of relevance to surgeons include those that cause nosocomial infections in surgical patients as part of polymicrobial infections or fungemia (e.g., C. 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 6-4. Table 6-4 Antifungal Agents and Their Characteristics Antifungal

Advantages

Disadvantages

Approximate Daily Cost

Amphotericin B

Broad-spectrum, inexpensive

Renal toxicity, premeds, IV only

$11

Liposomal amphotericin B

Broad-spectrum

Expensive, IV only, renal toxicity

$600

Fluconazole

IV and PO availability

Narrow-spectrum, drug interactions

$21 (IV), <$1 (PO)

Itraconazole

IV and PO availability

Narrow-spectrum, no CSF penetration, drug interactions, decreased cardiac contractility

$200 (IV), $3 (PO)

Posaconazole

Broad-spectrum, zygomycete activity

PO only

$100

Azoles

Voriconazole

IV and PO availability, broad-spectrum

IV diluent accumulates in renal failure, visual disturbances

$200 (IV), $70 (PO)

IV only, poor CNS penetration

$100–250

Echinocandins Anidulafungin, caspofungin, Broad-spectrum micafungin CSF = cerebrospinal fluid.

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 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 RNA using methods such as polymerase chain reaction. Similarly to many fungal infections, most 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 HIV infections, including their capacity to be transmitted to health care workers (see Blood-Borne Pathogens below). Prophylactic and therapeutic use of antiviral agents is discussed in Chap. 11.

PREVENTION AND TREATMENT OF SURGICAL INFECTIONS 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 above in Bacteria, 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 intraoperatively sterile technique is used. Similarly, application of an antibacterial agent to the skin of the patient at the proposed operative site takes place before 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 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 before 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.

Source Control 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.20 A discrete, walled-off 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, rapidlyspreading 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 to misdiagnosis or the need for additional diagnostic studies, is associated with increased morbidity and occasional mortality.21–23

Appropriate Use of Antimicrobial Agents A classification of antimicrobial agents, mechanisms of action, and spectrum of activity is shown in Table 6-5. Prophylaxis consists of the administration of an antimicrobial agent or agents before initiation of certain specific types of surgical procedures 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 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 amoebic bacteria. There are a wide variety of agents that meet these criteria. Table 6-5 Antimicrobial Agents Antibiotic Class, Generic Name

Organism Trade Name

Penicillins

Mechanism of Action

S. MSSA MRSA S. Enterococcus VRE E. P. Anaerobes pyogenes epidermidis coli aeruginosa

Cell wall synthesis inhibitors (bind penicillinbinding protein)

Penicillin G

1

±

1

Nafcillin

Nallpen, Unipen

1

1

±

Piperacillin

Pipracil

1

±

1

1

±

Penicillin/beta lactamase inhibitor combinations

Cell wall synthesis inhibitors/beta lactamase inhibitors

Ampicillinsulbactam

Unasyn

1

1

±

1

±

1

1

Ticarcillinclavulanate

Timentin

1

1

±

±

1

1

1

Piperacillintazobactam

Zosyn

1

1

1

±

1

1

1

1

1

±

1

First-generation cephalosporins

Cefazolin, cefalexin Secondgeneration cephalosporins

Cell wall synthesis inhibitors (bind penicillinbinding protein) Ancef, Keflex Cell wall synthesis inhibitors (bind penicillinbinding protein)

Cefoxitin

Mefoxin

1

1

±

1

1

Cefotetan

Cefotan

1

1

±

1

1

Cefuroxime

Ceftin

1

1

±

1

Third- and fourthgeneration cephalosporins

Cell wall synthesis inhibitors (bind penicillinbinding protein)

Ceftriaxone

Rocephin

1

1

±

1

Ceftazidime

Fortaz

1

±

±

1

1

Cefepime

Maxipime

1

1

±

1

1

Cefotaxime

Cefotaxime

1

1

±

1

±

Primaxin

1

1

1

±

1

1

1

Meropenem

Merrem

1

1

1

1

1

1

Ertapenem

Invanz

1

1

1

1

±

1

Aztreonam

Azactam

Cell wall 0 synthesis inhibitor (bind penicillinbinding protein)

1

1

Carbapenems

Imipenemcilastatin

Cell wall synthesis inhibitors (bind penicillinbinding protein)

Aminoglycosides

Alteration of cell membrane, binding and inhibition of 30S ribosomal unit

Gentamicin

1

±

1

1

1

Tobramycin, amikacin

1

±

1

1

Fluoroquinolones

Inhibit topoisomerase II and IV (DNA synthesis inhibition)

Ciprofloxacin

Cipro

±

1

1

1

1

Levofloxacin

Levaquin

1

1

1

1

±

Glycopeptides

Cell wall synthesis inhibition (peptidoglycan synthesis inhibition)

Vancomycin

Vancocin

1

1

1

1

1

Quinupristindalfopristin

Synercid

Inhibits two sites on 50S ribosome (protein synthesis inhibition)

1

1

1

1

1

1

±

Linezolid

Zyvox

Inhibits 50S ribosomal activity (protein synthesis inhibition)

1

1

1

1

1

1

±

Daptomycin

Cubicin

Binds bacterial 1 membrane, results in depolarization, lysis

1

1

1

1

1

Rifampin

Inhibits DNAdependent RNA polymerase

1

1

1

1

±

Clindamycin

Cleocin

Inhibits 50S ribosomal activity (protein synthesis inhibition)

1

1

1

Metronidazole

Flagyl

Production of toxic intermediates (free radical production)

1

Macrolides

Inhibit 50S ribosomal activity (protein synthesis inhibition)

Erythromycin

1

±

±

Azithromycin

Zithromax

1

1

Clarithromycin

Biaxin

1

1

Inhibits ± sequential steps of folate metabolism

1

±

1

Trimethoprimsulfamethoxazole

Bactrim, Septra

Tetracyclines

Bind 30S ribosomal unit (protein synthesis inhibition)

Minocycline

Minocin

1

1

±

Doxycycline

Vibramycin

1

±

1

±

Tigecycline

Tygacil

1

1

1

1

1

1

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 because these patterns may vary widely depending on location. By definition, prophylaxis is limited to the time before 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 below). 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. Nota bene: 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 6-6. Table 6-6 Prophylactic Use of Antibiotics Site

Antibiotic

Alternative (e.g., penicillin allergic)

Cardiovascular surgery

Cefazolin, cefuroxime

Vancomycin

Gastroduodenal area

Cefazolin, cefotetan, cefoxitin, ampicillin-sulbactam

Fluoroquinolone

Biliary tract with active infection (e.g., cholecystitis)

Ampicillin-sulbactam, ticarcillin-clavulanate, piperacillintazobactam

Fluoroquinolone plus clindamycin or metronidazole

Colorectal surgery, obstructed small bowel

Cefazolin plus metronidazole, ertapenem, ticarcillinclavulanate, piperacillin-tazobactam

Gentamicin or fluoroquinolone plus clindamycin or metronidazole

Head and neck

Cefazolin

Aminoglycoside plus clindamycin

Neurosurgical procedures

Cefazolin

Vancomycin

Orthopedic surgery

Cefazolin, ceftriaxone

Vancomycin

Breast, hernia

Cefazolin

Vancomycin

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 empiric therapy in situations in which the risk of infection increases markedly because of intraoperative findings. Empiric therapy also often is used in critically ill patients in whom a potential site of infection has been identified and severe sepsis or septic shock occurs. Invariably, empiric 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, empiric therapy merges into therapy of established infection in some patients as well. However, among surgical patients, the manner in which therapy is used, 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 SIRS (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 empiric antibiotic therapy. 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, however, to ensure that the antimicrobial coverage chosen is adequate, because delay in appropriate antibiotic treatment has been shown to be associated with increased mortality. Within 24 to 72 hours, culture and sensitivity reports will allow refinement of the antibiotic regimen to select the most efficacious agent. The clinical 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 above in Source Control, 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. 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.24 Duration of antibiotic administration should be decided at the time the drug regimen is prescribed. As noted below in Surgical Site Infections, prophylaxis is limited to a single dose administered immediately before 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. 25 This precept is highlighted by a study in which patients in whom SIRS was identified were closely monitored for the presence of infection: Less than half of them were found to harbor infection.26 Therapy for monomicrobial infections follows standard guidelines: 3 to 5 days for UTIs, 7 to 10 days for pneumonia, and 7 to 14 days for bacteremia. Longer courses of therapy in this setting do not result in improved care but are associated with increased risk of resistant organisms. 27,28 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 of a standard pure inoculum of 10 5 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 IV for 1 to 2 weeks, following which the treatment course is completed with 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 GI 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. 29 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. In the later phases of postoperative antibiotic treatment of serious intra-abdominal infection, the absence of an elevated WBC count, lack of band forms of PMNs on peripheral smear, and lack of fever [<38.6°C (100.5°F)] provide close to complete assurance that infection has been eradicated. 30 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 before 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 highest for carbapenems, much lower for cephalosporins (~5 to 7%), and extremely small or nonexistent for monobactams. Severe allergic manifestations to a specific class of agents, such as anaphylaxis, generally preclude the use of any agents in 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.31 This type of testing is rarely used 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 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. 32 The responsible practitioner limits prophylaxis to the period during the operative procedure, does not convert prophylaxis into empiric 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. The utility of prophylactic antibiotics to prevent infections related to thoracostomy tube insertion has been demonstrated, 33,34 but prolonged treatment while a thoracostomy tube remains in situ, or prolonged therapy of biliary, intra-abdominal, or abscess drain cultures is not to be condoned.

INFECTIONS OF SIGNIFICANCE IN SURGICAL PATIENTS Surgical Site Infections SSIs are infections of the tissues, organs, or spaces exposed by surgeons during performance 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. 35 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 6-7 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. Table 6-7 Risk Factors for Development of Surgical Site Infections Patient factors Older age Immunosuppression Obesity Diabetes mellitus Chronic inflammatory process Malnutrition Peripheral vascular disease Anemia Radiation Chronic skin disease Carrier state (e.g., chronic Staphylococcus carriage) Recent operation Local factors Poor skin preparation Contamination of instruments Inadequate antibiotic prophylaxis Prolonged procedure Local tissue necrosis

Hypoxia, hypothermia Microbial factors Prolonged hospitalization (leading to nosocomial organisms) Toxin secretion Resistance to clearance (e.g., capsule formation) Surgical wounds are classified based on the presumed magnitude of the bacterial load at the time of surgery (Table 6-8). 36 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 ID 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 bacterial flora is opened under controlled circumstances without significant spillage of contents. Interestingly, 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%).37–39 One study identified two thirds of infections presenting after discharge from hospital, highlighting the need for careful followup of these patients.37 Infection is also more common in cases involving entry into the rectal space.39 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 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. Table 6-8 Wound Class, Representative Procedures, and Expected Infection Rates Wound Class

Examples of Cases

Expected Infection Rates

Clean (class I)

Hernia repair, breast biopsy

1.0–5.4%

Clean/contaminated (class II)

Cholecystectomy, elective GI surgery (not colon)

2.1–9.5%

Clean/contaminated (class II)

Colorectal surgery

9.4–25%

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%

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.40 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. Several different SSI risk stratification schemes have been developed via retrospective, multivariate analysis of large surveillance data sets. The National Nosocomial Infection Surveillance (NNIS) risk index is commonly used and assesses three factors: (a) American Society of Anesthesiologists Physical Status score greater than 2, (b) class III/IV wound, and (c) duration of operation greater than the 75th percentile for that particular procedure, to refine the risk of infection beyond that achieved by use of wound classification alone. Intriguingly, the risk of SSIs for class I wounds varies from approximately 1 to 2% for patients with low NNIS scores, to approximately 15% for patients with high NNIS scores (e.g., long operations and/or high American Society of Anesthesiologists scores), and it seems clear that additional refinements are required.41 SSIs are associated with considerable morbidity and occasional lethality, as well as substantial health care costs and patient inconvenience and dissatisfaction.42 For that reason, surgeons strive to avoid SSIs by using the maneuvers described in the previous section Prevention and Treatment of Surgical Infections. 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 before commencing surgery for class ID, II, III, and IV types of wounds. 43 It seems reasonable that this practice should be extended to patients in any category with high 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 used 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 standard of care therapies, one of which being reduction in SSIs, because the morbidity (and subsequent cost) of this complication is high. Several of these organizations are noted in Table 6-9. Appropriate guidelines in this area incorporating the principles discussed above in Prevention and Treatment of Surgical Infections have been developed and published.44 However, adherence to these guidelines has been poor. 45 Driving incorporation of these guidelines into routine clinical practice is the belief that better adherence to evidence-based practice recommendations and more attention to designing systems of care with redundant safeguards will result in reduction of surgical complications and better patient outcomes. Importantly, the Center for Medicare and Medicaid Services, the largest third party 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 hospital, has led to significant improvement in reported rates of these process measures. The effects of this approach on SSIs are not known at this time. Table 6-9 Quality Improvement Organizations of Interest to Surgeons in the United States Abbreviation Organization

Website

SCIP

Surgical Care Improvement Project

http://www.medqic.org (Enter SCIP in search)

NSQIP

National Surgical Quality Improvement Program http://acsnsqip.org

IHI

Institute for Healthcare Improvement

http://www.ihi.org

CMS

Center for Medicare and Medicaid Services

http://www.hospitalcompare.hhs.gov

NCQA

National Committee for Quality Assurance

http://www.ncqa.org

Surgical management of the wound is also a critical determinant of the propensity to develop an 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 (approximately 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.46 It remains to be determined whether NNIS-type stratification schemes can be used prospectively to target specific subgroups of patients who 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%.47 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. 48 A number of recent studies have reported the effects of hyperglycemia in vivo in diabetic patients, with increased SSI rates being associated with hyperglycemia in cardiac surgery patients undergoing bypass. 49,50 On this basis, it is recommended that clinicians maintain appropriate blood sugar control in diabetic patients in the perioperative period to minimize the occurrence of SSIs. The effects of the level of inhaled oxygen and prewarming of the wound on SSI rates also have been studied. Although an initial study provided evidence that patients who received high levels of inhaled oxygen during colorectal surgery developed fewer SSIs, 51 data to the contrary recently have been reported.52,53 In another study, preoperative warming of the wound site for 30 minutes before surgery among patients undergoing clean surgery was associated with a decrease in SSIs (5% with warmed wounds vs. 14% without).54 Unfortunately, several of the aforementioned studies report SSI rates among study patients that are higher than those reported and expected among similar groups of patients, making comparison difficult. Of note, stratification using the NNIS classification methodology was not used. Further

evaluation via multicenter studies is needed before implementation of these modalities as standard therapies. Effective therapy for incisional SSIs consists solely of incision and drainage without the addition of antibiotics. Antibiotic therapy is reserved for patients in whom evidence of significant cellulitis is present, or who manifest concurrent SIRS. 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.55 Despite a paucity of prospective studies, 56 vacuum-assisted closure is increasingly used in management of problem wounds and can be applied to complex wounds in difficult locations (Fig. 6-2). Although culture results are of epidemiologic interest, they rarely serve to direct therapy because antibiotics are not routinely withheld until results are known. The treatment of organ/space infections is discussed in Intra-Abdominal Infections, below. Fig. 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, because typical clues of wound sepsis, such as odor and drainage, are hidden by the suction apparatus.

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 direct inoculation. This process is more common among patients who retain large amounts of peritoneal fluid due to ascites, and in 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 a patient who has ascites for medical reasons, physical examination that reveals diffuse tenderness and guarding without localized findings, absence of pneumoperitoneum on abdominal flat plate and upright roentgenograms, 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 will typically demonstrate the presence of gram-positive organisms in patients receiving 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., peritoneal dialysis catheter or 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 GI tract, or diverticulitis. As noted previously in Source Control, 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.57 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 will provide results similar to those achieved with IV antibiotics.58 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 leads to 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. 24,60 Patients in whom standard therapy fails develop an intra-abdominal abscess, leakage from a GI 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 E. faecalis and faecium, S. epidermidis, C. albicans, and P. aeruginosa can be identified, typically in combination, and may be selected based on 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%. 61,62 Formerly, the presence of an intra-abdominal abscess mandated surgical re-exploration 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.63 Formerly, pyogenic liver abscesses 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. C. albicans and other similar yeasts 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 above in Intra-Abdominal Infections. 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. 64 Current care of patients with severe acute pancreatitis includes staging with dynamic, contrast-enhanced helical CT scan with 3-mm tomographs to determine the extent of pancreatic necrosis, coupled with the use of one of several prognostic scoring systems. Patients who exhibit significant pancreatic necrosis (grade greater than C, Fig. 6-3) should be carefully monitored in the ICU and undergo follow-up CT examination. A recent change in practice has been the elimination of the routine use of prophylactic antibiotics for prevention of infected pancreatic necrosis. Early results were promising;65 however, several randomized multicenter trials have failed to show benefit and three meta-analyses have confirmed this finding. 66–68 Fig. 6-3.

Contrast-enhanced computed tomographic scan of pancreas with severe pancreatic necrosis. Note lack of IV contrast within the boggy pancreatic bed (large black arrow).

In two small studies, enteral feedings initiated early, using nasojejunal feeding tubes placed past the ligament of Treitz, have been associated with decreased development of infected pancreatic necrosis, possibly due to a decrease in gut translocation of bacteria. Recent guidelines support the practice of enteral alimentation in these patients, with the addition of parenteral nutrition if nutritional goals cannot be met by tube feeding alone.69,70 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 is of critical importance. A positive Gram's stain or culture from CT-guided aspiration, or identification of gas within the pancreas on CT scan, mandate operative intervention. Surgery for secondary pancreatic infection is designed to remove the infected inflammatory focus. It is the practice of the authors to expose the pancreatic bed through a transverse incision in the abdominal wall and lesser sac (Fig. 6-4). A jejunal feeding tube, gastrostomy tube, and cholecystectomy (if indicated) are all performed at the index operation if patient condition permits. The gastrocolic omentum is tacked to the abdominal wall on the peritoneal edges of the wound to sequester the intestines from the inflammatory process. After initial gentle débridement of necrotic tissue, the pancreatic bed is packed with gauze dressings and the abdomen closed temporarily with a permanent mesh or packed open. This mesh allows repeated reoperations without damage to the remaining fascia. In a similar fashion to surgery for necrotizing soft tissue infection, the surgeon should plan on scheduled relaparotomy and undertake débridement until necrotic tissue and purulence are absent and granulation tissue forms. Approximately 20 to 25% of patients will develop a GI fistula, which either heals or is amenable to surgical repair after resolution of the pancreatic infection. The laparoscopic approach to débridement first described in 1996 has been described using various techniqes.71,72 Fig. 6-4.

Infected pancreatic necrosis. A. Necrosectomy specimen with pancreatic stent in situ. It is important to gently débride only necrotic pancreatic tissue, relying on repeated operation to ensure complete removal. B. Typical incision for infected pancreatic necrosis. Polypropylene mesh has been secured to fascia and is used for re-entry into the pancreatic bed. Note gastrostomy and feeding jejunostomy tubes. The chest tube in the wound is placed to allow closed continuous suction.

Infections of the Skin and Soft Tissue Infections of the skin and soft tissue can be classified according to whether 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 source of infection should be undertaken. Generally, drugs that possess activity against the gram-positive skin microflora that are causative 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. Commonly acquired methicillin-resistant S. aureus infection should be suspected if infection persists after treatment with adequate drainage and antibiotics. These infections may require more aggressive drainage and altered antimicrobial therapy.73 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 (approximately 80 to 100%), and even with rapid recognition and intervention, current mortality rates remain high, approximately 16 to 25%. 74,75 Eponyms and classification in the past have been a hodgepodge of terminology, such as Meleney's synergistic 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 causes them. 76 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 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, 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 be undertaken only in patients in whom the diagnosis is not seriously 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). Fig. 6-5.

Necrotizing soft tissue infection. A. This patient presented with hypotension due to severe late necrotizing fasciitis and myositis due to betahemolytic streptococcal infection. The patient succumbed to his disease after 16 hours despite aggressive débridement. 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 débridement of fascia to viable muscle. During the procedure, a Gram's stain should be performed on tissue fluid. Antimicrobial agents directed against gram-positive and gramnegative aerobes and anaerobes (e.g., vancomycin plus a carbapenem), as well as high-dose aqueous penicillin G (16,000 to 20,000 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 S. pyogenes, P. aeruginosa, or C. 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 débridement should take place. Antibiotic therapy can be refined based on culture and sensitivity results, particularly in the case of monomicrobial soft tissue infections. Adjunctive treatments, including treatment with hyperbaric oxygen or IV Ig, have been described with contradictory results. Hyperbaric oxygen therapy should be strongly considered in patients with infection caused by gasforming organisms (e.g., C. perfringens). It may be reasonable to consider IV Ig in patients with group A streptococcal infection with toxic shock syndrome and in those patients with a high risk of death, such as the elderly or those with hypotension or bacteremia. 77

Postoperative Nosocomial Infections Surgical patients are prone to develop a wide variety of nosocomial infections during the postoperative period, which include SSIs, UTIs, pneumonia, and bacteremic episodes.78 SSIs are discussed above in Surgical Site Infections, 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 more than 10 4 CFU/mL of microbes are identified by culture techniques in symptomatic patients, or more than 10 5 CFU/mL in asymptomatic individuals. Treatment for 3 to 5 days with a single antibiotic that achieves high levels in the urine is appropriate. 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. Prolonged mechanical ventilation is associated with an increased incidence of pneumonia, and is frequently due to pathogens common in the nosocomial environment.79 Frequently these organisms are highly resistant to many different agents.80 The diagnosis of hospital-acquired pneumonia should be made using the presence of a purulent sputum, elevated leukocyte count, fever, and new chest x-ray abnormality. The presence of two of the clinical findings, plus chest x-ray findings, significantly increases the likelihood of ventilator-associated pneumonia. 81 Consideration should be given to performing bronchoalveolar lavage to obtain samples to assess by Gram's stain and obtaining a culture to assess for the presence of microbes. Surgical patients should be weaned from mechanical ventilation as soon as feasible, based on oxygenation and inspiratory effort. 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 perhaps the use of multilumen catheters increase the risk of infection. Although no randomized trials have been performed, peripherally inserted central venous catheters have a similar catheter-related infection rate. 82 Many patients who develop intravascular catheter infections are asymptomatic, often exhibiting 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 S. 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. 83 The use of antibiotic-bonded catheters is associated with lower rates of colonization.84 Routine, scheduled catheter changes over a guidewire are associated with slightly lower rates of infection, but an increase in the insertion-related complication rate. 85 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 antibacterial or antifungal agents to prevent catheter infection is of no utility and is contraindicated.

Sepsis Severe sepsis is increasing in incidence, with over 750,000 cases estimated per year in the United States. This rate is expected to increase as the population of aged in the United States increases. The treatment of sepsis has improved dramatically over the last decade, with mortality rates dropping to under 30%. 86 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 2008.87 These guidelines are summarized in Table 6-10. Table 6-10 Summary of Surviving Sepsis Campaign Guidelines Initial evaluation and infection issues Initial resuscitation: Begin resuscitation immediately in patients with hypotension or elevated serum lactate with resuscitation goal of CVP 8– !"##$%&"#'()"(*+'*,(-".*'//0*'"12"345"##$%&"()6"0*,)'"10+.0+"12"3785"#9:;%".'*"<10*8" Diagnosis: Obtain appropriate cultures before antibiotics but do not delay antibiotic therapy. 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; 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 as soon as possible after initial resuscitation. Remove intravascular access devices if potentially infected. Hemodynamic support and adjunctive therapy Fluid therapy: Fluid resuscitate using crystalloid or colloid, using fluid volumes of 1000 mL (crystalloid), target CVP of 8–12 mmHg. Vasopressors/inotropic therapy:"=(,)+(,)"=>?"12"345"##$%@"A')+*(--B"(6#,),/+'*'6")1*'.,)'.<*,)'"1*"61.(#,)'"(*'"2,*/+C-,)'"A<1,A'/@ dopamine should not be used for "renal protection"; insert arterial catheters for patients requiring vasopressors. Do not increase cardiac index to predetermined supranormal levels. Steroids:"D1)/,6'*"EF"

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 series including intra-abdominal infection, necrotizing soft tissue infection, and others demonstrate increased mortality with delayed treatment. A possible exception is that of infected pancreatic necrosis. Multiple trials have evaluated the use of vasopressors and inotropes for treatment of septic shock. Current suggestions for first-line agents based on effects on splanchnic perfusion include norepinephrine, dopamine, and vasopressin. 92,93 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 vasopressor-induced 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. Corticosteroids, first evaluated unsuccessfully in the 1980s for treatment of sepsis (high dose), have recently been reintroduced to the armamentarium of the practitioner after the observation that many patients with septic shock have a relative adrenal insufficiency. Low-dose corticosteroids (hydrocortisone at 300 mg/d or less) 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. Recombinant human activated protein C (drotrecogin alfa, Xigris) has been associated with significant survival benefit in patients with severe sepsis and at least one organ failure. 94 In surgical patients, this therapy should be reserved for patients with at least two organ failures or for patients with septic shock. 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 H 2 O or less. Finally, red blood cell transfusion should be reserved for patients with hemoglobin of less than 7 g/dL, with a more liberal transfusion strategy reserved for those patients with severe coronary artery disease, ongoing blood loss, or severe hypoxemia.

Blood-Borne Pathogens Although alarming to contemplate, the risk of HIV transmission from patient to surgeon is low. By December 31, 2001, there had been six cases of surgeons with HIV seroconversion from a possible occupational exposure, from a total of 469,850 HIV cases to that date reported to the Centers for Disease Control and Prevention. Of the groups of health care workers with likely occupationally acquired HIV infection (n = 195), surgeons were one of the lower risk groups (compared to nurses at 59 cases and nonsurgeon physicians at 18 cases).95 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 instruments during and after use. The current estimate of the risk of transmission is 0.3% after needlestick. 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., IV 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.96 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 (~6% of those infected are over 5 years of age), but can 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. 97 This vaccine has contributed to a significant decline in the number of new cases of HBV per year in the United States, from approximately 27,000 new cases in 1984 to 4700 new cases in 2006.98 In

the postexposure setting, hepatitis B immune globulin confers approximately 75% protection from HBV infection.99 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 developing chronic infection. The number of new infections per year has declined since the 1980s due to the incorporation of testing of the blood supply for this virus. Fortunately, HCV virus is not transmitted efficiently through occupational exposures to blood, with the seroconversion rate after accidental needlestick reported to be approximately 2%.100 To date, a vaccine to prevent HCV infection has not been developed. Experimental studies in chimpanzees with HCV Ig using a model of needlestick injury have failed to demonstrate a protective effect of this treatment in seroconversion after exposure, and no effective antiviral agents for postexposure prophylaxis are available. Early treatment of infection with INF- has been considered; however, this exposes patients who may not develop HCV infection–related sequelae to the side effects of this drug. 101

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 alternatives to nuclear weapons as weapons of mass destruction, as they are relatively inexpensive to make in terms of infrastructure development. If so, all physicians including surgeons would need to 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. Some potential agents are discussed in the Bacillus anthracis (Anthrax), Yersinia pestis (Plague), Smallpox, and Francisella tularensis (Tularemia) sections that follow.

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 nonspecific symptoms including malaise, myalgia, and fever. Over a short period of time, these symptoms worsen, with development of respiratory distress, chest pain, and diaphoresis. Characteristic chest roentgenographic findings include a widened mediastinum and pleural effusions. A key aspect in establishing the diagnosis is eliciting an exposure history. Rapid antigen tests are currently under development for identification of this gram-positive rod. Drugs such as cephalosporins and trimethoprim-sulfamethoxazole are not active against this agent. Postexposure prophylaxis consists of administration of either ciprofloxacin or doxycycline. 102 If an isolate is demonstrated to be penicillinsensitive, the patient should be switched to amoxicillin. Inhalational exposure followed by the development of symptoms is associated with a high mortality rate. Treatment options include combination therapy with ciprofloxacin, clindamycin, and rifampin, with clindamycin added to block production of toxin, and rifampin for its ability to penetrate the central nervous system and intracellular locations.

Yersinia pestis (Plague) 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 were used, or bubonic plague if fleas were used as carriers. Individuals who develop a painful 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 aminoglycosides, doxycycline, ciprofloxacin, and chloramphenicol.103

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.104 This has resulted in the United States undertaking a vaccination program for key health care workers. 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.105

Francisella tularensis (Tularemia) 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 are seen in approximately 85% of patients. The organism can be cultured from tissue samples, but this is difficult. Alternative diagnosis is based on acute-phase agglutination tests. Treatment of inhalational tularemia consists of administration of aminoglycosides or second-line agents such as doxycycline and ciprofloxacin.

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Schwartz's Principles of Surgery > Part I. Basic Considerations > Chapter 7. Trauma >

KEY POINTS 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. Blunt injuries to the carotid and vertebral arteries are usually managed with systemic antithrombotic therapy. 7. 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. 8. 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. 9. 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 gut edema and ascites). 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.

TRAUMA: INTRODUCTION Trauma, or injury, is defined as cellular disruption caused by an exchange with environmental energy that is beyond the body's resilience. 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. 1 It is also the number one cause of years of productive life lost. The U.S. government classifies injury-related death into the following categories: accidents (unintentional injuries), intentional selfharm (suicide), assault (homicide), legal intervention or war, and undetermined causes. 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 is a poor indicator of the magnitude of the problem, because most injured patients survive. For example, in 2004 there were approximately 167,000 injury-related deaths, but 29.6 million injured patients treated in emergency departments (EDs). 2 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 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 assumption that appropriate and timely care can significantly improve the outcome for the injured patient. 6 ATLS provides a structured approach to the trauma patient with standard algorithms of care; it emphasizes the "golden hour" concept that timely prioritized interventions are necessary to prevent death. The ATLS format and basic tenets are followed throughout this chapter, with minor modifications. The initial management of seriously injured patients consists of the primary survey, concurrent resuscitation, the secondary survey, diagnostic evaluation, and definitive care. 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 the concepts within the primary survey are presented in a sequential fashion, in reality they often proceed simultaneously. Lifethreatening injuries must be identified (Table 7-1) and treated before advancing to the secondary survey. Table 7-1 Immediately Life-Threatening Injuries to Be Identified during the Primary Survey Airway

Airway obstruction Airway injury Breathing Tension pneumothorax Open pneumothorax Flail chest with underlying pulmonary contusion Circulation Hemorrhagic shock Massive hemothorax Massive hemoperitoneum Mechanically unstable pelvis fracture Extremity losses Cardiogenic shock Cardiac tamponade Neurogenic shock Cervical spine injury Disability Intracranial hemorrhage/mass lesion

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. In general, patients who are conscious, do not show tachypnea, and have a normal voice do not require early attention to the airway. Exceptions are patients with penetrating injuries to the neck and an expanding hematoma; evidence of chemical or thermal 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 a satisfactory airway, it may become obstructed if soft tissue swelling, hematoma formation, or edema progresses. In these cases, elective intubation should be performed before evidence of airway compromise. 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 may be relieved by either a chin lift or jaw thrust. An oral airway or a nasal trumpet also can be helpful in maintaining airway patency, although the former is not usually tolerated by an awake patient. Establishment of 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 surgical routes. Nasotracheal intubation can be accomplished only in patients who are breathing spontaneously. Although nasotracheal intubation is frequently used by prehospital providers, the primary application for this technique in the ED is in those patients requiring emergent airway support in whom chemical paralysis cannot be used. Orotracheal intubation is the most common 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 direct laryngoscopy, capnography, audibility of bilateral breath sounds, and finally a chest film. The GlideScope, a video laryngoscope that uses fiberoptics to visualize the vocal cords, is being employed more frequently.7 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 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 surgical establishment of an airway. Cricothyroidotomy (Fig. 7-1) is performed through a generous vertical incision, with sharp division of the subcutaneous tissues and strap muscles. 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 through the space into the airway. 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 tracheostomy tube (maximum diameter in adults) is then advanced through the cricothyroid opening and sutured into place. In patients under the age of 8, cricothyroidotomy is contraindicated due to the risk of subglottic stenosis, and tracheostomy should be performed. Fig. 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 tracheostomy tube or endotracheal tube is inserted after digital confirmation of airway access.

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 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. Fig. 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.

BREATHING AND VENTILATION Once a secure airway is obtained, adequate oxygenation and ventilation must be assured. 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, and flail chest with underlying pulmonary contusion. All of these diagnoses should be made during the initial physical examination. The diagnosis of tension pneumothorax is implied by respiratory distress and hypotension in combination with any of the following physical signs in patients with chest trauma: 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 the superior vena cava, but the neck veins may be flat due to systemic hypovolemia. Vital signs differentiate a tension pneumothorax from a simple pneumothorax; each can 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). In cases of tension pneumothorax, the parenchymal tear in the lung acts as a one-way valve, with each inhalation allowing additional air to 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 results in cardiovascular collapse. Fig. 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 36F chest tube is directed superiorly and posteriorly with the aid of a large clamp.

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. Fig. 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.

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 may be evident in patients with spontaneous ventilation, due to the negative intrapleural pressure of inspiration. Rarely the additional work of breathing and chest wall pain caused by the flail segment is sufficient to compromise ventilation. However, it is the decreased compliance and increased shunt fraction caused by the associated pulmonary contusion that is typically the source of postinjury pulmonary dysfunction. Pulmonary contusion often progresses during the first 12 hours. Resultant hypoventilation and hypoxemia may require presumptive 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. Fig. 7-5.

A. Admission chest film may not show the full extent of the patient's thoracic injury. B. This patient's left pulmonary contusion blossomed 12 hours later, and its associated opacity is noted on repeat chest film.

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 status can be obtained by palpating peripheral pulses. In general, systolic blood pressure (SBP) must be 60 mmHg for the carotid pulse to be palpable, 70 mmHg for the femoral pulse, and 80 mmHg for the radial pulse. At this point in the patient's evaluation, any episode of hypotension (defined as a SBP <90 mmHg) is assumed to be caused by hemorrhage until proven otherwise. Blood pressure and pulse should be measured manually at least every 5 minutes in patients with significant blood loss until normal vital sign values are restored. IV access for fluid resuscitation is obtained with two peripheral catheters, 16-gauge or larger in adults. Blood should be drawn simultaneously and sent for measurement of hematocrit level, as well as for typing and cross-matching for possible blood transfusion in patients with evidence of hypovolemia. According to Poiseuille's law, the flow of liquid through a tube is proportional to the diameter and inversely proportional to the length; therefore, venous lines for volume resuscitation should be short with a large diameter. If peripheral access with large-bore angiocatheters is inadequate, 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 thoracoabdominal procedures. For patients requiring vigorous fluid resuscitation in whom peripheral angiocatheter access is difficult, saphenous vein cutdowns at the ankle provide excellent access (Fig. 7-6). 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 collapsed veins. Additional venous access often is obtained through the femoral or subclavian veins with Cordis introducer catheters. A rule of thumb to consider is placement of femoral access for thoracic trauma and jugular or subclavian access for abdominal trauma. However, placement of jugular or

subclavian central venous catheters provides a more reliable measurement of central venous pressure (CVP), which is helpful in determining the volume status of the patient and excluding cardiac tamponade. In hypovolemic patients under 6 years of age, an intraosseous needle can be placed in the proximal tibia (preferred) or distal femur of an unfractured extremity (Fig. 7-7). Flow through the needle should be continuous and does not require pressure. 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. Fig. 7-6.

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.

Fig. 7-7.

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.

External control of 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 x 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 from 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 open 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. For patients with open fractures, fracture reduction with stabilization via splints will limit bleeding externally and into the subcutaneous tissues. Scalp lacerations through the galea aponeurotica tend to bleed profusely; these can be temporarily controlled with skin staples, Rainey clips, or a large full-thickness continuous running nylon stitch. During the circulation section of the primary survey, four life-threatening injuries that must be identified are (a) massive hemothorax, (b) cardiac tamponade, (c) massive hemoperitoneum, and (d) mechanically unstable pelvic fractures. 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, one third of the patient's blood volume in the pleural space (Fig. 7-8). Although it may be suspected on chest radiograph, tube thoracostomy is the only reliable means to quantify the amount of hemothorax. After blunt trauma, a hemothorax usually is due to multiple rib fractures with severed intercostal arteries, but occasionally bleeding is from lacerated lung parenchyma. After penetrating trauma, a systemic 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 provide some degree of tamponade. Fig. 7-8.

More than 1500 mL of blood in the pleural space is 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 pleural space.

Cardiac tamponade (life-threatening injury number two) occurs most commonly after penetrating thoracic injuries, although occasionally blunt rupture of the heart, particularly the atrial appendage, is seen. Acutely, <100 mL of pericardial blood may cause pericardial tamponade. The classic diagnostic Beck's triad—dilated neck veins, muffled heart tones, and a decline in arterial pressure—often is not observed in the trauma bay because of the noisy environment and 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 leads to decreased right ventricular output and increased CVP. Increased intrapericardial pressure also impedes myocardial blood flow, which leads to subendocardial ischemia and a further reduction in cardiac output. Diagnosis 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. 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, prevent subendocardial ischemia and associated lethal arrhythmias, and allow 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 <70 mmHg warrant emergency department thoracotomy (EDT) with opening of the pericardium to address the injury. Fig. 7-9.

Subxiphoid pericardial ultrasound reveals a large pericardial fluid collection.

Fig. 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.

The utility of EDT has been debated for many years. Current indications are based on 30 years of prospective data (Table 7-2). 7 EDT is associated with the highest survival rate after isolated cardiac injury; 35% of patients presenting in shock and 20% without vital signs (i.e., pulse or obtainable blood pressure) are resuscitated after isolated penetrating injury to the heart. For all penetrating wounds, survival rate is 15%. Conversely, patient outcome is poor when EDT 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 EDT selectively based on injury and transport time (Fig. 7-11). EDT is best accomplished using a left anterolateral thoracotomy, with the incision started to the right of the sternum (Fig. 7-12). A longitudinal pericardiotomy anterior to the phrenic nerve releases cardiac tamponade and allows access to the heart for cardiac repair and open cardiac massage. Cross-clamping of the aorta sustains central circulation, augments cerebral and coronary blood flow, and limits any abdominal blood loss (Fig. 7-13). The patient must sustain an SBP of 70 mmHg after EDT and associated interventions to be considered resuscitatable and hence transported to the OR. 8 Table 7-2 Current Indications and Contraindications for Emergency Department Thoracotomy

Indications Salvageable postinjury cardiac arrest: Patients sustaining witnessed penetrating trauma with <15 min of prehospital CPR Patients sustaining witnessed blunt trauma with <5 min of prehospital CPR !"#$%$&"'& $"("#" )*$&%'+,#- .-)*&"'$%*' /01! 234 55678 9," &*: Cardiac tamponade Hemorrhage—intrathoracic, intra-abdominal, extremity, cervical Air embolism Contraindications Penetrating trauma: CPR >15 min and no signs of life (pupillary response, respiratory effort, motor activity) Blunt trauma: CPR >5 min and no signs of life or asystole CPR = cardiopulmonary resuscitation; SBP = systolic blood pressure. Fig. 7-11.

Algorithm directing the use of emergency department thoracotomy (EDT) in the injured patient undergoing cardiopulmonary resuscitation (CPR). ECG = electrocardiogram; OR = operating room; SBP = systolic blood pressure.

Fig. 7-12.

A. Emergency department thoracotomy 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 repair. 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.

Fig. 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.

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 eye opening. Scores range from 3 (the lowest) to 15 (normal). Scores of 13 to 15 indicate mild head injury, 9 to 12 moderate injury, and <9 severe injury. The GCS is a quantifiable determination of neurologic function that is useful for both triage and prognosis. Table 7-3 Glasgow Coma Scalea Adults Eye opening

Verbal

Infants/Children

4 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

Motor response 6 Obeys commands 5 Localizes pain

Spontaneous, purposeful Localizes pain

4 Withdraws

Withdraws

3 Abnormal flexion

Abnormal flexion

2 Abnormal extension

Abnormal extension

1 None

None

a 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).

Neurologic evaluation before administration of neuromuscular blockade for intubation is critical. 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 re-evaluation 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. 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, mental status changes, diaphoresis, and pallor (Table 7-4). The quantity of acute blood loss correlates with physiologic abnormalities. For example, although patients in class II shock may be tachycardic, they do not exhibit a reduction in blood pressure until over 1500 mL of blood loss, or class III shock. Physical findings should be viewed as a constellation and 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, this is repeated once in an adult and twice in a child before red blood cells (RBCs) are administered. Patients who have a good response to fluid infusion (i.e., normalization of vital signs, clearing of the sensorium) and evidence of good 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 resuscitation-related variable is time dependent, it is more useful in the OR and intensive care unit (ICU) setting than in initial evaluation in the trauma bay. Table 7-4 Signs and Symptoms of Advancing Stages of Hemorrhagic Shock Class I

Class II

Class III

Blood loss (mL)

Up to 750

750–1500

1500–2000

Class IV >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 (mmHg) 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. There are several caveats to be considered and pitfalls to be avoided when evaluating the injured patient for shock. Tachycardia is often the earliest sign of ongoing blood loss. However, 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 despite significant stress. Bradycardia occurs with severe blood loss; 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, hypotension is not a reliable early sign of hypovolemia, because blood volume must decrease by >30% before hypotension occurs. Additionally, younger patients with good sympathetic tone may surprise even the experienced clinician by maintaining SBP 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 blood before manifesting signs and symptoms of hypovolemia (see "Special Trauma Populations" below). 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" below). At the other end of the spectrum are patients classified as "nonresponders" who have persistent hypotension despite aggressive resuscitation. These patients require immediate identification of the source of hypotension with appropriate intervention to prevent a fatal outcome. Patients considered as "transient responders" are those who respond initially to volume loading by an increase in blood pressure only to then hemodynamically deteriorate once more. This group of patients can be challenging to triage

for definitive management.

PERSISTENT HYPOTENSION Patients with ongoing hemodynamic instability, whether "nonresponders" or "transient responders," require systematic evaluation and prompt intervention. The spectrum of disease in patients with persistent hypotension ranges from nonsurvivable 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. 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. In most cases, however, the two broad categories of shock causing persistent hypotension are hemorrhagic and cardiogenic. An evaluation of the CVP will usually distinguish between these two categories. A patient with flat neck veins and a CVP of <5 cm H 2 O is hypovolemic and is likely to have ongoing hemorrhage. A patient with distended neck veins or a CVP of >15 cm H 2 O 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. Serial base deficit measurements also are helpful; a persistent base deficit of >8 mmol/L implies ongoing cellular shock. Evolving technology, such as near infrared spectroscopy, will provide noninvasive monitoring of oxygen delivery to tissue. 9 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 blunt cardiac injury, few such injuries result in hemodynamic embarrassment. Patients with electrocardiographic (ECG) abnormalities or dysrhythmias require continuous ECG monitoring and antidysrhythmic treatment as needed. Unless myocardial infarction is suspected, there is no role for measurement of cardiac enzyme levels—they lack specificity and do not predict significant dysrhythmias.10 The patient with hemodynamic instability requires aggressive resuscitation and may benefit from the placement of a pulmonary artery catheter to optimize preload and guide inotropic support. Echocardiography may be indicated to exclude pericardial tamponade or valvular or septal injuries. It typically demonstrates right ventricular dyskinesia but is less helpful in titrating treatment and monitoring the response to therapy unless done repeatedly. Patients with refractory cardiogenic shock may 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 or undiagnosed lethal complication of pulmonary injury. Air emboli can occur after blunt or penetrating trauma, when 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 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 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 may be 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. Fig. 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.

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 type-specific RBCs, when available, should be administered. In patients with penetrating trauma and clear indications for operation, essential films should be taken and the patient should be transported to the OR immediately. Such patients include those with massive hemothorax, those with initial chest tube output of >1 L with ongoing output of >200 mL/h, and those with abdominal trauma and ultrasound evidence of 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, physical examination and chest radiograph of a patient with a gunshot wound to the right chest must evaluate the left hemithorax. If a patient has 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

in which knives are embedded in the head or neck, preoperative imaging may be useful to exclude arterial injuries. Blunt trauma patients with clear operative indications include hypotensive patients with massive hemothorax and those with a FAST examination documenting extensive free intraperitoneal fluid. Fig. 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. 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 detect 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. 11 Extremity examination and radiographs should be used to search for associated fractures. Fracture-related blood loss, when additive, may be a potential source of the patient's hemodynamic instability. For each rib fracture there is approximately 100 to 200 mL of blood loss; for tibial fractures, 300 to 500 mL; for femur fractures, 800 to 1000 mL; and for pelvic fractures >1000 mL. Although no single injury may appear to cause a patient's hemodynamic instability, the sum of the injuries may result in life-threatening blood loss. The diagnostic measures advocated earlier are those that can be easily performed in the trauma bay. Transport of a hypotensive patient out of the ED for computed tomographic (CT) scanning may be hazardous; monitoring is compromised, and the environment is suboptimal for dealing with acute problems. The surgeon must accompany the patient and be prepared to abort the CT scan with direct transport to the OR. This dilemma is becoming less common in large trauma centers where CT scanning can be accomplished in the ED. The role of treatment of hypotension in the ED remains controversial, and it is primarily relevant for patients with penetrating vascular injuries. Experimental work suggests that an endogenous sealing clot of an injured artery may be disrupted at an SBP of >90 mmHg12 ; thus, many believe that this should be the preoperative blood pressure target for patients with torso arterial injuries. On the other hand, optimal management of traumatic brain injury (TBI) includes maintaining the SBP at >90 mmHg. 13

Secondary Survey 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 head to toe, with special attention to the patient's back, axillae, and perineum, because injuries here are easily overlooked. All potentially seriously injured patients should undergo digital rectal examination to evaluate for sphincter tone, presence of blood, rectal perforation, or a high-riding prostate; this is particularly critical in patients with suspected spinal cord injury, pelvic fracture, or transpelvic gunshot wounds. Vaginal examination with a speculum also should be performed in women with pelvic fractures to exclude an open fracture. Specific injuries, their associated signs and symptoms, diagnostic options, and treatments are discussed in detail later in this chapter. Adjuncts to the physical examination include vital sign and CVP monitoring, ECG monitoring, nasogastric tube placement, Foley catheter placement, repeat FAST, laboratory measurements, and radiographs. A nasogastric tube should be inserted in all intubated patients to decrease the risk of gastric aspiration but may not be indicated in the awake patient. Nasogastric tube placement in patients with complex facial fractures is contraindicated; rather, a tube should be placed orally if required. Nasogastric tube evaluation of stomach contents for blood may suggest occult gastroduodenal injury or the path of the nasogastric tube on a chest film may suggest a diaphragm injury. A Foley catheter should be inserted in patients unable to void to decompress the bladder, obtain a urine specimen, and monitor urine output. Gross hematuria demands evaluation of the genitourinary system for injury. Foley catheter placement should be deferred until urologic evaluation in patients with signs of urethral injury: blood at the meatus, perineal or scrotal hematomas, or a high-riding prostate. Although policies vary at individual institutions, patients in extremis with need for Foley catheter placement should undergo one attempt at catheterization; if the catheter does not pass easily, a percutaneous suprapubic cystostomy should be considered. Repeat FAST is performed if there are any signs of abdominal injury or occult blood loss. Selective radiography and laboratory tests are done early in the evaluation after the primary survey. For patients with severe blunt trauma, lateral cervical spine, chest, and pelvic radiographs should be obtained, often termed the big three. For patients with truncal gunshot wounds, anteroposterior and lateral radiographs of the chest and abdomen are warranted. It is important to mark the entrance and exit sites of penetrating wounds with ECG pads, metallic clips, or staples so that the trajectory of the missile can be estimated. Limited one-shot extremity radiographs also may be taken. In critically injured patients, blood samples for a routine trauma panel (type and cross-match, complete blood count, blood chemistries, coagulation studies, lactate level, and arterial blood gas analysis) should be sent to the laboratory. For less severely injured patients only a complete blood count and urinalysis may be required. Because older patients may present in subclinical shock, even with minor injuries, routine analysis of arterial blood gases in patients over the age of 55 should be considered. Many trauma patients cannot provide specific information about the mechanism of their injury. Emergency medical service personnel and police are trained to evaluate an injury scene and should be questioned. For automobile collisions, the speed of the vehicles involved, angle of impact (if any), use of restraints, airbag deployment, condition of the steering wheel and windshield, amount of intrusion, ejection or nonejection of the patient from the vehicle, and fate of other passengers should all be ascertained. For other injury mechanisms, critical information includes such things as height of a fall, surface impact, helmet use, and weight of an object by which the patient was crushed. In patients sustaining gunshot wounds, velocity, caliber, and presumed path of the bullet are important, if known. For patients with stab wounds, the length and type of object is helpful. Finally, some patients experience a combination of blunt and penetrating trauma. Do not assume that someone who was stabbed was not also assaulted; the patient may have a multitude of injuries and cannot be presumed to have only injuries associated with the more obvious penetrating mechanism. In sum, these details of information are critical to the clinician to determine overall mechanism of injury and anticipate its associated injury patterns.

Mechanisms and Patterns of Injury In general, more energy is transferred over a wider area during blunt trauma than from a gunshot or stab wound. As a result, blunt trauma is associated with multiple widely distributed injuries, whereas in penetrating wounds the damage is localized to the path of the bullet or knife. In blunt trauma, organs that cannot yield to impact by elastic deformation are most likely to be injured, namely, the solid organs (liver, spleen, and kidneys). For penetrating trauma, organs with the largest surface area when viewed from the front are most prone to injury (small bowel, liver, and colon). Additionally, because bullets and knives usually follow straight lines, adjacent structures are commonly injured (e.g., the pancreas and duodenum). Trauma surgeons often separate patients who have sustained blunt trauma into categories according to their risk for multiple injuries: those sustaining high energy transfer injuries and those sustaining low energy transfer injuries. Injuries involving high energy transfer include auto-pedestrian accidents, motor vehicle collisions in which the car's change of velocity ( V) exceeds 40 km/h or in which the patient has been ejected, motorcycle collisions, and falls from heights >20 ft. 14 In fact, for motor vehicle accidents the variables strongly associated with life-threatening injuries, and hence reflective of the magnitude of the mechanism, are death of another occupant in the vehicle, extrication time of >20 minutes,

V >40 km/h, lack of restraint use, and lateral impact.14 Low-energy trauma, such as being struck with a club or falling from a

bicycle, usually does not result in widely distributed injuries. However, potentially lethal lacerations of internal organs still can occur, because the net energy transfer to any given location may be substantial. In blunt trauma, particular constellations of injury or injury patterns are associated with specific injury mechanisms. Frontal impact collisions typically produce multisystem trauma. When an unrestrained driver sustains a frontal impact, the head strikes the windshield, the chest and upper abdomen hit the steering column, and the legs or knees contact the dashboard. The resultant injuries can include facial fractures, cervical spine fractures, laceration of the thoracic aorta, myocardial contusion, injury to the spleen and liver, and fractures of the pelvis and lower extremities. When such patients are evaluated, the discovery of one of these injuries should prompt a search for others. Collisions with side impact also carry the risk of cervical spine and thoracic trauma, diaphragm rupture, and crush injuries of the pelvic ring, but solid organ injury usually is limited to either the liver or spleen based on the direction of impact. Not surprisingly, any time a patient is ejected from the vehicle or thrown a significant distance from a motorcycle, the risk of any injury increases. Penetrating injuries are classified according to the wounding agent (i.e., stab wound, gunshot wound, or shotgun wound). Gunshot wounds are subdivided further into highand low-velocity injuries, because the speed of the bullet is much more important than its weight in determining kinetic energy. High-velocity gunshot wounds (bullet speed >2000 ft/s) are infrequent in the civilian setting. Shotgun injuries are divided into close-range (<7 m) and long-range wounds. Close-range shotgun wounds are tantamount

to high-velocity wounds because the entire energy of the load is delivered to a small area, often with devastating results. Long-range shotgun blasts result in a diffuse pellet pattern in which many pellets miss the victim, and those that do strike are dispersed and of comparatively low energy.

Regional Assessment and Special Diagnostic Tests Based on mechanism, location of injuries identified on physical examination, screening radiographs, and the patient's overall condition, additional diagnostic studies often are indicated. However, the seriously injured patient is in constant jeopardy when undergoing special diagnostic testing; therefore, the surgeon must be in attendance and must be prepared to alter plans as circumstances demand. Hemodynamic, respiratory, and mental status will determine the most appropriate course of action. With these issues in mind, additional diagnostic tests are discussed on an anatomic basis.

HEAD Evaluation of the head includes examination for injuries to the scalp, eyes, ears, nose, mouth, facial bones, and intracranial structures. Palpation of the head will identify scalp lacerations, which should be evaluated for depth, and depressed or open skull fractures. The eye examination includes not only pupillary size and reactivity, but also examination for visual acuity and for hemorrhage within the globe. Ocular entrapment, caused by orbital fractures with impingement on the ocular muscles, is evident when the patient cannot move his or her eyes through the entire range of motion. It is important to perform the eye examination early, because significant orbital swelling may prevent later evaluation. The tympanic membrane is visualized to identify hemotympanum, otorrhea, or rupture, which may signal an underlying head injury. Otorrhea, rhinorrhea, raccoon eyes, and Battle's sign (ecchymosis behind the ear) suggest a basilar skull fracture. Although such fractures may not require treatment, there is an association with blunt cerebrovascular injuries and a small risk of development of meningitis. Anterior facial structures should be examined to rule out fractures. This entails palpating for bony step-off of the facial bones and instability of the midface (by grasping the upper palate and seeing if this moves separately from the patient's head). A good question to ask awake patients is whether their bite feels normal to them; abnormal dental closure suggests malalignment of facial bones and a possibility for a mandible or maxillary fracture. Nasal fractures, which may be evident on direct inspection or palpation, typically bleed vigorously. This may result in the patient's having airway compromise due to blood running down the posterior pharynx, or there may be vomiting provoked by swallowed blood. Nasal packing or balloon tamponade may be necessary to control bleeding. Examination of the oral cavity includes inspection for open fractures, loose or fractured teeth, and sublingual hematomas. All patients with a significant closed head injury (GCS score <14) should undergo CT scanning of the head. For penetrating injuries, plain skull films may be helpful in the trauma bay to determine the extent of injury in hemodynamically unstable patients who cannot be transported for CT scan. The presence of lateralizing findings (e.g., a unilateral dilated pupil unreactive to light, asymmetric movement of the extremities either spontaneously or in response to noxious stimuli, or unilateral Babinski's reflex) suggests an intracranial mass lesion or major structural damage. Such lesions include hematomas, contusions, hemorrhage into ventricular and subarachnoid spaces, and diffuse axonal injury (DAI). Epidural hematomas occur when blood accumulates between the skull and dura, and are caused by disruption of the middle meningeal artery or other small arteries in that potential space, typically after a skull fracture (Fig. 7-16). Subdural hematomas occur between the dura and cortex and are caused by venous disruption or laceration of the parenchyma of the brain. Due to associated parenchymal injury, subdural hematomas typically have a worse prognosis than epidural collections. Hemorrhage into the subarachnoid space may cause vasospasm and reduce cerebral blood flow. Intraparenchymal hematomas and contusions can occur anywhere within the brain. DAI results from high-speed deceleration injury and represents direct axonal damage. CT scan may demonstrate blurring of the gray and white matter interface and multiple small punctate hemorrhages, but magnetic resonance imaging is a more sensitive test. Although prognosis for these injuries is extremely variable, early evidence of DAI is associated with a poor outcome. Stroke syndromes should prompt a search for carotid or vertebral artery injury using standard four-vessel angiography or 16-slice CT angiography (Fig. 7-17). Fig. 7-16.

Epidural hematomas (A) have a distinctive convex shape on computed tomographic scan, whereas subdural hematomas (B) are concave along the surface of the brain.

Fig. 7-17.

A. A right middle cerebral infarct noted on a computed tomographic scan of the head. Such a finding should prompt imaging to rule out an associated extracranial cerebrovascular injury. B. An internal carotid artery pseudoaneurysm documented by angiography. Significant intracranial penetrating injuries usually are produced by bullets from handguns, but an array of other weapons or instruments can injure the cerebrum via the orbit or through the thinner temporal region of the skull. Although the diagnosis usually is obvious, in some instances wounds in the auditory canal, mouth, and nose can be elusive. Prognosis is variable, but most supratentorial wounds that injure both hemispheres are fatal.

NECK All blunt trauma patients should be assumed to have cervical spine injuries until proven otherwise. During cervical examination one must maintain cervical spine precautions and in-line stabilization. During the primary survey, identification of penetrating injuries to the neck with exsanguination, expanding hematomas, and airway obstruction is a priority. A more subtle injury that may not be identified is a fracture of the larynx due to blunt trauma. Signs and symptoms include hoarseness, subcutaneous emphysema (Fig. 7-18), and a palpable fracture. Fig. 7-18.

A laryngeal fracture results in air tracking around the trachea along the prevertebral space (arrows).

Due to the devastating consequences of quadriplegia, a diligent evaluation for occult cervical spine injuries is mandatory. In the awake patient, the presence of posterior midline pain or tenderness should provoke a thorough radiologic evaluation. Additionally, intubated patients, patients experiencing trauma associated with significant injury mechanisms, and patients with distracting injuries or another identified spine fracture should undergo imaging. Imaging options include CT scan or five plain radiograph views of the cervical spine: lateral view with visualization of C7 through T1, anteroposterior view, transoral odontoid views, and bilateral oblique views. If pain or tenderness persists but no injuries are identified on plain radiographs, or if the patient cannot be examined in a timely manner, a CT scan should be performed. However, a ligamentous injury may not be visible with standard imaging techniques. 15 Flexion and extension views are typically obtained after a delay in patients with persistent pain but negative imaging findings. However, this should be done only in the presence of an experienced spinal surgeon, because patients can be rendered permanently quadriplegic when flexed and extended by inexperienced individuals.

Spinal cord injuries can be complete or partial. Complete injuries cause either permanent quadriplegia or paraplegia, depending on the level of injury. These patients have a complete loss of motor function and sensation two or more levels below the bony injury. Patients with high spinal cord disruption are at risk for shock due to physiologic disruption of sympathetic fibers. Significant neurologic recovery is rare. There are several partial or incomplete spinal cord injury syndromes. Central cord syndrome usually occurs in older persons who experience hyperextension injuries. Motor function and pain and temperature sensation are preserved in the lower extremities but diminished in the upper extremities. Some functional recovery usually occurs, but is often not a return to normal. Anterior cord syndrome is characterized by diminished motor function and pain and temperature sensation below the level of the injury, but position sensing, vibratory sensation, and crude touch are maintained. Prognosis for recovery is poor. Brown-Séquard syndrome is usually the result of a penetrating injury in which the right or left half of the spinal cord is transected. This rare lesion is characterized by the ipsilateral loss of motor function, proprioception, and vibratory sensation, whereas pain and temperature sensation are lost on the contralateral side. Penetrating injuries of the anterior neck that violate the platysma are potentially life-threatening because of the density of critical structures in this region. Although presumptive exploration may be appropriate in some circumstances, selective nonoperative management is practiced in most centers (Fig. 7-19). 16,17 Indications for immediate operative intervention for penetrating cervical injury include hemodynamic instability or significant external 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 (Fig. 7-20). Zone I is between the clavicles and cricoid cartilage, zone II is between the cricoid cartilage and the angle of the mandible, and zone III is above the angle of the mandible. Due to technical difficulties of injury exposure and varying operative approaches, a precise preoperative diagnosis is desirable for symptomatic zone I and III injuries. Therefore, these patients should ideally undergo diagnostic imaging before operation if they remain hemodynamically stable. CT scanning of the neck and chest determines the injury track, and further studies are performed based on proximity to major structures. 18 Such additional imaging includes CT angiography, angiography of the great vessels, soluble contrast esophagram followed by barium esophagram, esophagoscopy, or bronchoscopy. Angiographic diagnosis, particularly of zone III injuries, may be followed by endovascular intervention for definitive treatment. Fig. 7-19.

Algorithm for the selective management of penetrating neck injuries. CT = computed tomography; CTA = computed tomographic angiography; GSW = gunshot wound; IR Embo = interventional radiology embolization.

Fig. 7-20.

For the purpose of evaluating penetrating injuries, the neck is divided into three zones. Zone I is up to the level of the cricoid and is also known as the thoracic outlet. Zone II is located between the cricoid cartilage and the angle of the mandible. Zone III is above the angle of the mandible. Patients with zone II wounds that do not penetrate the platysma can be discharged from the ED. Patients with zone II penetrating wounds are divided into those who are symptomatic and those who are not. Specific symptoms that should be elucidated include airway compromise, an expanding or pulsatile hematoma, dysphagia, hoarseness, and subcutaneous emphysema. Symptomatic patients should undergo emergent neck exploration. Asymptomatic patients with zone II injuries should be further divided into those with and those without a transcervical gunshot wound. Those without a transcervical component may be observed for 12 to 24 hours, whereas those with transcervical gunshot wounds should undergo CT scanning to determine the track of the bullet. Based on location of the track and transfer of kinetic injury, further diagnostic imaging with angiography, esophagram, or bronchoscopy should be performed.

CHEST Blunt trauma to the chest may involve the chest wall, thoracic spine, heart, lungs, thoracic aorta and great vessels, and rarely the esophagus. Most of these injuries can be evaluated by physical examination and chest radiography, with supplemental CT scanning based on initial findings. Any patient who undergoes intervention—intubation, central line placement, tube thoracostomy—needs a repeat chest radiograph to document the adequacy of the procedure. This is particularly true in patients undergoing tube thoracostomy for a pneumothorax or hemothorax. Patients with persistent pneumothorax, large air leaks after tube thoracostomy, or difficulty ventilating should undergo fiber-optic bronchoscopy to exclude a bronchial injury or presence of a foreign body. Patients with hemothorax must have a chest radiograph documenting complete evacuation of the chest; a persistent hemothorax that is not drained by two chest tubes is termed a caked hemothorax and mandates prompt thoracotomy (Fig. 7-21). Fig. 7-21.

Persistence of a hemothorax despite two tube thoracostomies is termed a caked hemothorax and is an indication for prompt thoracotomy.

Occult thoracic vascular injury must be diligently sought due to the high mortality of a missed lesion. Widening of the mediastinum on initial anteroposterior chest radiograph, caused by a hematoma around an injured vessel that is contained by the mediastinal pleura, suggests an injury of the great vessels. The mediastinal abnormality may suggest the location of the arterial injury (i.e., left-sided hematomas are associated with descending torn aortas, whereas right-sided hematomas are commonly seen with innominate injuries) (Fig. 7-22). Posterior rib fractures, sternal fractures, and laceration of small vessels also can produce similar hematomas. Other chest radiographic findings suggestive of an aortic tear are summarized in Table 7-5 (Fig. 7-23). However, at least 7% of patients with a descending torn aorta have a normal chest radiograph. 19 Therefore, screening spiral CT scanning is performed based on the mechanism of injury: high-energy deceleration motor vehicle collision with frontal or lateral impact, motor vehicle collision with ejection, falls of >25 ft, or direct impact (horse kick to chest, snowmobile or ski collision with tree).20 In >95% of patients who survive to reach the ED, the aortic injury occurs just distal to the left subclavian artery, where it is tethered by the ligamentum arteriosum (Fig. 7-24). In 2 to 5% of patients the injury occurs in the ascending aorta, in the transverse arch, or at the diaphragm. Reconstructions with multislice CT scanning obviate the need for invasive angiography. 20 Fig. 7-22.

Location of the hematoma within the mediastinal silhouette suggests the type of great vessel injury. A predominant hematoma on the left suggests the far more common descending torn aorta (A;arrows), whereas a hematoma on the right indicates a relatively unusual but life-threatening innominate artery injury (B;arrows).

Table 7-5 Findings on Chest Radiograph Suggestive of a Descending Thoracic Aortic Tear 1. Widened mediastinum 2. Abnormal aortic contour 3. Tracheal shift 4. Nasogastric tube shift 5. Left apical cap 6. Left or right paraspinal stripe thickening 7. Depression of the left main bronchus 8. Obliteration of the aorticopulmonary window 9. Left pulmonary hilar hematoma

Fig. 7-23.

Chest film findings associated with descending torn aorta include apical capping (A;arrows) and tracheal shift (B;arrows).

Fig. 7-24.

Imaging to diagnose descending torn aorta includes computed tomographic angiography (A), with three-dimensional reconstructions (B, anterior; C, posterior) demonstrating the proximal and distal extent of the injury (arrows). For penetrating thoracic trauma physical examination, plain posteroanterior and lateral chest radiographs with metallic markings of entrance and exit wounds, pericardial ultrasound, and CVP measurement will identify the majority of injuries. Injuries of the esophagus and trachea are exceptions. Bronchoscopy should be performed to evaluate the trachea in patients with a persistent air leak from the chest tube or mediastinal air. Because esophagoscopy can miss injuries, patients at risk should undergo soluble contrast esophagraphy followed by barium examination to look for extravasation of contrast to identify an injury. 21 As with neck injuries, hemodynamically stable patients with transmediastinal gunshot wounds should undergo CT scanning to determine the path of the bullet; this identifies the vascular or visceral structures at risk for injury and directs angiography or endoscopy as appropriate. If there is a suspicion of a subclavian artery injury, brachial-brachial indices should be measured, but >60% of patients with an injury may not have a pulse deficit.22 Therefore, CT angiography should be performed based on injury proximity to intrathoracic vasculature. Finally, despite entry wounds on the chest, penetrating trauma should not be presumed to be isolated to the thorax. Injury to contiguous body cavities (i.e., the abdomen and neck) must be excluded.

ABDOMEN The abdomen is a diagnostic black box. Fortunately, with few exceptions, it is not necessary to determine in the ED which intra-abdominal organs are injured, only whether an exploratory laparotomy is necessary. Physical examination of the abdomen is unreliable in making this determination, and drugs, alcohol, and head and spinal cord injuries complicate clinical evaluation. However, the presence of abdominal rigidity or hemodynamic compromise is an indication for prompt surgical exploration. For the remainder of patients, a variety of diagnostic adjuncts are used to identify abdominal injury. The diagnostic approach differs for penetrating trauma and blunt abdominal trauma. As a rule, minimal evaluation is required before laparotomy for gunshot or shotgun wounds that penetrate the peritoneal cavity, because over 90% of patients have significant internal injuries. Anterior truncal gunshot wounds between the fourth intercostal space and the pubic symphysis whose trajectory as determined by radiograph or entrance and exit wounds indicates peritoneal penetration should be operatively explored (Fig. 7-25). The exception is penetrating trauma isolated to the right upper quadrant; in hemodynamically stable patients with bullet trajectory confined to the liver by CT scan, nonoperative observation may be considered. 23,24 Gunshot wounds to the back or flank are more difficult to evaluate because of the retroperitoneal location of the injured abdominal organs. Triple-contrast CT scan can delineate the trajectory of the bullet and identify peritoneal violation or retroperitoneal entry, but may miss specific injuries.25 Similarly, in obese patients, if the gunshot wound is thought to be tangential through the subcutaneous tissues, CT scan can delineate the track and exclude peritoneal violation. Laparoscopy is another option to assess peritoneal penetration and is followed by laparotomy to repair injuries if found. If there is doubt, it is always safer to explore the abdomen than to equivocate. Fig. 7-25.

Algorithm for the evaluation of penetrating abdominal injuries. AASW = anterior abdominal stab wound; CT = computed tomography; DPL = diagnostic peritoneal lavage; GSW = gunshot wound; LWE = local wound exploration; RUQ = right upper quadrant; SW = stab wound.

In contrast to gunshot wounds, stab wounds that penetrate the peritoneal cavity are less likely to injure intra-abdominal organs. Anterior abdominal stab wounds (from costal margin to inguinal ligament and bilateral midaxillary lines) should be explored under local anesthesia in the ED to determine if the fascia has been violated. Injuries that do not penetrate the peritoneal cavity do not require further evaluation, and the patient is discharged from the ED. Patients with fascial penetration must be further evaluated for intra-abdominal injury, because there is up to a 50% chance of requiring laparotomy. Debate remains over whether the optimal diagnostic approach is serial examination, diagnostic peritoneal lavage (DPL), or CT scanning. 26 If DPL is pursued, an infraumbilical approach is used (Fig. 7-26). After placement of the catheter, a 10mL syringe is connected and the abdominal contents aspirated (termed a diagnostic peritoneal aspiration). The aspirate is considered to show positive findings if >10 mL of blood is aspirated. If <10 mL is withdrawn, a liter of normal saline is instilled. The effluent is withdrawn via siphoning and sent to the laboratory for RBC count, white blood cell (WBC) count, and determination of amylase, bilirubin, and alkaline phosphatase levels. Values representing positive findings are summarized in Table 7-6. Fig. 7-26.

Diagnostic peritoneal lavage is performed through an infraumbilical incision unless the patient has a pelvic fracture or is pregnant. A. The linea alba is sharply incised, and the catheter is directed into the pelvis. B. The abdominal contents should initially be aspirated using a 10-mL syringe.

Table 7-6 Criteria for "Positive" Finding on Diagnostic Peritoneal Lavage Anterior Abdominal Stab Wounds Thoracoabdominal Stab Wounds Red blood cell count

>100,000/mL

>10,000/mL

White blood cell count

>500/mL

>500/mL

Amylase level

>19 IU/L

>19 IU/L

Alkaline phosphatase level

>2 IU/L

>2 IU/L

Bilirubin level

>0.01 mg/dL

>0.01 mg/dL

Abdominal stab wounds in three body regions require a unique diagnostic approach: thoracoabdominal stab wounds, right upper quadrant stab wounds, and back and flank stab wounds. Occult injury to the diaphragm must be ruled out in patients with stab wounds to the lower chest. For patients undergoing DPL evaluation, laboratory value cutoffs are different for those with thoracoabdominal stab wounds and for those with standard anterior abdominal stab wounds (see Table 7-6). An RBC count of >10,000/ L is considered a positive finding and an indication for laparotomy; patients with a DPL RBC count between 1000/ L and 10,000/ L should undergo laparoscopy or thoracoscopy. Patients with stab wounds to the right upper quadrant can undergo CT scanning to determine trajectory and confinement to the liver for potential nonoperative care. 23,24 Those with stab wounds to the flank and back should undergo triple-contrast CT to detect occult retroperitoneal injuries of the colon, duodenum, and urinary tract. 25 Blunt abdominal trauma initially is evaluated by FAST examination in most major trauma centers, and this has largely supplanted DPL (Fig. 7-27). 27 FAST is not 100% sensitive, however, so diagnostic peritoneal aspiration is still advocated in hemodynamically unstable patients without a defined source of blood loss to rule out abdominal hemorrhage.11 FAST is used to identify free intraperitoneal fluid (Fig. 7-28) in Morison's pouch, the left upper quadrant, and the pelvis. Although this method is exquisitely sensitive for detecting intraperitoneal fluid of >250 mL, it does not reliably determine the source of hemorrhage nor grade solid organ injuries.28,29 Patients with fluid on FAST examination, considered a "positive FAST," who do not have immediate indications for laparotomy and are hemodynamically stable undergo CT scanning to quantify their injuries. Injury grading using the American Association for the Surgery of Trauma grading scale (Table 7-7) is a key component of nonoperative management of solid organ injuries. Additional findings that should be noted on CT scan in patients with solid organ injury include contrast extravasation (i.e., a "blush"), the amount of intraabdominal hemorrhage, and presence of pseudoaneurysms (Fig. 7-29). CT also is indicated for hemodynamically stable patients for whom the physical examination is unreliable. Despite the increasing diagnostic accuracy of multislice CT scanners, CT still has limited sensitivity for identification of intestinal injuries. Bowel injury is suggested by findings of thickened bowel wall, "streaking" in the mesentery, free fluid without associated solid organ injury, or free intraperitoneal air.30 Patients with free intraabdominal fluid without solid organ injury are closely monitored for evolving signs of peritonitis; if patients have a significant closed head injury or cannot be serially examined, DPL should be performed to exclude bowel injury. Fig. 7-27.

Algorithm for the initial evaluation of a patient with suspected blunt abdominal trauma. CT = computed tomography; DPA = diagnostic peritoneal aspiration; FAST = focused abdominal sonography for trauma; Hct = hematocrit.

Fig. 7-28.

Focused abdominal sonography for trauma imaging detects intra-abdominal hemorrhage. Hemorrhage is presumed when a fluid stripe is visible between the right kidney and liver (A), between the left kidney and spleen (B), or in the pelvis (C).

Table 7-7 American Association for the Surgery of Trauma Grading Scales for Solid Organ Injuries Subcapsular Hematoma

Laceration

<10% of surface area

<1 cm in depth

Liver Injury Grade Grade I Grade II

10–50% of surface area

1–3 cm

Grade III

>50% of surface area or >10 cm in depth

>3 cm

Grade IV

25–75% of a hepatic lobe

Grade V

>75% of a hepatic lobe

Grade VI

Hepatic avulsion

Splenic Injury Grade Grade I

<10% of surface area

<1 cm in depth

Grade II

10–50% of surface area

1–3 cm

Grade III

>50% of surface area or >10 cm in depth

>3 cm

Grade IV

>25% devascularization

Hilum

Grade V

Shattered spleen Complete devascularization

Fig. 7-29.

Computed tomographic images reveal critical information about solid organ injuries, such as associated contrast extravasation from a grade IV laceration of the spleen (A;arrows) and the amount of subcapsular hematoma in a grade III liver laceration (B;arrows).

PELVIS Blunt injury to the pelvis may produce complex fractures with major hemorrhage (Fig. 7-30). Plain radiographs will reveal gross abnormalities, but CT scanning may be necessary to determine the precise geometry. Sharp spicules of bone can lacerate the bladder, rectum, or vagina. Alternatively, bladder rupture may result from the direct blow to the torso if the bladder is full. CT cystography is performed if the urinalysis findings are positive for RBCs. Urethral injuries are suspected if examination reveals blood at the meatus, scrotal or perineal hematomas, or a high-riding prostate on rectal examination. Urethrograms should be obtained for stable patients before placing a Foley catheter to avoid false passage and subsequent stricture. Major vascular injuries causing exsanguination are uncommon in blunt pelvic trauma; however, thrombosis of either the arteries or veins in the iliofemoral system may occur, and CT angiography or formal angiography is diagnostic. Life-threatening hemorrhage can be associated with pelvic fractures and may initially preclude definitive imaging. Treatment algorithms for patients with complex pelvic fractures and hemodynamic instability are presented later in the chapter. Fig. 7-30.

The three types of mechanically unstable pelvis fractures are lateral compression (A), anteroposterior compression (B), and vertical shear (C).

EXTREMITIES Blunt or penetrating trauma to the extremities requires an evaluation for fractures, ligamentous injury, and neurovascular injury. Plain radiographs are used to evaluate fractures, whereas ligamentous injuries, particularly those of the knee and shoulder, can be imaged with magnetic resonance imaging. Physical examination often identifies arterial injuries, and findings are classified as either hard signs or soft signs of vascular injury (Table 7-8). In general, hard signs constitute indications for operative exploration, whereas soft signs are indications for further testing or observation. Bony fractures or knee dislocations should be realigned before definitive vascular examination. On-table angiography may be useful to localize the arterial injury and thus limit tissue dissection in patients with hard signs of vascular injury. For example, a patient with an absent popliteal pulse and femoral shaft fracture due to a bullet that entered the lateral hip and exited below the medial knee could have injured either the femoral or popliteal artery anywhere along its course (Fig. 7-31). Table 7-8 Signs and Symptoms of Peripheral Arterial Injury Hard Signs

Soft Signs

(Operation Mandatory)

(Further Evaluation Indicated)

Pulsatile hemorrhage

Proximity to vasculature

Absent pulses

Significant hematoma

Acute ischemia

Associated nerve injury A-A index of <0.9 Thrill or bruit

A-A index = systolic blood pressure on the injured side compared with that on the uninjured side. Fig. 7-31.

On-table angiography in the operating room isolates the area of vascular injury to the superficial femoral artery in a patient with a femoral fracture. In management of vascular trauma, controversy exists regarding the treatment of patients with soft signs of injury, particularly those with injuries in proximity to major vessels. It is known that some of these patients will have arterial injuries that require repair. One approach has been to measure SBP using Doppler ultrasonography and compare the value for the injured side with that for the uninjured side, termed the A-A index.31 If the pressures are within 10% of each other, a significant injury is unlikely and no further evaluation is performed. If the difference is >10%, CT angiography or arteriography is indicated. Others argue that there are occult injuries, such as pseudoaneurysms or injuries of the profunda femoris or peroneal arteries, which may not be detected with this technique. If hemorrhage occurs from these injuries, compartment syndrome and limb loss may occur. Although busy trauma centers continue to debate this issue, the surgeon who is obliged to treat the occasional injured patient may be better served by performing CT angiography in selected patients with soft signs.

GENERAL PRINCIPLES OF MANAGEMENT Over the past 20 years there has been a remarkable change in management practices and operative approach for the injured patient. With the advent of CT scanning, nonoperative management of solid organ injuries has replaced routine operative exploration. Those patients who do require operation may be treated with less radical

resection techniques such as splenorrhaphy or partial nephrectomy. Colonic injuries, previously mandating colostomy, are now repaired primarily in virtually all cases. Additionally, the type of anastomosis has shifted from a double-layer closure to a continuous running single-layer closure; this method is technically equivalent to and faster than the interrupted multilayer techniques. 32 Adoption of damage control surgical techniques in physiologically deranged patients has resulted in limited initial operative time, with definitive injury repair delayed until after resuscitation in the surgical intensive care unit (SICU) with physiologic restoration. 33 Abdominal drains, once considered mandatory for parenchymal injuries and some anastomoses, have disappeared; fluid collections are managed by percutaneous techniques. Newer endovascular techniques such as stenting of arterial injuries and angioembolization are routine adjuncts. Blunt cerebrovascular injuries have been recognized as a significant, preventable source of neurologic morbidity and mortality. The use of preperitoneal pelvic packing for unstable pelvic fractures as well as early fracture immobilization with external fixators are paradigm shifts in management. Finally, the institution of massive transfusion protocols balances the benefit of blood component therapy against immunologic risk. These conceptual changes have significantly improved survival of critically injured patients; they have been promoted and critically reviewed by academic trauma centers via forums such as the American College of Surgeons Committee on Trauma, the American Association for the Surgery of Trauma, the International Association of Trauma Surgery and Intensive Care, the Pan-American Trauma Congress, and other surgical organizations.

Transfusion Practices Injured patients with life-threatening hemorrhage may develop marked coagulopathy requiring clotting factor replacement. Fresh whole blood, arguably the optimal replacement, is no longer available in the United States. Rather, its component parts, packed red blood cells (PRBCs), fresh-frozen plasma, platelets, and cryoprecipitate, are administered. Specific transfusion triggers for individual blood components exist. Although current critical care guidelines indicate that PRBC transfusion should occur once the patient's hemoglobin level is <7 g/dL, 34 in the acute phase of resuscitation the endpoint is 10 g/dL. 35 Fresh-frozen plasma is transfused to keep the patient's International Normalized Ratio (INR) less than 1.5 and partial thromboplastin time (PTT) <45 seconds. Primary hemostasis relies on platelet adherence and aggregation to injured endothelium, and a platelet count of 50,000/ L is considered adequate if platelet function is normal. With massive transfusion, however, platelet dysfunction is common, and therefore a target of 100,000/ L is advocated. If fibrinogen levels drop below 100 mg/dL, cryoprecipitate should be administered. Such guidelines are designed to limit the transfusion of immunologically active blood components and decrease the risk of transfusion-associated lung injury and multiple organ failure. 36,37 In the critically injured patient requiring large amounts of blood component therapy, a massive transfusion protocol should be followed (Fig. 7-32). This approach calls for administration of various components in a specific ratio during transfusion to achieve restoration of blood volume and correction of coagulopathy. Although the optimal ratio is yet to be determined, 38 the majority of trauma centers use a presumptive 1:1 or 1:2 red cell:plasma ratio in patients at risk for massive transfusion (10 units of PRBCs in 6 hours). Because complete typing and cross-matching takes up to 45 minutes, patients requiring emergent transfusions are given type O, type-specific, or biologically compatible RBCs. Blood typing, and to a lesser extent cross-matching, is essential to avoid life-threatening intravascular hemolytic transfusion reactions. Trauma centers and their associated blood banks must have the capability of transfusing tremendous quantities of blood components, because it is not unusual to have 100 component units transfused during one procedure and have the patient survive. Massive transfusion protocols, established preemptively, permit coordination of the activities of surgeons, anesthesiologists, and blood bank directors to facilitate transfusion at these rates should a crisis occur. Fig. 7-32.

Denver Health Medical Center's Massive Transfusion Protocol. ACT = activated clotting time; Cryo = cryoprecipitate; EPL = estimated percent lysis; FFP = fresh-frozen plasma; INR = International Normalized Ratio; MA = maximum amplitude; PRBCs = packed red blood cells; PTT = partial thromboplastin time; SBP = systolic blood pressure. Postinjury coagulopathy is associated with core hypothermia and metabolic acidosis, termed the bloody vicious cycle. 33 The pathophysiology is multifactorial and includes inhibition of temperature-dependent enzyme-activated coagulation cascades, platelet dysfunction, endothelial abnormalities, and a poorly understood fibrinolytic activity. Such coagulopathy may be insidious, so the surgeon must be cognizant of subtle signs such as excessive bleeding from the cut edges of skin. Although the coagulopathic "ooze" may seem minimal compared with the torrential hemorrhage from a hole in the aorta, blood loss from the entire area of dissection can lead to exsanguination. Obtaining results for the usual laboratory tests of coagulation capability (i.e., INR, PTT, and platelet count) requires approximately 30 minutes. Such a delay is particularly troublesome for patients who have lost two blood volumes while waiting for the test results to return. Under such conditions, transfusion of fresh-frozen plasma and platelets must be empiric. Using damage control techniques to limit operative time and provide physiologic restoration in the SICU can be life saving (see "Damage Control Surgery" later).

Prophylactic Measures All injured patients undergoing an operation should receive preoperative antibiotics. The type of antibiotic is determined by the anticipated source of contamination in the abdomen or other operative region; additional doses should be administered during the procedure based on blood loss and the half-life of the antibiotic. Extended postoperative antibiotic therapy is administered only for open fractures or significant intra-abdominal contamination. Tetanus prophylaxis is administered to all patients according to published guidelines. Trauma patients are at risk for venous thromboembolism and its associated complications. In fact, pulmonary embolus can occur much earlier in the patient's hospital course than previously believed. 39 Patients at higher risk for venous thromboembolism are (a) those with multiple fractures of the pelvis and lower extremities, (b) those with coma or spinal cord injury, and (c) those requiring ligation of large veins in the abdomen and lower extremities. Morbidly obese patients and those over 55 years of age are at additional risk. Administration of low molecular weight heparin is initiated as soon as bleeding has been controlled and there is no intracranial pathology. In highrisk patients, removable inferior vena caval filters should be considered if there are contraindications to administration of low molecular weight heparin. Additionally, pulsatile compression stockings (also termed sequential compression devices) are used routinely unless there is a fracture. A final prophylactic measure that is usually not considered is thermal protection. Hemorrhagic shock impairs perfusion and metabolic activity throughout the body, with resultant decrease in heat production and body temperature. Removing the patient's clothes causes a second thermal insult, and infusion of cold RBCs or room temperature crystalloid exacerbates the problem. As a result, injured patients can become hypothermic, with temperatures below 34°C (93.2°F) upon arrival in the OR. Hypothermia causes coagulopathy and myocardial irritability. Therefore, prevention must begin in the ED by maintaining a comfortable ambient temperature, covering stabilized patients with warm blankets, and administering warmed IV fluids and blood products. Additionally, in the OR a Bair Hugger warmer (the upper body or lower body blanket) and heated inhalation via the ventilatory circuit is instituted. For cases of severe hypothermia [temperature <30°C (86°F)], arteriovenous rewarming should be considered.

Operative Approaches and Exposure CERVICAL EXPOSURE Operative exposure for midline structures of the neck (trachea, thyroid, bilateral carotid sheaths) is obtained through a collar incision; this is typically performed two finger breadths above the sternal notch, but can be varied based on the level of injury. After subplatysmal flap elevation, the strap muscles are divided in the midline to gain access to the central neck compartment. More superior and lateral structures are accessed by extending the collar incision upward along the sternocleidomastoid muscle; this may be done bilaterally if necessary. Unilateral neck exploration is done through an incision extending from the mastoid down to the clavicle, along the anterior border of the sternocleidomastoid muscle (Fig. 7-33). The carotid sheath, containing the carotid artery, jugular vein, and vagus nerve, is opened widely to examine these structures. The facial vein, which marks the carotid bifurcation, is usually ligated for exposure of the internal carotid artery. Fig. 7-33.

From Lycan / Dr. MV

A. Unilateral neck exploration is performed through an incision along the anterior border of the sternocleidomastoid muscle; exposure of the carotid artery requires early division of the facial vein. B. The distal internal carotid artery is exposed by dividing the ansa cervicalis, which permits mobilization of the hypoglossal nerve. C. Further exposure is facilitated by resection of the posterior belly of the digastric muscle. Exposure of the distal carotid artery in zone III is difficult (see Fig. 7-33). The first step is division of the ansa cervicalis to facilitate mobilization of the hypoglossal nerve. Next, the posterior portion of the digastric muscle, which overlies the internal carotid, is transected. The glossopharyngeal and vagus nerves are mobilized and retracted as necessary. If accessible, the styloid process and attached muscles are removed. At this point anterior displacement of the mandible (subluxation) may be helpful. In desperate situations, the vertical ramus of the mandible may be divided. However, this maneuver often entails resection of the parotid gland and facial nerve for exposure of the distal internal carotid.

THORACIC INCISIONS An anterolateral thoracotomy, with the patient placed supine, is the most versatile incision for emergent thoracic exploration. The location of the incision is in the fifth interspace, in the inframammary line (Fig. 7-34). If access is needed to bilateral pleural cavities, the original incision can be extended across the sternum with a Lebsche knife, into a "clamshell" thoracotomy (Fig. 7-35). If the sternum is divided, the internal mammary arteries should be ligated to prevent blood loss. The heart, lungs, descending aorta, pulmonary hilum, and esophagus are accessible with this approach. For control of the great vessels, the superior portion of the sternum may be opened and extension of the incision into the neck considered. A method advocated for access to the proximal left subclavian artery is through a fourth interspace anterolateral thoracotomy, superior sternal extension, and left supraclavicular incision ("trap door" thoracotomy). Although the trap door procedure is appropriate after resuscitative thoracotomy, the proximal left subclavian artery can be accessed more easily via a sternotomy with a supraclavicular extension. If the left subclavian artery is injured outside the thoracic outlet, vascular control can be obtained via the sternotomy and definitive repair done through the supraclavicular incision. Median sternotomy is of limited utility in cases of cardiac trauma but can be used for anterior stab wounds to the heart. Typically, these patients have pericardial tamponade and undergo placement of a pericardial drain before a semiurgent median sternotomy is performed. Patients in extremis, however, should undergo anterolateral thoracotomy. Fig. 7-34.

Options for thoracic exposure include the most versatile incision, the anterolateral thoracotomy (1), as well as a median sternotomy (2) and a "trap door" thoracotomy (3). Any thoracic incision may be extended into a supraclavicular or anterior neck incision for wider exposure.

Fig. 7-35.

A. A "clamshell" thoracotomy provides exposure to bilateral thoracic cavities. B. Sternal transection requires individual ligation of both the proximal and distal internal mammary arteries on the undersurface of the sternum. Median sternotomy with cervical extension may also be used for rapid exposure in patients with presumed proximal subclavian, innominate, or proximal carotid artery injuries. Care must be taken to avoid injury to the phrenic and vagus nerves that pass over the subclavian artery and to the recurrent laryngeal nerve passing posteriorly. Posterolateral thoracotomies are used for exposure of injuries to the posterior aspect of the trachea or main stem bronchi near the carina (right posterolateral thoracotomy), tears of the descending thoracic aorta (left posterolateral thoracotomy with left heart bypass), and intrathoracic esophageal injuries.

EMERGENT ABDOMINAL EXPLORATION Abdominal exploration in adults is performed using a generous midline incision because of its versatility. For children under the age of 6, a transverse incision may be advantageous. Making the incision is faster with a scalpel than with an electrosurgical unit; incisional abdominal wall bleeding should be ignored until intra-abdominal sources of hemorrhage are controlled. Liquid and clotted blood is evacuated with multiple laparotomy pads and suction to identify the major source(s) of active bleeding. After blunt trauma the spleen and liver should be palpated and packed if fractured, and the infracolic mesentery inspected to exclude injury. In contrast, after a penetrating wound the search for bleeding should pursue the trajectory of the penetrating device. If the patient has an SBP of <70 mmHg when the abdomen is opened, digital pressure or a clamp should be placed on the aorta at the diaphragmatic hiatus. After the source of hemorrhage is localized, direct digital occlusion (vascular injury) or laparotomy pad packing (solid organ injury) is used to control bleeding (Fig. 7-36). If the liver is the source in a hemodynamically unstable patient, additional control of bleeding is obtained by clamping the hepatic pedicle (Pringle maneuver) (Fig. 7-37). Similarly, clamping the splenic hilum may more effectively control bleeding than packing alone. When the spleen is mobilized, it should be gently rotated medially to expose the lateral peritoneum; this peritoneum and endoabdominal fascia are incised, which allows blunt dissection of the spleen and pancreas as a composite from the retroperitoneum (Fig. 7-38). Fig. 7-36.

A sagittal view of packs placed to control hepatic hemorrhage. Lap = laparotomy.

Fig. 7-37.

The Pringle maneuver, performed with a vascular clamp, occludes the hepatic pedicle containing the portal vein, hepatic artery, and common bile duct.

Fig. 7-38.

To mobilize the spleen, an incision is made into the endoabdominal fascia 1 cm lateral to the reflection of the peritoneum onto the spleen (A). While the spleen is gently rotated medially, a plane is developed between the pancreas and left kidney (B). With complete mobilization, the spleen can reach the level of the abdominal incision.

Rapid exposure of the intra-abdominal vasculature can prove challenging in the face of exsanguinating hemorrhage. The aorta, celiac axis, proximal superior mesenteric artery (SMA), and left renal arteries can be exposed with a left medial visceral rotation (Fig. 7-39). This is done by incising the lateral peritoneal reflection (white line of Toldt) beginning at the distal descending colon and extending the incision along the colonic splenic flexure, around the posterior aspect of the spleen, and behind the gastric fundus, ending at the esophagus. The left colon, spleen, pancreas, and stomach are then rotated toward the midline. The authors prefer to leave the kidney in situ when mobilizing the viscera because this exaggerates the separation of the renal vessels from the SMA. Proximal control of the aorta is obtained at the diaphragmatic hiatus; if an aortic injury is supraceliac, transecting the left crus of diaphragm or performing left thoracotomy may be necessary. Inferior vena cava injuries are approached by a right medial visceral rotation (Fig. 7-40). Proximal control is obtained just above the aortic bifurcation with direct pressure via a sponge stick; the injury is identified by cephalad dissection along the anterior surface of the inferior vena cava. The operative approach for SMA injuries is based on the level of injury. Fullen zone I SMA injuries, located posterior to the pancreas, can be exposed by a left medial visceral rotation. Fullen zone II SMA injuries, extending from the pancreatic edge to the middle colic branch, are approached via the lesser sac along the inferior edge of the pancreas at the base of the transverse mesocolon; the pancreatic body may be divided to gain proximal vascular access. More distal SMA injuries, Fullen zones III and IV, are approached directly within the mesentery. A venous injury behind the pancreas, from the junction of the superior mesenteric, splenic, and portal veins, is accessed by dividing the neck of the pancreas. Fig. 7-39.

A left medial visceral rotation is used to expose the abdominal aorta.

Fig. 7-40.

A right medial visceral rotation is used to expose the infrahepatic vena cava.

Injuries of the iliac vessels pose a unique problem for emergent vascular control due to the number of vessels, their close proximity, and cross circulation. Proximal control at the infrarenal aorta arrests the arterial bleeding and avoids splanchnic and renal ischemia; however, venous injuries are not controlled with aortic clamping. Tamponade with a folded laparotomy pad held directly over the bleeding site usually will establish hemostasis sufficient to prevent exsanguination. If hemostasis is not adequate to expose the vessel proximal and distal to the injury, sponge sticks can be strategically placed on either side of the injury and carefully adjusted to improve hemostasis. Alternatively, complete pelvic vascular isolation (Fig. 7-41) may be required to control hemorrhage for adequate visualization of the injuries. The right common iliac artery obscures the bifurcation of the vena cava and the right iliac vein; the iliac artery can be divided to expose venous injuries of this area (Fig. 7-42). The artery must be

repaired after the venous injury is treated, however, because of limb-threatening ischemia. Fig. 7-41.

Pelvic vascular isolation. A. Initially, clamps are placed on the aorta, inferior vena cava, and bilateral external iliac vessels. B. With continued dissection, the clamps can be moved progressively closer to the vascular injury to limit unwarranted ischemia.

Fig. 7-42.

The right common iliac artery can be divided to expose the bifurcation of the inferior vena cava and the right common iliac vein. Once overt hemorrhage is controlled, sources of enteric contamination are identified by serially running along the small and large bowel, looking at all surfaces. Associated hematomas should be unroofed to rule out adjacent bowel injury. The anterior and posterior aspects of the stomach should be inspected, which requires opening the lesser sac for complete visualization. Duodenal injuries should be evaluated with a wide Kocher maneuver. During exploration of the lesser sac, visualization and palpation of the pancreas is done to exclude injury. Palpating the anterior surface is not sufficient, because the investing fascia may mask a pancreatic injury; mobilization, including evaluation of the posterior aspect, is critical. After injuries are identified, whether to use damage control techniques or perform primary repair of injuries is based on the patient's intraoperative physiologic status (see "Damage Control Surgery" and "Treatment of Specific Injuries" later). In a patient with multisystem trauma, enteral access via gastrostomy tube and needle-catheter jejunostomy should be considered. If abdominal closure is indicated after the patient's injuries are addressed, the abdomen is irrigated with warm saline and the midline fascia is closed with a running heavy suture. The skin is closed selectively based on the amount of intra-abdominal contamination.

VASCULAR REPAIR TECHNIQUES Initial control of vascular injuries is accomplished digitally by applying enough direct pressure to stop the hemorrhage. Sharp dissection with fine scissors defines the injury and mobilizes sufficient length for proximal and distal control. Heparinized saline (50 units/mL) is injected into the proximal and distal ends of the injured vessel to prevent

small clot formation on the exposed intima and media. Ragged edges of the injury site should be judiciously débrided using sharp dissection. Options for the treatment of vascular injuries are listed in Table 7-9. Arterial repair should always be done for the aorta and the carotid, innominate, brachial, superior mesenteric, proper hepatic, renal, iliac, femoral, and popliteal arteries. In the extremities, at least one artery with distal runoff should be salvaged. Venous repair should be attempted for injuries of the superior vena cava, the inferior vena cava proximal to the renal veins, and the portal vein, although the portal vein may be ligated in extreme cases. Arterial injuries that may be treated conservatively include small pseudoaneurysms, intimal dissections, small intimal flaps, and small arteriovenous fistulas in the extremities. Follow-up imaging is performed 1 to 2 weeks after injury to confirm healing. Table 7-9 Options for the Treatment of Vascular Injuries Observation Ligation Lateral suture repair End-to-end primary anastomosis Interposition grafts Autogenous vein Polytetrafluoroethylene graft Dacron graft Transpositions Extra-anatomic bypass Interventional radiology Stents Embolization

The type of operative repair for a vascular injury is based on the extent and location of injury. Lateral suture repair is preferred for arterial injuries with minimal loss of tissue. End-to-end primary anastomosis is performed if the vessel can be repaired without tension. Arterial defects of 1 to 2 cm often can be bridged by mobilizing the severed ends of the vessel after ligating small branches. The surgeon should not be reluctant to divide small branches to obtain additional length, because most injured patients have normal vasculature, and the preservation of potential collateral flow is not as important as in surgery for atherosclerosis. The aorta, subclavian artery, and brachial artery, however, are difficult to mobilize for additional length. To avoid postoperative stenosis, particularly in smaller arteries, beveling or spatulation should be used so that the completed anastomosis is slightly larger in diameter than the native artery (Fig. 7-43). The authors emphasize the parachute technique to ensure precision placement of the posterior suture line (Fig. 7-44). If this technique is used, traction must be maintained on both ends of the suture, or leakage from the posterior aspect of the suture line may occur. A single temporary suture 180 degrees from the posterior row may be used to maintain alignment for challenging anastomoses. Fig. 7-43.

Small arteries repaired with an end-to-end anastomosis are prone to stricture. Enlarging the anastomosis by beveling the cut ends of the injured vessel can minimize this problem. A curved hemostat is a useful adjunct to create the curve.

Fig. 7-44.

The parachute technique is helpful for accurate placement of the posterior sutures of an anastomosis when the arterial end is fixed and an interposition graft is necessary. Traction must be maintained on both ends of the suture to prevent loosening and leakage of blood. Six stitches should be placed before the graft is pulled down to the artery.

Interposition grafts are used when end-to-end anastomosis cannot be accomplished without tension despite mobilization. For vessels <6 mm in diameter (e.g., internal carotid, brachial, superficial femoral, and popliteal arteries), autogenous saphenous vein from the contralateral groin should be used, because polytetrafluoroethylene (PTFE) grafts of <6 mm have a prohibitive rate of thrombosis. Larger arteries (e.g., subclavian, innominate, aorta, common iliac) are bridged by PTFE grafts. Aortic or iliac arterial injuries may be complicated by enteric contamination from colon or small bowel injuries. There is a natural reluctance to place artificial grafts in such circumstances, but graft infections are rare and the time required to perform an axillofemoral bypass is excessive. Therefore, after the control of hemorrhage, bowel contamination is contained and the abdomen irrigated before placing PTFE grafts. After placement of the graft, it is covered with peritoneum or omentum before definitive treatment of the enteric injuries. Transposition procedures can be used when an artery has a bifurcation and one vessel can safely be ligated. Injuries of the proximal internal carotid can be treated by mobilizing the adjacent external carotid, dividing it distal to the internal injury, and performing an end-to-end anastomosis between it and the distal internal carotid (Fig. 745). The proximal stump of the internal carotid is oversewn, with care taken to avoid a blind pocket where a clot may form. Injuries of the common and external iliac arteries can be handled in a similar fashion (Fig. 7-46), while maintaining flow in at least one internal iliac artery. Fig. 7-45.

Carotid transposition is an effective approach for treating injuries of the proximal internal carotid artery.

Fig. 7-46.

Transposition procedures can be used for iliac artery injuries to eliminate the dilemma of placing an interposition polytetrafluoroethylene graft in the presence of enteric contamination. A. Right common iliac artery transposed to left common iliac artery. B. Left internal iliac artery transposed to the distal right common iliac artery. C. Right internal iliac artery transposed to the right external iliac artery. Venous injuries are inherently more difficult to reconstruct due to their propensity to thrombose. Small injuries without loss of tissue can be treated with lateral suture repair. More complex repairs with interposition grafts often fail; this typically does not occur acutely but rather gradually over 1 to 2 weeks. During this time adequate collateral circulation typically develops, which is sufficient to avoid acute venous hypertension. Therefore, it is reasonable to use PTFE for venous interposition grafting and accept a gradual, but eventual, thrombosis while allowing time for collateral circulation to develop. Such an approach is reasonable for venous injuries of the superior vena cava, suprarenal vena cava, and popliteal vein because ligation of these is associated with significant morbidity. In the remainder of venous injuries the vein may be ligated. In such patients, chronic venous hypertensive complications in the lower extremities often can be avoided by (a) temporary use of elastic bandages (Ace wraps) applied from the toes to the hips at the end of the procedure, and (b) temporary continuous elevation of the lower extremities to 30 to 45 degrees. These measures should be maintained for 1 week; if the patient has no peripheral edema with ambulation, these maneuvers are no longer required.

Damage Control Surgery The recognition of the bloody vicious cycle and the introduction of damage control surgery (DCS) have improved the survival of critically injured patients. The bloody vicious

cycle, first described in 1981, is the lethal combination of coagulopathy, hypothermia, and metabolic acidosis (Fig. 7-47). 33 Hypothermia from evaporative and conductive heat loss and diminished heat production occurs despite the use of warming blankets and blood warmers. The metabolic acidosis of shock is exacerbated by aortic clamping, administration of vasopressors, massive transfusions, and impaired myocardial performance. Coagulopathy is caused by dilution, hypothermia, and acidosis. Once the cycle starts, each component magnifies the others, which leads to a downward spiral and ultimately a fatal arrhythmia. The purpose of DCS is to limit operative time so that the patient can be returned to the SICU for physiologic restoration and the cycle thus broken. Indications to limit the initial operation and institute DCS techniques include temperature <35°C (95°F), arterial pH <7.2, base deficit <15 mmol/L (or <6 mmol/L in patients over 55 years of age), and INR or PTT >50% of normal. The decision to abbreviate a trauma laparotomy is made intraoperatively as laboratory values become available and the patient's clinical course becomes clearer. Fig. 7-47.

The bloody vicious cycle. FFP = fresh-frozen plasma; RBC= red blood cell.

The goal of DCS is to control surgical bleeding and limit GI spillage. The operative techniques used are temporary measures, with definitive repair of injuries delayed until the patient is physiologically replete. Controlling surgical bleeding while preventing ischemia is of utmost importance during DCS. Aortic injuries must be repaired using an interposition PTFE graft. Although celiac artery injuries may be ligated, the SMA must maintain flow, and the insertion of an intravascular shunt is advocated. Similarly, perfusion of the iliac system and infrainguinal vessels can be restored with a vascular shunt, with interposition graft placement delayed until hours later. Venous injuries are preferentially treated with ligation in damage control situations, except for the suprarenal inferior vena cava and popliteal vein. For solid organ injuries to the spleen or one kidney, excision is indicated rather than an attempt at repair such as splenorrhaphy. For hepatic injuries, packing of the liver causes compression tamponade of bleeding (see Fig. 7-36). Translobar gunshot wounds of the liver are best controlled with balloon catheter tamponade, whereas deep lacerations can be controlled with Foley catheter inflation deep within the injury track (Fig. 7-48). For thoracic injuries requiring DCS several options exist. For bleeding peripheral pulmonary injuries, wedge resection using a gastrointestinal anastomosis (GIA) stapler is performed. In penetrating injuries, pulmonary tractotomy is used to divide the parenchyma (Fig. 7-49); individual vessels and bronchi are then ligated using a 3-0 polydioxanone (PDS) suture and the track left open. Patients who sustain more proximal injuries may require pulmonary lobectomy or pneumonectomy to control bleeding. Cardiac injuries may be temporarily controlled using a running 3-0 nonabsorbable polypropylene suture or skin staples. If this technique does not definitely control hemorrhage, pledgeted repair of the injury should be performed. Fig. 7-48.

A. An intrahepatic balloon used to tamponade hemorrhage from transhepatic penetrating injuries is made by placing a red rubber catheter inside a 1-inch Penrose drain, with both ends of the Penrose drain ligated. B. Once placed inside the injury track, the balloon is inflated with saline until hemorrhage stops. C. A Foley catheter with a 30mL balloon can be used to halt hemorrhage from deep lacerations to the liver.

Fig. 7-49.

Pulmonary tractotomy divides the pulmonary parenchyma using either a transection/anastomosis (TA) or gastrointestinal anastomosis (GIA) stapler. The opened track permits direct access to injured vessels or bronchi for individual ligation.

The second key component of DCS is limiting enteric content spillage. Small GI injuries (stomach, duodenum, small intestine, and colon) may be controlled using a rapid whipstitch of 2-0 nonabsorbable polypropylene. Complete transection of the bowel or segmental damage is controlled using a GIA stapler, often with resection of the injured segment. Alternatively, open ends of the bowel may be ligated using umbilical tapes to limit spillage. Pancreatic injuries, regardless of location, are packed and the evaluation of ductal integrity postponed. Before the patient is returned to the SICU, the abdomen must be temporarily closed. Originally, penetrating towel clips were used to approximate the skin; however, the ensuing bowel edema often produced a delayed abdominal compartment syndrome. Currently, temporary closure of the abdomen is accomplished using an antimicrobial surgical incise drape (Ioban) (Fig. 7-50). In this technique, the bowel is covered with a fenestrated subfascial sterile drape (45 x 60 cm Steri-Drape), and two Jackson-Pratt drains are placed along the fascial edges; this is then covered using an Ioban drape, which allows closed suction to control reperfusionrelated ascitic fluid egress while providing adequate space for bowel expansion to prevent abdominal compartment syndrome. During the initial DCS stage, the subfascial sterile drape is not covered by a blue towel so that the status of the bowel and hemorrhage control can be assessed. Return to the OR in 12 to 24 hours is planned once the patient clinically improves, as evidenced by normothermia, normalization of coagulation test results, and correction of acidosis. Fig. 7-50.

Temporary closure of the abdomen entails covering the bowel with a fenestrated subfascial 45 x 60 cm sterile drape (A), placing Jackson-Pratt drains and a blue towel (B), and then occluding with an Ioban drape (C).

TREATMENT OF SPECIFIC INJURIES Head Injuries INTRACRANIAL INJURIES CT scanning, performed on all patients with a significant closed head injury (GCS score <14), identifies and quantitates intracranial lesions. Patients with intracranial hemorrhage, including epidural hematoma, subdural hematoma, subarachnoid hemorrhage, intracerebral hematoma or contusion, and diffuse axonal injury, are admitted to the SICU. In patients with abnormal findings on CT scans and GCS scores of ð8, intracranial pressure (ICP) should be monitored using fiber-optic intraparenchymal devices or intraventricular catheters. 13 Although an ICP of 10 mmHg is believed to be the upper limit of normal, therapy is not initiated until ICP is >20 mmHg. 13 Indications for operative intervention to remove space-occupying hematomas are based on the clot volume, amount of midline shift, location of the clot, GCS score, and ICP. 13 A shift of >5 mm typically is considered an indication for evacuation, but this is not an absolute rule. Smaller hematomas that are in treacherous locations, such as the posterior fossa, may require drainage due to brain stem compression or impending herniation. Removal of small hematomas may also improve ICP and cerebral perfusion in patients with elevated ICP that is refractory to medical therapy. Patients with diffuse cerebral edema resulting in excessive ICP may require a decompressive craniectomy. Patients with open or depressed skull fractures, with or without sinus involvement, may require operative intervention. Penetrating injuries to the head require operative intervention for hemorrhage control, evacuation of blood, skull fracture fixation, or débridement. General surgeons in communities without emergency neurosurgical coverage should have a working knowledge of burr hole placement in the event that emergent evacuation is required for a life-threatening epidural hematoma (Fig. 7-51). 40 The typical clinical course of an epidural hematoma is an initial loss of consciousness, a lucid interval, recurrent loss of consciousness with an ipsilateral fixed and dilated pupil, and finally cardiac arrest. The final stages of this sequence are caused by blood accumulation that forces the temporal lobe medially, with resultant compression of the third cranial nerve and eventually the brain stem. The burr hole is made on the side of the dilated pupil to decompress the intracranial space. After stabilization, the patient is transferred to a facility with emergency neurosurgical capability for formal craniotomy. Fig. 7-51.

A burr hole is made for decompression of an epidural hematoma as a life-saving maneuver. One or more branches of the external carotid artery usually must be ligated to gain access to the skull. No attempt should be made to control intracranial hemorrhage through the burr hole. Rather, the patient's head should be wrapped with a bulky absorbent dressing and the patient transferred to a neurosurgeon for definitive care. In addition to operative intervention, postinjury care directed at limiting secondary injury to the brain is critical. The goal of resuscitation and management in patients with head injuries is to avoid hypotension (SBP of <90 mmHg) and hypoxia (partial pressure of arterial oxygen of <60 or arterial oxygen saturation of <90).13 Attention, therefore, is focused on maintaining cerebral perfusion rather than merely lowering ICP. Resuscitation efforts aim for a euvolemic state and an SBP of >90 mmHg. Cerebral perfusion pressure (CPP) is equal to the mean arterial pressure minus the ICP, with a target range of 50 to 70 mmHg. 13 CPP can be increased by either lowering ICP or raising mean arterial pressure. Sedation, osmotic diuresis, paralysis, ventricular drainage, and barbiturate coma are used in sequence, with coma induction being the last resort. The partial pressure of carbon dioxide (PCO2 ) should be maintained in a normal range (35 to 40 mmHg), but for temporary management of acute intracranial hypertension, inducing cerebral vasoconstriction by hyperventilation to a P CO2 of <30 mmHg is occasionally warranted. Moderate hypothermia [32° to 33°C (89.6° to 91.4°F)] may decrease mortality risk and improve neurologic outcomes when maintained for at least 48 hours, but its ultimate role remains to be defined.13 Patients with intracranial hemorrhage should be monitored for postinjury seizures, and prophylactic anticonvulsant therapy (e.g., phenytoin [Dilantin]) is indicated for 7 days after injury. 13

MAXILLOFACIAL INJURIES Maxillofacial injuries are common with multisystem trauma and require coordinated management by the trauma surgeon and the specialists in otolaryngology, plastic surgery, ophthalmology, and oral and maxillofacial surgery. Delay in addressing these systems that control vision, hearing, smelling, breathing, eating, and phonation may produce dysfunction and disfigurement with serious psychologic impact. The maxillofacial complex is divided into three regions; the upper face containing the frontal sinus and brain, the midface containing the orbits, nose, and zygomaticomaxillary complex, and the lower face containing the mandible. High-impact kinetic energy is required to fracture the frontal sinus, orbital rims, and mandible, whereas low-impact forces will injure the nasal bones and zygoma. The most common scenario, which at times may be life-threatening, is bleeding from facial fractures. 41 Temporizing measures include nasal packing, Foley catheter tamponade of posterior nasal bleeding, and oropharyngeal packing. Prompt angioembolization will halt exsanguinating hemorrhage. Fractures of tooth-bearing bone are considered open fractures and require antibiotic therapy and semiurgent repair to preserve the airway as well as the functional integrity of the occlusion (bite) and the aesthetics of the face. Orbital fractures may compromise vision, produce muscle injury causing diplopia, or change orbital volume to produce a sunken appearance to the orbit. Nose and nasoethmoidal fractures should be assessed carefully to identify damage to the lacrimal drainage system or to the cribriform plate producing cerebrospinal fluid rhinorrhea. After initial stabilization, a systematic physical examination of the head and neck should be performed that also includes cranial nerve examination and coronal and three-dimensional CT scanning of the maxillofacial complex (Fig. 7-52). Early consultation with the surgical specialists in this area is essential to prevent complications to these vital structures. Fig. 7-52.

Three-dimensional computed tomographic scan illustrating Le Fort II maxillary (L) and alveolar (A) fractures, and fracture of the mandible (M) at the midline and at the weaker condyle (C). (Image courtesy of Vincent D. Eusterman, MD, DDS.)

Neck and Cervical Spine Injuries Blunt trauma can involve virtually every structure in the neck. Treatment of injuries to the cervical spine is based on the level of injury, the stability of the spine, the presence of subluxation, the extent of angulation, the level of neurologic deficit, and the overall condition of the patient. In general, physician-supervised axial traction, via cervical tongs or the more commonly used halo vest, is used to reduce subluxations and stabilize the injury. Immobilization of injuries also is achieved with spinal orthoses (braces), particularly in those with associated thoracolumbar injuries. Surgical fusion typically is performed in patients with neurologic deficit, those with angulation of >11 degrees or translation of >3.5 mm, and those who remain unstable after external fixation. Indications for immediate operative intervention are deterioration in neurologic function and fractures or dislocations with incomplete deficit. Methylprednisolone generally is administered to patients with acute spinal cord injury. Although controversy exists, clinical data suggest initiating a 24-hour infusion if started within 3 hours and a 48-hour infusion if started 3 to 8 hours. 42 Current guidelines suggest an initial bolus of 30 mg/kg methylprednisolone followed by a 5.4-mg/kg infusion for 23 hours in patients with nonpenetrating injuries. The role and timing of operative surgical decompression after acute spinal cord injury is a matter of debate. However, evidence supports urgent decompression of bilateral locked facets in patients with incomplete tetraplegia or with neurologic deterioration. Urgent decompression in acute cervical spinal cord injury is safe. Performing surgery within 24 hours may decrease length of stay and complications. 43 Complete injuries of the spinal cord remain essentially untreatable. However, approximately 3% of patients who present with flaccid quadriplegia have concussive injuries, and these patients represent the very few who seem to have miraculous recoveries. Subclinical fractures of the larynx and trachea may manifest as cervical emphysema, but fractures documented by CT scan often are repaired. Common injuries include thyroid cartilage fractures, rupture of the thyroepiglottic ligament, disruption of the arytenoids or vocal cord tears, and cricoid fractures. After necessary débridement of devitalized tissue, tracheal injuries are repaired end to end using a single layer of interrupted absorbable sutures. Associated injuries of the esophagus are common in penetrating injuries due to its close proximity. After débridement and repair, vascularized tissue is interposed between the repair and the injured trachea, and a closed suction drain is placed. The sternocleidomastoid muscle or strap muscles are useful for interposition and help prevent postoperative fistulas. Cervical vascular injuries due to either blunt or penetrating trauma can result in devastating neurologic sequelae or exsanguination. Penetrating injuries to the carotid artery and internal jugular vein usually are obvious on operative neck exploration. The principles of vascular repair techniques (discussed previously) apply to carotid injuries, and options for repair include end-to-end primary repair (often possible with mobilization of the common carotid), graft interposition, and transposition procedures. All carotid injuries that can be repaired without undue physiologic ramifications should be. However, in patients who present in coma, particularly with a delay, ligation should be considered. In patients with uncontrolled hemorrhage, an alternative is temporary vascular control and revascularization using a Pruitt-Inahara shunt. Tangential wounds of the internal jugular vein should be repaired by lateral venorrhaphy, but extensive wounds are efficiently addressed by ligation. However, it is not advisable to ligate both jugular veins. Vertebral artery injuries due to penetrating trauma are difficult to control operatively because of the artery's protected location within the foramen transversarium. Although exposure from an anterior approach can be accomplished by removing the anterior elements of the bony canal and the tough fascia covering the artery between the elements, typically the most efficacious control of such injuries is angioembolization. Fogarty catheter balloon occlusion may be useful for controlling acute bleeding. Blunt injury to the carotid or vertebral arteries may cause dissection, thrombosis, or pseudoaneurysm, typically in the surgically inaccessible distal internal carotid (Fig. 753). 44 Early recognition and management of these injuries is paramount, because patients treated with antithrombotics have a stroke rate of <1% compared with stroke

rates between 5 and 50% in untreated patients based on grade of injury. Because treatment must be instituted during the latent period between injury and onset of neurologic sequelae, diagnostic imaging is performed based on identified screening criteria (Fig. 7-54). 45 After identification of an injury, antithrombotics are administered if the patient does not have contraindications (intracranial hemorrhage, falling hemoglobin level with solid organ injury or pelvic fracture). Heparin, started without a loading dose at 15 units/kg per hour, is titrated to achieve a PTT between 40 and 50 seconds or antiplatelet agents are initiated (aspirin 325 mg/d and clopidogrel 75 mg/d). The types of antithrombotic treatment appear equivalent in published studies to date, and the duration of treatment is empirically recommended to be 6 months. 46,47 Thrombosis of the internal jugular veins caused by blunt trauma can occur unilaterally or bilaterally and is often discovered incidentally, because most patients are asymptomatic. Bilateral thrombosis can aggravate cerebral edema in patients with serious head injuries; stent placement should be considered in such patients if ICP remains elevated. Fig. 7-53.

The Denver grading scale for blunt cerebrovascular injuries. Grade I: irregularity of the vessel wall, dissection/intramural hematoma with <25% luminal stenosis. Grade II: visualized intraluminal thrombus or raised intimal flap, or dissection/intramural hematoma with 25% or more luminal narrowing. Grade III: pseudoaneurysm. Grade IV: vessel occlusion. Grade V: vessel transection. CAI = carotid artery injury; VAI = vertebral artery injury.

Fig. 7-54.

Screening and treatment algorithm for blunt cerebrovascular injuries (BCVIs). Angio = angiography; ASA = acetylsalicylic acid; BRB = bright red blood; CHI = closed head injury; C-spine = cervical spine; CT = computed tomography; DAI = diffuse axonal injury; GCS = Glasgow Coma Scale score; MRI = magnetic resonance imaging; MS = mental status; Neg = negative; pt = patient; PTT = partial thromboplastin time; TIA = transient ischemic attack.

Chest Injuries The most common injuries from both blunt and penetrating thoracic trauma are hemothorax and pneumothorax. Few require operative intervention because >85% of patients can be definitively treated with a chest tube. The indications for thoracotomy include significant initial or ongoing hemorrhage from the tube thoracostomy and specific imaging-identified diagnoses (Table 7-10). One caveat concerns the patient who presents after a delay. Even when the initial chest tube output is 1.5 L, if the output ceases and the lung is re-expanded, the patient may be managed through observation. Table 7-10 Indications for Operative Treatment of Thoracic Injuries Initial tube thoracostomy drainage of >1000 mL (penetrating injury) or >1500 mL (blunt injury) Ongoing tube thoracostomy drainage of >200 mL/h for 3 consecutive hours in noncoagulopathic patients Caked hemothorax despite placement of two chest tubes Selected descending torn aortas Great vessel injury (endovascular techniques may be used in selected patients) Pericardial tamponade

Cardiac herniation Massive air leak from the chest tube with inadequate ventilation Tracheal or main stem bronchial injury diagnosed by endoscopy or imaging Open pneumothorax Esophageal perforation

GREAT VESSELS Over 90% of thoracic great vessel injuries are due to penetrating trauma, although blunt injury to the innominate, subclavian, or descending aorta may cause a pseudoaneurysm or frank rupture. 22,48,49 Simple lacerations of the ascending or transverse aortic arch can be repaired with lateral aortorrhaphy. Repair of posterior injuries, or those requiring interposition grafting of the arch, call for cardiopulmonary bypass, and repair of complex injuries may require circulatory arrest. Innominate artery injuries are repaired using the bypass exclusion technique, 49 which avoids the need for cardiopulmonary bypass. Bypass grafting from the proximal aorta to the distal innominate with a prosthetic tube graft is performed before the postinjury hematoma is entered. The PTFE graft is anastomosed end to side from the proximal undamaged aorta and anastomosed end to end to the innominate artery (Fig. 7-55). The origin of the innominate is then oversewn at its base to exclude the pseudoaneurysm or other injury. Subclavian artery injuries can be repaired using lateral arteriorrhaphy or PTFE graft interposition; due to its multiple branches and tethering of the artery, end-toend anastomosis is not advocated. Fig. 7-55.

A. Angiography reveals a 1-cm pseudoaneurysm of the innominate artery origin. B. In the first stage of the bypass exclusion technique, a 12-mm polytetrafluoroethylene graft is anastomosed end to side from the proximal undamaged aorta, tunneled under the vein, and anastomosed end to end to the innominate artery. C. The origin of the innominate is then oversewn at its base to exclude the pseudoaneurysm.

Descending thoracic aortic injuries may require urgent if not emergent intervention. However, operative intervention for intracranial or intra-abdominal hemorrhage or unstable pelvic fractures takes precedence. To prevent aortic rupture, pharmacologic therapy with an esmolol infusion should be instituted in the trauma bay, with a target SBP of <100 mmHg and heart rate of <100/min. 50 Open operative reconstruction of the thoracic aorta remains the mainstay of treatment, 19,51 although endovascular stenting is being used more frequently as the technology improves.52 Endovascular techniques are particularly appealing in patients who cannot tolerate single lung ventilation, patients >65 years old who are at risk for cardiac decompensation with aortic clamping, or patients with uncontrolled intracranial hypertension. The major limitations are current endograft sizes, which are too large compared to the diameter of the thoracic aorta, and a lack of long-term follow-up data in young patients. Open repair of the descending aorta entails placement of an interposition graft using partial left heart bypass. 53 With the patient in a right lateral decubitus position, the patient's hips and legs are rotated 45 degrees toward the supine position to gain access to the left groin for common femoral artery cannulation. Using a left posterolateral thoracotomy, the fourth rib is transected to expose the aortic arch and left pulmonary hilum. Partial left heart bypass is performed by cannulating the superior pulmonary

vein with return through the left common femoral artery (Fig. 7-56). A centrifugal pump provides flow rates of 2.5 to 4 L/min to maintain a distal perfusion pressure of >65 mmHg. This prevents ischemic injury of the spinal cord as well as the splanchnic bed, and reduces left ventricular afterload. 19 Heparinization is not required, a significant benefit in patients with multiple injuries, particularly in those with intracranial hemorrhage. Unless contraindicated, however, low-dose heparin (100 units/kg) typically is administered to prevent thromboembolic events. Once bypass is initiated, vascular clamps are applied on the aorta between the left common carotid and left subclavian arteries, on the left subclavian, and on the aorta distal to the injury. In most patients a short PTFE graft (usually 18 mm in diameter) is placed using a running 3-0 polypropylene suture. Primary arterial repair should be done when possible. Air and thrombus are flushed from the aortic graft before the final suture is tied, and the occluding vascular clamps are removed. The patient is then weaned from the centrifugal pump, the cannulas are removed, and primary repair of the cannulated vessels is performed. Fig. 7-56.

When a tear of the descending thoracic aorta is repaired, perfusion of the spinal cord while the aorta is clamped is achieved by using partial left heart bypass. The venous cannula is inserted into the left superior pulmonary vein (solid arrow) because it is less prone to tearing than the left atrium. The subclavian artery (dashed arrow) is identified for vascular control. The phrenic nerve (PN) and vagus nerve (VN) should be identified during mediastinal exploration to prevent inadvertent injury.

HEART Blunt and penetrating cardiac injuries have widely differing presentations and therefore disparate treatments. Survivable penetrating cardiac injuries consist of wounds that can be closed; most are stab wounds. Before repair of the injury is attempted, hemorrhage should be controlled; injuries to the atria can be clamped with a Satinsky vascular clamp, whereas digital pressure occludes the majority of ventricular wounds. Foley catheter occlusion of larger stellate lesions may be effective, but even minimal traction may enlarge the original injury. Temporary control of hemorrhage, and at times definitive repair, may be accomplished with skin staples for left ventricular lacerations. Definitive repair of cardiac injuries is performed with either running 3-0 polypropylene suture or interrupted, pledgeted 2-0 polypropylene suture (Fig. 7-57). 54

Use of pledgets may be particularly effective in the right ventricle to prevent sutures from pulling through the thinner myocardium. Injuries adjacent to coronary arteries should be repaired using horizontal mattress sutures, because use of running sutures results in coronary occlusion and distal infarction. Gunshot wounds may result in stellate lesions or contused, extremely friable myocardium adjacent to the wound. When the edges of such complex wounds cannot be fully approximated and hence the repair is not hemostatic, the authors have used surgical adhesive (BioGlue) to achieve hemostasis. Occasionally, interior structures of the heart may be damaged. Intraoperative auscultation or postoperative hemodynamic assessment usually identifies such injuries.55 Echocardiography can diagnose the injury and quantitate its effect on cardiac output. Immediate repair of valvular damage or septal defects rarely is necessary and would require cardiopulmonary bypass, which is associated with a high mortality in this situation. Fig. 7-57.

A variety of techniques may be necessary to repair cardiac wounds. Generally, pledget support is used for the relatively thin-walled right ventricle. Patients with blunt cardiac injury typically present with persistent tachycardia or rhythm disturbances, but occasionally present with tamponade due to atrial or right ventricular rupture. There are no pathognomonic ECG findings, and cardiac enzyme levels do not correlate with the risk of cardiac complications. 10 Therefore, patients for whom there is high clinical suspicion of cardiac contusion and who are hemodynamically stable should be monitored for dysrhythmias for 24 hours by telemetry. Patients with hemodynamic instability should undergo echocardiography to evaluate for wall motion abnormalities, valvular dysfunction, chordae rupture, or diminished ejection fraction. If such findings are noted or if vasoactive agents are required, cardiac function can be continuously monitored using a pulmonary artery catheter. A precisely timed blow to the precordium can provoke sudden cardiac death, termed commotio cordis. 56 This phenomenon, affecting primarily adolescent males, usually is fatal unless cardiopulmonary resuscitation and defibrillation are instituted immediately.

TRACHEA, BRONCHI, PULMONARY PARENCHYMA, AND ESOPHAGUS Fewer than 1% of all injured patients sustain intrathoracic tracheobronchial injuries, and only a small number require operative intervention. Although penetrating injuries may occur throughout the tracheobronchial system, blunt injuries occur within 2.5 cm of the carina. For patients with a massive air leak requiring emergent exploration, initial control of the injury to provide effective ventilation is obtained by passing an endotracheal tube either beyond the injury or into the contralateral mainstem bronchus. Principles of repair are similar to those for repair of cervical tracheal injuries. Devitalized tissue is débrided, and primary end-to-end anastomosis with 3-0 PDS suture is performed. Dissection should be careful and limited to the area of injury to prevent disruption of surrounding bronchial vasculature and ensuing ischemia and stricture. Suture lines should be encircled with vascularized tissue, either pericardium, intercostal muscle, or pleura. Expectant management is employed for bronchial injuries that are less than one-third the circumference of the airway and have no evidence of a persistent major air leak. In patients with peripheral bronchial injuries, indicated by persistent air leaks from the chest tube and documented by endoscopy, bronchoscopically directed fibrin glue sealing is occasionally required. Injuries to the pulmonary parenchyma typically are discovered during exploration for a massive hemothorax after penetrating trauma. Peripheral lacerations with persistent bleeding can be managed with stapled wedge resection. More central injuries traditionally have been managed with pulmonary lobectomy or pneumonectomy. But current treatment relies on pulmonary tractotomy, which permits selective ligation of individual bronchioles and bleeders, prevents the development of an intraparenchymal hematoma or air embolism, and reduces the need for formal lobar resection (see Fig. 7-49). 57,58 A stapling device, preferably the longest GIA stapler available, is inserted directly into the injury track and positioned along the thinnest section of overlying parenchyma. The injury track is thus filleted open, which allows direct access to the bleeding vessels and leaking bronchi. The majority of injuries are definitively managed with selective ligation, and the defect is left open. Occasionally, tractotomy reveals a more proximal vascular injury that must be treated with formal lobectomy. Parenchymal injuries severe enough to mandate pneumonectomy usually are fatal because of right heart decompensation, and major pulmonary hilar injuries necessitating pneumonectomy are usually lethal in the field.59 One parenchymal injury that may be incidentally discovered during thoracic imaging is a posttraumatic pulmonary pseudocyst, colloquially termed a pneumatocele. Traumatic pneumatoceles typically follow a benign clinical course and are treated with aggressive pain management, pulmonary toilet, and serial chest radiography to monitor for resolution of the lesion. If the patient has persistent fever or leukocytosis, however, chest CT is done to evaluate for an evolving abscess, because up to 30% of pneumatoceles become infected. CT-guided catheter drainage may be required in such cases, because 25% of patients do not respond to antibiotic therapy alone. Surgery, ranging from partial resection to anatomic lobectomy, is indicated for unresolving complex pneumatoceles or infected lesions refractory to antibiotic therapy and drainage.

The most common complication after thoracic injury is development of an empyema. Management is based on CT diagnostic criteria. Percutaneous drainage is indicated for single loculations without appreciable rind. Early decortication via video-assisted thoracic surgery is pursued in patients with multiple loculations or a pleural rind of >1 cm. 60 Antibiotic treatment is based on definitive culture results. Due to the proximity of the structures, esophageal injuries often occur with tracheobronchial injuries, particularly in cases of penetrating trauma. Operative options are based on the extent and location of esophageal injury. With sufficient mobilization, a primary single-layer end-to-end anastomosis may be performed after appropriate débridement. As with cervical repairs, if there are two suture lines in close approximation (trachea or bronchi and esophagus) interposition of a vascularized pedicle will prevent fistula formation. Perforations close to the gastroesophageal junction may be best treated with segmental resection and gastric pull-up. With large destructive injuries or delayed presentation of injuries, esophageal exclusion with wide drainage, diverting loop esophagostomy, and placement of a gastrostomy tube should be considered.

CHEST WALL AND DIAPHRAGM Virtually all chest wall injuries, consisting of rib fractures and laceration of intercostal vessels, are treated nonoperatively with pain control, pulmonary toilet or ventilatory management, and drainage of the pleural space as indicated. Early institution of effective pain control is essential. The authors advocate rib blocks with 0.25% bupivacaine hydrochloride (Marcaine) in the trauma bay, followed by epidural placement supplemented with patient-controlled anesthesia. Persistent hemorrhage from a chest tube after blunt trauma most often is due to injured intercostal arteries; for unusual persistent bleeding (see Table 7-10), thoracotomy with direct ligation or angioembolization may be required to arrest hemorrhage. In rare cases of extensive flail chest segments or markedly displaced rib fractures, open reduction and internal fixation of the fracture with plates may be warranted. Chest wall defects, particularly those seen with open pneumothorax, are repaired using local approximation of tissues or tissue transfer for coverage. Scapular and sternal fractures rarely require operative intervention but are markers for significant thoracoabdominal force during injury. Careful examination and imaging should exclude associated injuries, including blunt cardiac injury and aortic tears. On the other hand, clavicle fractures often are isolated injuries and should be managed with pain control and immobilization. The exception is posterior dislocation of the clavicular head, which may injure the subclavian vessels. Blunt diaphragmatic injuries result in a linear tear in the central tendon, whereas penetrating injuries are variable in size and location depending on the agent of injury. Regardless of the etiology, acute injuries are repaired through an abdominal incision or with thoracoscopy/laparoscopy. After delineation of the injury, the chest should be evacuated of all blood and particulate matter, and thoracostomy tube placed if not previously done. Allis clamps are used to approximate the diaphragmatic edges, and the defect is closed with a running No. 1 polypropylene suture. Occasionally, large avulsions or shotgun wounds with extensive tissue loss will require polypropylene mesh or acellular dermal matrix (AlloDerm) to bridge the defect. Alternatively, transposition of the diaphragm cephalad one to two intercostal spaces may allow repair without undue tension. 61

Abdominal Injuries LIVER AND GALLBLADDER The liver's large size makes it the organ most susceptible to blunt trauma, and it is frequently involved in upper torso penetrating wounds. Nonoperative management of solid organ injuries is pursued in hemodynamically stable patients who do not have overt peritonitis or other indications for laparotomy. These patients should be admitted to the SICU with frequent hemodynamic monitoring, determination of hematocrit, and abdominal examination. The only absolute contraindication to nonoperative management is hemodynamic instability. Factors such as high injury grade, large hemoperitoneum, contrast extravasation, or pseudoaneurysms may predict complications or failure of nonoperative management. However, angioembolization and endoscopic retrograde cholangiopancreatography (ERCP) are useful adjuncts that can improve the success rate of nonoperative management.62,63 The indication for angiography to control hepatic hemorrhage is transfusion of 4 units of RBCs in 6 hours or 6 units of RBCs in 24 hours without hemodynamic instability. In the >10% of patients for whom emergent laparotomy is mandated, the primary goal is to arrest hemorrhage. Initial control of hemorrhage is best accomplished using perihepatic packing and manual compression. In either case, the edges of the liver laceration should be opposed for local pressure control of bleeding. Hemorrhage from most major hepatic injuries can be controlled with effective perihepatic packing. The right costal margin is elevated, and the pads are strategically placed over and around the bleeding site (see Fig. 7-36). Additional pads should be placed between the liver, diaphragm, and anterior chest wall until the bleeding has been controlled. Ten to 15 pads may be required to control the hemorrhage from an extensive right lobar injury. Packing of injuries of the left lobe is not as effective, because there is insufficient abdominal and thoracic wall anterior to the left lobe to provide adequate compression with the abdomen open. Fortunately, hemorrhage from the left lobe usually can be controlled by mobilizing the lobe and compressing it between the surgeon's hands. If the patient has persistent bleeding despite packing, injuries to the hepatic artery, portal vein, and retrohepatic vena cava should be considered. The Pringle maneuver can help delineate the source of hemorrhage. Hemorrhage from hepatic artery and portal vein injuries will halt with the application of a vascular clamp across the portal triad, whereas bleeding from the hepatic veins and retrohepatic vena cava will not. Injuries of the portal triad vasculature should be addressed immediately. In general, ligation from the celiac axis to the level of the common hepatic artery at the gastroduodenal arterial branch is tolerated due to the extensive collaterals, but the proper hepatic artery should be repaired. The right or left hepatic artery, or in urgent situations the portal vein, may be selectively ligated; occasionally, lobar necrosis will necessitate delayed anatomic resection. If the right hepatic artery is ligated, cholecystectomy also should be performed. If the vascular injury is a stab wound with clean transection of the vessels, primary end-to-end repair is done. If the injury is destructive, temporary shunting should be performed followed by interposition reversed saphenous vein graft (RSVG). Blunt avulsions of the portal structures are particularly problematic if located at the hepatic plate, flush with the liver; hemorrhage control at the liver can be attempted with directed packing or Fogarty catheters. If the avulsion is more proximal, flush with the border of the pancreatic body or even retropancreatic, the pancreas must be transected to gain access for hemorrhage control and repair. If massive venous hemorrhage is seen from behind the liver despite use of the Pringle maneuver, the patient likely has a hepatic vein or retrohepatic vena cava injury. If bleeding is controlled, the packing should be left undisturbed and the patient observed in the SICU. If bleeding continues despite repeat perihepatic packing, then direct

repair, with or without hepatic vascular isolation, should be attempted. Three techniques have been used to accomplish hepatic vascular isolation: (a) isolation with clamps on the diaphragmatic aorta, the suprarenal vena cava, and the suprahepatic vena cava; (b) atriocaval shunt; and (c) Moore-Pilcher balloon shunt. All techniques are performed with an associated Pringle maneuver. Even in experienced centers with readily available equipment, however, such techniques carry a mortality rate of >80%. Instead, recent efforts to control this highly lethal injury have used venovenous bypass (Fig. 7-58). 64 Fig. 7-58.

Venovenous bypass permits hepatic vascular isolation with continued venous return to the heart. IMV = inferior mesenteric vein; IVC = inferior vena cava; SMV = superior mesenteric vein.

Numerous methods for the definitive control of hepatic parenchymal hemorrhage have been developed. Minor lacerations may be controlled with manual compression applied directly to the injury site. Topical hemostatic techniques include the use of an electrocautery (with the device set at 100 watts), argon beam coagulator, microcrystalline collagen, thrombin-soaked gelatin foam sponge, fibrin glue, and BioGlue. Suturing of the hepatic parenchyma is an effective hemostatic technique. However, the "liver suture," blunt 0 chromic suture, may tear the liver capsule, and its use generally is discouraged due to the associated hepatic necrosis. A running suture is used to approximate the edges of shallow lacerations, whereas deeper lacerations are approximated using interrupted horizontal mattress sutures placed parallel to the edge of the laceration. When the suture is tied, tension is adequate when visible hemorrhage ceases or the liver blanches around the suture. This technique of placing large liver sutures controls bleeding through reapproximation of the liver laceration rather than direct ligation of bleeding vessels. Aggressive finger fracture to identify bleeding vessels followed by individual clip or suture ligation was advocated previously but currently has a limited role in hemostasis. Hepatic lobar arterial ligation may be appropriate for patients with recalcitrant arterial hemorrhage from deep within the liver and is a reasonable alternative to a deep hepatotomy, particularly in unstable patients. Omentum can be used to fill large defects in the liver. The tongue of omentum not only obliterates potential dead space with viable tissue but also provides an excellent source of macrophages. Additionally, the omentum can provide buttressing support for parenchymal sutures. Translobar penetrating injuries are particularly challenging, because the extent of the injury cannot be fully visualized. As discussed later in "Damage Control Surgery," options include intraparenchymal tamponade with a Foley catheter or balloon occlusion (see Fig. 7-48). 65 If tamponade is successful with either modality, the balloon is left inflated for 24 to 48 hours followed by judicious deflation in the SICU and removal at a second laparotomy. Hepatotomy, using the finger fracture technique, with ligation of individual bleeders occasionally may be required. However, division of the overlying viable hepatic tissue may cause considerable blood loss in the coagulopathic patient. Finally, angioembolization is an effective adjunct in any of these scenarios and should be considered early in the course of treatment. Several centers have reported patients with devastating hepatic injuries or necrosis of the entire liver who have undergone successful hepatic transplantation. Clearly this is dramatic therapy, and the patient must have all other injuries delineated, particularly those of the central nervous system, and have an excellent chance of survival excluding the hepatic injury. Because donor availability will limit such procedures, hepatic transplantation for trauma will continue to be performed only in extraordinary circumstances. Cholecystectomy is performed for injuries of the gallbladder and after operative ligation of the right hepatic artery. Injuries of the extrahepatic bile ducts are a challenge due to their small size and thin walls. Because of the proximity of other portal structures and the vena cava, associated vascular injuries are common. These factors may preclude primary repair. Small lacerations with no accompanying loss or devitalization of adjacent tissue can be treated by the insertion of a T tube through the wound or by

lateral suturing using 6-0 monofilament absorbable suture. Virtually all transections and any injury associated with significant tissue loss will require a Roux-en-Y choledochojejunostomy.66 The anastomosis is performed using a single-layer interrupted technique with 4-0 or 5-0 monofilament absorbable suture. To reduce anastomotic tension, the jejunum can be sutured to the areolar tissue of the hepatic pedicle or porta hepatis. Injuries of the hepatic ducts are almost impossible to satisfactorily repair under emergent circumstances. One approach is to intubate the duct for external drainage and attempt a repair when the patient recovers. Alternatively, the duct can be ligated if the opposite lobe is normal and uninjured. Patients undergoing perihepatic packing for extensive liver injuries typically are returned to the OR for pack removal 24 to 48 hours after initial injury. Earlier exploration may be indicated in patients with evidence of ongoing hemorrhage. Signs of rebleeding include a falling hematocrit, accumulation of blood clots under the temporary abdominal closure device, and bloody output from drains; the magnitude of hemorrhage is reflected in hemodynamic instability and the findings of metabolic monitoring. Patients with hepatic ischemia due to prolonged intraoperative use of the Pringle maneuver have an expected elevation but subsequent resolution of transaminases levels, whereas patients requiring hepatic artery ligation may have frank hepatic necrosis. Although patients should be evaluated for infectious complications, patients with complex hepatic injuries typically have intermittent "liver fever" for the first 5 days after injury. The complications after significant hepatic trauma include delayed hemorrhage, bilomas, hepatic necrosis, arterial pseudoaneurysms, and various fistulas (Fig. 7-59). In patients requiring perihepatic packing, postoperative hemorrhage should be re-evaluated in the OR once the patient's coagulopathy is corrected. Alternatively, angioembolization is appropriate for complex injuries. Bilomas are loculated collections of bile, which may or may not be infected. If infected, they should be treated like an abscess via percutaneous drainage. Although small, sterile bilomas eventually will be reabsorbed, larger fluid collections should also be drained. Biliary ascites, due to the disruption of a major bile duct, often requires reoperation and wide drainage. Primary repair of the injured duct is unlikely to be successful. Resectional débridement is indicated for the removal of peripheral portions of nonviable hepatic parenchyma. Fig. 7-59.

Complications after hepatic trauma include bilomas (A;arrow), hepatic duct injuries (B), and hepatic necrosis after hepatic artery ligation or embolization (C). Pseudoaneurysms and biliary fistulas are rare complications in patients with hepatic injuries. Because hemorrhage from hepatic injuries often is treated without isolating individual bleeding vessels, arterial pseudoaneurysms may develop, with the potential for rupture. Rupture into a bile duct results in hemobilia, which is characterized by intermittent episodes of right upper quadrant pain, upper GI hemorrhage, and jaundice. If the aneurysm ruptures into a portal vein, portal venous hypertension with bleeding esophageal varices may occur. Either scenario is best managed with hepatic arteriography and embolization. Biliovenous fistulas, causing jaundice due to rapid increases in serum bilirubin levels, should be treated with ERCP and sphincterotomy. Rarely, a biliary fistulous communication will form with intrathoracic structures in patients with associated diaphragm injuries, resulting in a bronchobiliary or pleurobiliary fistula. Due to the pressure differential between the biliary tract (positive) and the pleural cavity (negative), the majority require operative closure. Occasionally, endoscopic sphincterotomy with stent placement will effectively address the pressure differential, and the pleurobiliary fistula will close spontaneously.

SPLEEN Until the 1970s, splenectomy was considered mandatory for all splenic injuries. Recognition of the immune function of the spleen refocused efforts on operative splenic salvage in the 1980s. 67,68 After success in pediatric patients, nonoperative management has become the preferred means of splenic salvage. The identification of contrast extravasation as a risk factor for failure of nonoperative management led to liberal use of angioembolization. The true value of angioembolization in splenic salvage has not been rigorously evaluated. It is clear, however, that 20 to 30% of patients with splenic trauma deserve early splenectomy and that failure of nonoperative management

often represents poor patient selection. 69,70 Unlike hepatic injuries, which rebleed in 24 to 48 hours, delayed hemorrhage or rupture of the spleen can occur up to weeks after injury. Indications for prompt laparotomy include initiation of blood transfusion within the first 12 hours and hemodynamic instability. Splenic injuries are managed operatively by splenectomy, partial splenectomy, or splenic repair (splenorrhaphy), based on the extent of the injury and the physiologic condition of the patient. Splenectomy is indicated for hilar injuries, pulverized splenic parenchyma, or any injury of grade II or higher in a patient with coagulopathy or multiple injuries. The authors use autotransplantation of splenic implants (Fig. 7-60) to achieve partial immunocompetence in younger patients.71 Drains are not used. Partial splenectomy can be employed in patients in whom only the superior or inferior pole has been injured. Hemorrhage from the raw splenic edge is controlled with horizontal mattress sutures, with gentle compression of the parenchyma (Fig. 7-61). As in repair of hepatic injuries, in splenorrhaphy hemostasis is achieved by topical methods (electrocautery; argon beam coagulation; application of thrombin-soaked gelatin foam sponges, fibrin glue, or BioGlue), envelopment of the injured spleen in absorbable mesh, and pledgeted suture repair. Fig. 7-60.

Autologous splenic transplantation is performed by placing sections of splenic parenchyma, 40 x 40 x 3 mm in size, into pouches in the greater omentum.

Fig. 7-61.

Interrupted pledgeted sutures may effectively control hemorrhage from the cut edge of the spleen. After splenectomy or splenorrhaphy, postoperative hemorrhage may be due to loosening of a tie around the splenic vessels, an improperly ligated or unrecognized short gastric artery, or recurrent bleeding from the spleen if splenic repair was used. An immediate postsplenectomy increase in platelets and WBCs is normal; however, beyond postoperative day 5, a WBC count above 15,000/mm 3 and a platelet/WBC ratio of <20 are strongly associated with sepsis and should prompt a thorough search for underlying infection.72 A common infectious complication after splenectomy is a subphrenic abscess, which should be managed with percutaneous drainage. Additional sources of morbidity include a concurrent but unrecognized iatrogenic injury to the pancreatic tail during rapid splenectomy resulting in pancreatic ascites or fistula. Enthusiasm for splenic salvage was driven by the rare, but often fatal, complication of overwhelming postsplenectomy sepsis. Overwhelming postsplenectomy sepsis is caused by encapsulated bacteria, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are resistant to antimicrobial treatment. In patients undergoing splenectomy, prophylaxis against these bacteria is provided via vaccines administered optimally at 14 days.

STOMACH AND SMALL INTESTINE Little controversy exists regarding the repair of injuries to the stomach or small bowel. Gastric wounds can be oversewn with a running single-layer suture line or closed with a transection/anastomosis (TA) stapler. If a single-layer closure is chosen, full-thickness bites should be taken to ensure hemostasis from the well-vascularized gastric wall. The most commonly missed gastric injury is the posterior wound of a through-and-through penetrating injury. Injuries also can be overlooked if the wound is located within the mesentery of the lesser curvature or high in the posterior fundus. To delineate a questionable injury, the stomach can be digitally occluded at the pylorus while methylene blue–colored saline is instilled via a nasogastric tube. Partial gastrectomy may be required for destructive injuries, with resections of the distal antrum or pylorus reconstructed using a Billroth I or II procedure. Patients with injuries that damage both Latarjet nerves or vagi should undergo a drainage procedure (see Chap. 26). Small intestine injuries can be repaired using a transverse running 3-0 PDS suture if the injury is less than one third the circumference of the bowel. Destructive injuries or multiple penetrating injuries occurring close together are treated with segmental resection followed by end-to-end anastomosis using a continuous, single-layer 3-0 polypropylene suture.73 Mesenteric injuries may result in an ischemic segment of intestine, which mandates resection. Following repair of GI tract injuries, there is an obligatory postoperative ileus. Return of bowel function is indicated by a decrease in gastrostomy or nasogastric tube output. The topic of nutrition is well covered in other chapters, but a few issues warrant mention. Multiple studies have confirmed the importance of early total enteral nutrition (TEN) in the trauma population, particularly its impact in reducing septic complications. 74 The route of enteral feedings (stomach vs. small bowel) tends to be less important, because gut tolerance appears equivalent unless there is upper GI tract pathology. Although early enteral nutrition is the goal, one should be wary with any bowel anastomoses; evidence of bowel function should be apparent before advancing to goal tube feedings. Overzealous jejunal feeding can lead to small bowel necrosis in the patient recovering from profound shock. Patients undergoing monitoring for nonoperative management of grade II or higher solid organ injuries should receive nothing by mouth for at least 48 hours in case they require an operation. Although there is general reluctance to initiate TEN in patients with an open abdomen, tube feeding by any route may be started within 24 hours of abdominal closure, because over 90% of patients will tolerate TEN. Moreover, in patients relegated to an open abdomen, TEN is frequently tolerated at low volumes—that is, trophic tube feeds (25 mL/h)—while active attempts are made to close fascia. In general, wounds sustained from trauma should be examined daily for progression of healing and signs of infection. Complex soft tissue wounds of the abdomen, such as degloving injuries after blunt trauma (termed Morel-Lavallee lesions), shotgun wounds, and other destructive blast injuries, are particularly difficult to manage. Following initial débridement of devitalized tissue, wound care includes wet-to-dry dressing changes twice daily or application of a vacuum-assisted wound closure (VAC) device. Repeated operative débridement may be necessary, and early involvement of the reconstructive surgery service for possible flap coverage is advised. Midline laparotomy wounds are inspected 48 hours postoperatively by removing the sterile surgical dressing. If an ileostomy or colostomy was required, one should inspect it daily to ensure that it is viable. If the patient develops high-grade fever, the wound should be inspected sooner to exclude an early necrotizing infection. If a wound infection is identified— as evidenced by erythema, pain along the wound, or purulent drainage—the wound should be widely opened by removing skin staples. After ensuring that the midline fascia is intact with digital palpation, the wound is initially managed with wet-to-dry dressing changes. The most common intra-abdominal complications are anastomotic failure and abscess. The choice between percutaneous and operative therapy is based on the location, timing, and extent of the collection.

DUODENUM AND PANCREAS The spectrum of injuries to the duodenum includes hematomas, perforation (blunt blow-outs, lacerations from stab wounds, or blast injury from gunshot wounds), and

combined pancreaticoduodenal injuries. The majority of duodenal hematomas are managed nonoperatively with nasogastric suction and parenteral nutrition. Patients with suspected associated perforation, suggested by clinical deterioration or imaging with retroperitoneal free air or contrast extravasation, should undergo operative exploration. A marked drop in nasogastric tube output heralds resolution of the hematoma, which typically occurs within 2 weeks; repeat imaging to confirm these clinical findings is optional. If the patient shows no clinical or radiographic improvement within 3 weeks, operative evaluation is warranted. Small duodenal perforations or lacerations can be treated by primary repair using a running single-layer suture of 3-0 monofilament. The wound should be closed in a direction that results in the largest residual lumen. Challenges arise when there is a substantial loss of duodenal tissue. Extensive injuries of the first portion of the duodenum (proximal to the duct of Santorini) can be repaired by débridement and end-to-end anastomosis because of the mobility and rich blood supply of the distal gastric atrium and pylorus. In contrast, the second portion is tethered to the head of the pancreas by its blood supply and the ducts of Wirsung and Santorini; therefore, no more than 1 cm of duodenum can be mobilized away from the pancreas, and this does not effectively alleviate tension on the suture line. Moreover, suture repair using an end-to-end anastomosis in the second portion often results in an unacceptably narrow lumen. Therefore, defects in the second portion of the duodenum should be patched with a vascularized jejunal graft. Duodenal injuries with tissue loss distal to the papilla of Vater and proximal to the superior mesenteric vessels are best treated by Rouxen-Y duodenojejunostomy with the distal portion of the duodenum oversewn (Fig. 7-62). In particular, injuries in the distal third and fourth portions of the duodenum (behind the mesenteric vessels) should be resected, and a duodenojejunostomy performed on the left side of the superior mesenteric vessels. Fig. 7-62.

Roux-en-Y duodenojejunostomy is used to treat duodenal injuries between the papilla of Vater and superior mesenteric vessels when tissue loss precludes primary repair.

Optimal management of pancreatic trauma is determined by where the parenchymal damage is located and whether the intrapancreatic common bile duct and main pancreatic duct remain intact. Patients with pancreatic contusions (defined as injuries that leave the ductal system intact) can be treated nonoperatively or with closed suction drainage if undergoing laparotomy for other indications. In contrast, pancreatic injuries associated with ductal disruption require intervention to prevent a pancreatic fistula or ascites. To determine the integrity of the pancreatic duct, several options exist. Direct exploration of the parenchymal laceration will often confirm the diagnosis of a ductal injury. Operative pancreatography can be performed through a duodenotomy by cannulating the duct using a 5F pediatric feeding tube. Under fluoroscopy, fullstrength contrast material is slowly injected while observing for obstruction or extravasation. An alternative to pancreatography is to pass a 1.5- to 2.0-mm coronary artery dilator into the main duct via the papilla and observe the depth of the pancreatic wound. If the dilator is seen in the wound, a ductal injury is confirmed. Either technique requires the creation of a duodenal wound and hence the potential for anastomotic leak and a lateral duodenal fistula; this possibility may dampen a surgeon's enthusiasm for this approach. A third method for identifying pancreatic ductal injuries is endoscopic retrograde pancreatography. Although challenging to perform emergently in the OR, it can be performed postoperatively once resuscitation is accomplished and is particularly advantageous in stable patients or those with a delayed presentation. Several options exist for treating injuries of the pancreatic body and tail when the pancreatic duct is transected. In stable patients, spleen-preserving distal pancreatectomy should be performed. An alternative, which preserves both the spleen and distal transected end of the pancreas, is either a Roux-en-Y pancreaticojejunostomy or pancreaticogastrostomy. If the patient is physiologically compromised, distal pancreatectomy with splenectomy is the preferred approach. Regardless of the choice of definitive procedure, the pancreatic duct in the proximal edge of transected pancreas should be individually ligated or occluded with a TA stapler. Application of fibrin glue over the stump may be advantageous. Injuries to the pancreatic head add an additional element of complication because the intrapancreatic portion of the common bile duct traverses this area and often

converges with the pancreatic duct. In contrast to diagnosis of pancreatic duct injuries, identification of intrapancreatic common bile duct disruption is relatively simple. The first method is to squeeze the gallbladder and look for bile leaking from the pancreatic wound. Otherwise, cholangiography, optimally via the cystic duct, is diagnostic. Definitive treatment of this injury entails division of the common bile duct superior to the first portion of the duodenum, with ligation of the distal duct and reconstruction with a Roux-en-Y choledochojejunostomy. For injuries to the head of the pancreas that involve the main pancreatic duct but not the intrapancreatic bile duct, there are few options. Distal pancreatectomy alone is rarely indicated due to the extended resection of normal gland and the resultant risk of pancreatic insufficiency. Central pancreatectomy preserves the common bile duct, and mobilization of the pancreatic body permits drainage into a Roux-en-Y pancreaticojejunostomy (Fig. 7-63). Although this approach avoids a pancreaticoduodenectomy (Whipple procedure), the complexity may make the pancreaticoduodenectomy more appropriate in patients with multiple injuries. Some injuries of the pancreatic head do not involve either the pancreatic or common bile duct; if no clear ductal injury is present, drains are placed. Rarely, patients sustain destructive injuries to the head of the pancreas or combined pancreaticoduodenal injuries that require pancreaticoduodenectomy. Examples of such injuries include transection of both the intrapancreatic bile duct and the main pancreatic duct in the head of the pancreas, avulsion of the papilla of Vater from the duodenum, and destruction of the entire second portion of the duodenum. Fig. 7-63.

For injuries of the pancreatic head that involve the pancreatic duct but spare the common bile duct, central pancreatic resection with Roux-en-Y pancreaticojejunostomy prevents pancreatic insufficiency.

Pyloric exclusion often is used to divert the GI stream after high-risk, complex duodenal repairs (Fig. 7-64). 75 If the duodenal repair breaks down, the resultant fistula is an end fistula, which is easier to manage and more likely to close than a lateral fistula. To perform a pyloric exclusion, first a gastrostomy is made on the greater curvature near the pylorus. The pylorus is then grasped with a Babcock clamp, via the gastrostomy, and oversewn with an O polypropylene suture. A gastrojejunostomy restores GI tract continuity. Vagotomy is not necessary because a risk of marginal ulceration has not been documented. Perhaps surprisingly, the sutures maintain diversion for only 3 to 4 weeks. Alternatively, the most durable pyloric closure is a double external staple line across the pylorus using a TA stapler. Fig. 7-64.

A. Pyloric exclusion is used to treat combined injuries of the duodenum and the head of the pancreas as well as isolated duodenal injuries when the duodenal repair is less than optimal. B and C. The pylorus is oversewn through a gastrotomy, which is subsequently used to create a gastrojejunostomy. The authors frequently use needlecatheter jejunostomy tube feedings for these patients. Complications should be expected after such injuries. Delayed hemorrhage is rare but may occur with pancreatic necrosis or abdominal infection; this usually can be managed by angioembolization. If closed suction drains have been inserted for major pancreatic trauma, these should remain in place until the patient is tolerating an oral diet or enteral nutrition. Pancreatic fistula is diagnosed after postoperative day 5 in patients with drain output of >30 mL/d and a drain amylase level three times the serum value. Pancreatic fistula develops in over 20% of patients with combined injuries and should be managed similar to fistulas after elective surgery (see Chap. 33). Similarly, a duodenal fistula, presumptively an end fistula if a pyloric exclusion has been done, will typically heal in 6 to 8 weeks with adequate drainage and control of intra-abdominal sepsis. Pancreatic pseudocysts in patients managed nonoperatively suggest a missed injury, and ERCP should be done to evaluate the integrity of the pancreatic duct. Late pseudocysts may be a complication of operative management and are treated much like those in patients with pancreatitis (see Chap. 33). Intra-abdominal abscesses are common and routinely managed with percutaneous drainage.

COLON AND RECTUM Currently, three methods for treating colonic injuries are used: primary repair, end colostomy, and primary repair with diverting ileostomy. Primary repairs include lateral suture repair or resection of the damaged segment with reconstruction by ileocolostomy or colocolostomy. All suturing and anastomoses are performed using a running single-layer technique (Fig. 7-65). 73 The advantage of definitive treatment must be balanced against the possibility of anastomotic leakage if suture lines are created under suboptimal conditions. Alternatively, although use of an end colostomy requires a second operation, an unprotected suture line with the potential for breakdown is avoided. Numerous large retrospective and several prospective studies have now clearly demonstrated that primary repair is safe and effective in virtually all patients with penetrating wounds. 76 Colostomy is still appropriate in a few patients, but the current dilemma is how to select which patients should undergo the procedure. Currently, the overall physiologic status of the patient, rather than local factors, directs decision making. Patients with devastating left colon injuries requiring damage control are clearly candidates for temporary colostomy. Ileostomy with colocolostomy, however, is used for most other high-risk patients. Fig. 7-65.

Technique for bowel repair and anastomosis. A. The running, single-layer suture is started at the mesenteric border. B. Stitches are spaced 3 to 4 mm from the edge of the bowel and advanced 3 to 4 mm, including all layers except the mucosa. C. The continuous suture is tied near the antimesenteric border.

Rectal injuries are similar to colonic injuries with respect to the ecology of the luminal contents, overall structure, and blood supply of the wall, but access to extraperitoneal injuries is limited due to the surrounding bony pelvis. Therefore, indirect treatment with intestinal diversion usually is required. The current options are loop ileostomy and sigmoid loop colostomy. These are preferred because they are quick and easy to perform, and provide essentially total fecal diversion. For sigmoid colostomy, technical elements include (a) adequate mobilization of the sigmoid colon so that the loop will rest on the abdominal wall without tension, (b) maintenance of the spur of the colostomy (the common wall of the proximal and distal limbs after maturation) above the level of the skin with a one-half-inch nylon rod or similar device, (c) longitudinal incision in the tenia coli, and (d) immediate maturation in the OR (Fig. 7-66). If the injury is accessible (e.g., in the posterior intraperitoneal portion of the rectum), repair of the injury should also be attempted. However, it is not necessary to explore the extraperitoneal rectum to repair a distal perforation. If the rectal injury is extensive, another option is to divide the rectum at the level of the injury, oversew or staple the distal rectal pouch if possible, and create an end colostomy (Hartmann's procedure). Extensive injuries may warrant presacral drainage with Penrose drains placed along Waldeyer's fascia via a perianal incision (see Fig. 7-66). In rare instances in which destructive injuries are present, an abdominoperineal resection may be necessary to avert lethal pelvic sepsis. Fig. 7-66.

Loop colostomy will completely divert the fecal flow, allowing the low rectal injury to heal. For extensive wounds, presacral drains are inserted through a perianal incision

(box) and advanced along Waldeyer's fascia (dashed line). Complications related to colorectal injuries include intra-abdominal abscess, fecal fistula, wound infection, and stomal complications. Intra-abdominal abscesses occur in approximately 10% of patients, and most are managed with percutaneous drainage. Fistulas occur in 1 to 3% of patients and usually present as an abscess or wound infection with subsequent continuous drainage of fecal output; the majority will heal spontaneously with routine care (see Chap. 29). Stomal complications (necrosis, stenosis, obstruction, and prolapse) occur in 5% of patients and may require either immediate or delayed reoperation. Stomal necrosis should be carefully monitored, because spread beyond the mucosa may result in septic complications, including necrotizing fasciitis of the abdominal wall. Penetrating injuries that involve both the rectum and adjacent bony structures are prone to development of osteomyelitis. Bone biopsy is performed for diagnosis and bacteriologic analysis, and treatment entails long-term IV antibiotic therapy and occasionally débridement.

ABDOMINAL VASCULATURE Injury to the major arteries and veins in the abdomen are a technical challenge. 77–83 Although penetrating trauma indiscriminately affects all blood vessels, blunt trauma most commonly involves renal vasculature and rarely the abdominal aorta. Patients with a penetrating aortic wound who survive to reach the OR frequently have a contained hematoma within the retroperitoneum. Due to lack of mobility of the abdominal aorta, few injuries are amenable to primary repair. Small lateral perforations may be controlled with 4-0 polypropylene suture or a PTFE patch, but end-to-end interposition grafting with a PTFE tube graft is the most common repair. In contrast, blunt injuries are typically intimal tears of the infrarenal aorta and are readily exposed via a direct approach. To avoid future vascular-enteric fistulas, the vascular suture lines should be covered with omentum. Penetrating wounds to the superior mesenteric artery (SMA) are typically encountered upon exploration for a gunshot wound, with "black bowel" and associated supramesocolic hematoma being pathognomonic. Blunt avulsions of the SMA are rare but should be considered in patients with a seat belt sign who have midepigastric pain or tenderness and associated hypotension. For injuries of the SMA, temporary damage control with a Pruitt-Inahara shunt can prevent extensive bowel necrosis; additionally, temporary shunting allows control of visceral contamination before placement of a PTFE graft. For definitive repair, end-to-end interposition RSVG from the proximal SMA to the SMA past the point of injury can be performed if there is no associated pancreatic injury. Alternatively, if the patient has an associated pancreatic injury, the graft should be tunneled from the distal aorta beneath the duodenum to the distal SMA. For proximal SMV injuries, digital compression for hemorrhage control is followed by attempted venorrhaphy; ligation is an option in a life-threatening situation, but the resultant bowel edema requires aggressive fluid resuscitation. Temporary abdominal closure and a second-look operation to evaluate bowel viability should be done. Transpelvic gunshot wounds or blunt injuries with associated pelvic fractures are the most common scenarios in patients with iliac artery injuries. A Pruitt-Inahara shunt can be used for temporary shunting of the vessel for damage control. Definitive interposition grafting with excision of the injured segment is appropriate (see "Vascular Repair Techniques"). Careful monitoring for distal embolic events and reperfusion injury necessitating fasciotomy is imperative. In general, outcome after vascular injuries is related to (a) the technical success of the vascular reconstruction and (b) associated soft tissue and nerve injuries. Vascular repairs rarely fail after the first 12 hours, whereas, soft tissue infection is a limb threat for several weeks. Following aortic interposition grafting, the patient's SBP should not exceed 120 mmHg for at least the first 72 hours postoperatively. Patients requiring ligation of an inferior vena cava injury often develop marked bilateral lower extremity edema. To limit the associated morbidity the patient's legs should be wrapped with elastic bandages from the toes to the hips and elevated at a 45- to 60-degree angle. For superior mesenteric vein injuries, either ligation or thrombosis after venorrhaphy results in marked bowel edema; fluid resuscitation should be aggressive and abdominal pressure monitoring routine in these patients. Prosthetic graft infections are rare complications, but prevention of bacteremia is imperative; administration of antibiotics perioperatively and treatment of secondary infections is indicated. Long-term arterial graft complications such as stenosis or pseudoaneurysms are uncommon, and routine graft surveillance rarely is performed. Consequently, long-term administration of antiplatelet agents or antithrombotics is not routine.

GENITOURINARY TRACT When undergoing laparotomy for trauma, the best policy is to explore all penetrating wounds to the kidneys. Parenchymal renal injuries are treated with hemostatic and reconstructive techniques similar to those used for injuries of the liver and spleen: topical methods (electrocautery; argon beam coagulation; application of thrombin-soaked gelatin foam sponge, fibrin glue, or BioGlue) and pledgeted suture repair. Two caveats are recognized, however: The collecting system should be closed separately, and the renal capsule should be preserved to close over the repair of the collecting system (Fig. 7-67). Renal vascular injuries are common after penetrating trauma and may be deceptively tamponaded, which results in delayed hemorrhage. Arterial reconstruction using graft interposition should be attempted for renal preservation. For destructive parenchymal or irreparable renovascular injuries, nephrectomy may be the only option; a normal contralateral kidney must be palpated, because unilateral renal agenesis occurs in 0.1% of patients. Fig. 7-67.

When renorrhaphy is undertaken, effective repair is assisted by attention to several key points: A. Vascular occlusion controls bleeding and permits adequate visualization. B. The renal capsule is carefully preserved. C. The collecting system is closed separately with absorbable suture. D. The preserved capsule is closed over the collecting system repair. Over 90% of all blunt renal injuries are treated nonoperatively. Hematuria typically resolves within a few days with bed rest, although rarely bleeding is so persistent that bladder irrigation to dispel blood clots is warranted. Persistent gross hematuria may require embolization, whereas urinomas can be drained percutaneously. Operative intervention after blunt trauma is limited to renovascular injuries and destructive parenchymal injuries that result in hypotension. The renal arteries and veins are uniquely susceptible to traction injury caused by blunt trauma. As the artery is stretched, the inelastic intima and media may rupture, which causes thrombus formation and resultant stenosis or occlusion. The success rate for renal artery repair approaches 0%, but an attempt is reasonable if the injury is <3 hours old or if the patient has a solitary kidney or bilateral injuries.84 Reconstruction after blunt renal injuries may be difficult, however, because the injury is typically at the level of the aorta. If repair is not possible within this time frame, leaving the kidney in situ does not necessarily lead to hypertension or abscess formation. The renal vein may be torn or completely avulsed from the vena cava due to blunt trauma. Typically, the large hematoma causes hypotension, which leads to operative intervention. During laparotomy for blunt trauma, expanding or pulsatile perinephric hematomas should be explored. If necessary, emergent vascular control can be obtained by placing a curved vascular clamp across the hilum from an inferior approach. Techniques of repair and hemostasis are similar to those described earlier. Injuries to the ureters are uncommon but may occur in patients with pelvic fractures and penetrating trauma. An injury may not be identified until a complication (i.e., a urinoma) becomes apparent. If an injury is suspected during operative exploration but is not clearly identified, methylene blue or indigo carmine is administered IV with observation for extravasation. Injuries are repaired using 5-0 absorbable monofilament, and mobilization of the kidney may reduce tension on the anastomosis. Distal ureteral injuries can be treated by reimplantation facilitated with a psoas hitch and/or Boari flap. In damage control circumstances, the ureter can be ligated on both sides of the injury and a nephrostomy tube placed. Bladder injuries are subdivided into those with intraperitoneal extravasation and those with extraperitoneal extravasation. Ruptures or lacerations of the intraperitoneal bladder are operatively closed with a running, single-layer, 3-0 absorbable monofilament suture. Laparoscopic repair is becoming common in patients not requiring laparotomy for other injuries. Extraperitoneal ruptures are treated nonoperatively with bladder decompression for 2 weeks. Urethral injuries are managed by bridging the defect with a Foley catheter, with or without direct suture repair. Strictures are not uncommon but can be managed electively.

FEMALE REPRODUCTIVE TRACT Gynecologic injuries are rare. Occasionally the vaginal wall will be lacerated by a bone fragment from a pelvic fracture. Although repair is not mandated, it should be performed if physiologically feasible. More important, however, is recognition of the open fracture, need for possible drainage, and potential for pelvic sepsis. Penetrating injuries to the vagina, uterus, fallopian tubes, and ovaries are also uncommon, and routine hemostatic techniques are used. Repair of a transected fallopian tube can be attempted but probably is unjustified, because a suboptimal repair will increase the risk of tubal pregnancy. Transection at the injury site with proximal ligation and distal salpingectomy is a more prudent approach.

Pelvic Fractures and Emergent Hemorrhage Control Patients with pelvic fractures who are hemodynamically unstable are a diagnostic and therapeutic challenge for the trauma team. These injuries often occur in conjunction with other life-threatening injuries, and there is no universal agreement among clinicians on management. Current management algorithms in the United States incorporate variable time frames for bony stabilization and fixation, as well as hemorrhage control by preperitoneal pelvic packing and/or angioembolization. Early institution of a multidisciplinary approach with the involvement of trauma surgeons, orthopedic surgeons, interventional radiologists, the director of the blood bank, and anesthesiologists is imperative due to high associated mortality rates (Fig. 7-68). Fig. 7-68.

Management algorithm for patients with pelvic fractures with hemodynamic instability. CT = computed tomography; ED = emergency department; FAST = focused abdominal sonography for trauma; HD = hemodynamic; PLT = platelets; PRBCs = packed red blood cells; SICU = surgical intensive care unit.

Evaluation in the ED focuses on identification of injuries mandating operative intervention (e.g., massive hemothorax, ruptured spleen) and injuries related to pelvic fracture that alter management (e.g., injuries to the iliac artery). Immediate temporary stabilization with sheeting of the pelvis or application of commercially available compression devices should be performed. If the patient's primary source of bleeding is the fracture-related hematoma, several options exist for hemorrhage control. Because 85% of bleeding due to pelvic fractures is venous or bony in origin the authors advocate immediate external fixation and preperitoneal pelvic packing.85 Anterior external fixation decreases pelvic volume, which promotes tamponade of venous bleeding and prevents secondary hemorrhage from the shifting of bony elements. Pelvic packing, in which six laparotomy pads (four in children) are placed directly into the paravesical space through a small suprapubic incision, provides tamponade for the bleeding (Fig. 7-69). Pelvic packing also eliminates the often difficult decision by the trauma surgeon: OR vs. Interventional Radiology? All patients can be rapidly transported to the OR and packing can be accomplished in under 30 minutes. In the authors' experience, this results in hemodynamic stability and abrupt cessation of the need for ongoing blood transfusion in the majority of cases. Patients also can undergo additional procedures such as laparotomy, thoracotomy, external fixation of extremity fractures, open fracture débridement, or craniotomy. Currently, angiography is reserved for patients with evidence of ongoing pelvic bleeding after admission to the SICU. Patients undergo standard posttrauma resuscitative SICU care, and the pelvic packs are removed within 48 hours, a time frame chosen empirically based on the authors' experience with liver packing. The authors elect to repack the patient's pelvis if there is persistent oozing and perform serial washouts of the preperitoneal space if it appears infected. Fig. 7-69.

A. Pelvic packing is performed through a 6- to 8-cm midline incision made from the pubic symphysis cephalad, with division of the midline fascia. B. The pelvic hematoma often dissects the preperitoneal and paravesical space down to the presacral region, which facilitates packing; alternatively, blunt digital dissection opens the preperitoneal space for packing. C. Three standard surgical laparotomy pads are placed on each side of the bladder, deep within the preperitoneal space; the fascia is closed with an O polydioxanone monofilament suture and the skin with staples. Another clinical challenge is the open pelvic fracture. In many instances the wounds are located in the perineum, and the risk of pelvic sepsis and osteomyelitis is high. To reduce the risk of infection, performance of a diverting sigmoid colostomy is recommended. The pelvic wound is manually débrided and then irrigated daily with a highpressure pulsatile irrigation system until granulation tissue covers the wound. The wound is then left to heal by secondary intention with a wound VAC device.

Extremity Fractures, Vascular Injuries, and Compartment Syndromes Patients with injured extremities often require a multidisciplinary approach with involvement of trauma, orthopedic, and plastic surgeons to address vascular injuries, fractures, soft tissues injuries, and compartment syndromes. Immediate stabilization of fractures or unstable joints is done in the ED using Hare traction, knee immobilizers, or plaster splints. In patients with open fractures the wound should be covered with povidone iodine (Betadine)–soaked gauze and antibiotics administered. Options for fracture fixation include external fixation or open reduction and internal fixation with plates or intramedullary nails. Vascular injuries, either isolated or in combination with fractures, require emergent repair. Common combined injuries include clavicle/first rib fractures and subclavian artery injuries, dislocated shoulder/proximal humeral fractures and axillary artery injuries, supracondylar fractures/elbow dislocations and brachial artery injuries, femur fracture and superficial femoral artery injuries, and knee dislocation and popliteal vessel injuries. On-table angiography in the OR facilitates rapid intervention and is warranted in patients with evidence of limb threat at ED arrival. Arterial access for on-table lower extremity angiography can be obtained percutaneously at the femoral vessels with a standard arterial catheter, via femoral vessel exposure and direct cannulation, or with superficial femoral artery (SFA) exposure just above the medial knee. Controversy exists regarding which should be done first, fracture fixation or arterial repair. The authors prefer placement of temporary intravascular shunts with arterial occlusions to minimize ischemia during fracture treatment, with definitive vascular repair following. Rarely, immediate amputation may be considered due to the severity of orthopedic and neurovascular injuries. This is particularly true if primary nerve transection is present in addition to fracture and arterial injury. 86 Collaborative decision making by the trauma, orthopedic, and plastic/reconstructive team is encouraged. Operative intervention for vascular injuries should follow standard principles of repair (see "Vascular Repair Techniques"). For subclavian or axillary artery repairs, 6-mm PTFE graft and RSVG are used. Because associated injuries of the brachial plexus are common, a thorough neurologic examination of the extremity is mandated before operative intervention. Operative approach for a brachial artery injury is via a medial upper extremity longitudinal incision; proximal control may be obtained at the axillary artery, and an S-shaped extension through the antecubital fossa provides access to the distal brachial artery. The injured vessel segment is excised, and an end-to-end interposition RSVG graft is performed. Upper extremity fasciotomy is rarely required unless the patient manifests preoperative neurologic changes or diminished pulse upon revascularization, or the time to operative intervention is extended. For SFA injuries, external fixation of the femur typically is performed, followed by end-to-end RSVG of the injured SFA segment. Close monitoring for calf compartment syndrome is mandatory. Preferred access to the popliteal space for an acute injury is the medial oneincision approach with detachment of the semitendinosus, semimembranosus, and gracilis muscles (Fig. 7-70). Another option is a medial approach with two incisions using a longer RSVG, but this requires interval ligation of the popliteal artery and geniculate branches. Rarely, with open wounds a straight posterior approach with an S-shaped incision can be used. If the patient has an associated popliteal vein injury, this should be repaired first with a PTFE interposition graft while the artery is shunted. For an isolated popliteal artery injury, RSVG is performed with an end-to-end anastomosis. Compartment syndrome is common, and presumptive four-compartment fasciotomies are warranted in patients with combined arterial and venous injury. Once the vessel is repaired and restoration of arterial flow documented, completion angiography should be done in the OR if there is no palpable distal pulse. Vasoparalysis with verapamil, nitroglycerin, and papaverine may be used to treat vasoconstriction (Table 7-11). Fig. 7-70.

A. The popliteal space is commonly accessed using a single medial incision (the detached semitendinosus, semimembranosus, and gracilis muscles are identified by different suture types). B. Alternatively, a medial approach with two incisions may be used. Insertion of a Pruitt-Inahara shunt (arrow) provides temporary restoration of blood flow, which prevents ischemia during fracture treatment.

Table 7-11 Arterial Vasospasm Treatment Guideline Step 1: Intra-arterial alteplase (tissue plasminogen activator) 5 mg/20 mL bolus If spasm continues, proceed to step 2. Step 2: Intra-arterial nitroglycerin 200 g/20 mL bolus Repeat same dose once as needed. If spasm continues, proceed to step 3. Step 3: Inter-arterial verapamil 10 mg/10 mL bolus If spasm continues, proceed to step 4. Step 4: Inter-arterial papaverine drip 60 mg/50 mL given over 15 min

Compartment syndromes, which can occur anywhere in the extremities, involve an acute increase in pressure inside a closed space, which impairs blood flow to the structures within. Causes of compartment syndrome include arterial hemorrhage into a compartment, venous ligation or thrombosis, crush injuries, and ischemia and reperfusion. In conscious patients, pain is the prominent symptom, and active or passive motion of muscles in the involved compartment increases the pain. Paresthesias may also be described. In the lower extremity, numbness between the first and second toes is the hallmark of early compartment syndrome in the exquisitely sensitive anterior compartment and its enveloped deep peroneal nerve. Progression to paralysis can occur, and loss of pulses is a late sign. In comatose or obtunded patients, the diagnosis is more difficult to secure. In patients with a compatible history and a tense extremity, compartment pressures should be measured with a hand-held Stryker device. Fasciotomy is indicated in patients with a gradient of <35 mmHg (gradient = diastolic pressure – compartment pressure), ischemic periods of >6 hours, or combined arterial and venous injuries. The lower extremity is most frequently involved, and compartment release is performed using a two-incision, four-compartment fasciotomy (Fig. 7-71). Of note, the soleus muscle must be detached from the tibia to decompress the deep flexor compartment. Fig. 7-71.

A. The anterior and lateral compartments are approached from a lateral incision, with identification of the fascial raphe between the two compartments. Care must be taken to avoid the superficial peroneal nerve running along the raphe. B. To decompress the deep flexor compartment, which contains the tibial nerve and two of the three arteries to the foot, the soleus muscle must be detached from the tibia.

INTENSIVE CARE UNIT MANAGEMENT AND POSTOPERATIVE CONSIDERATIONS Postinjury Resuscitation ICU management of the trauma patient, either with direct admission from the ED or after emergent operative intervention, is considered in distinct phases, because there are differing goals and priorities. The period of acute resuscitation, typically lasting for the first 12 to 24 hours after injury, combines several key principles: optimizing tissue perfusion, ensuring normothermia, and restoring coagulation. There are a multitude of management algorithms aimed at accomplishing these goals, the majority of which involve goal-directed resuscitation with initial volume loading to attain adequate preload, followed by judicious use of inotropic agents or vasopressors. 87 Although the optimal hemoglobin level remains debated, during shock resuscitation a hemoglobin level of >10 g/dL is generally accepted to optimize oxygen delivery. After the first 24

hours of resuscitation, a more judicious transfusion trigger of a hemoglobin level of <7 g/dL in the euvolemic patient limits the adverse inflammatory effects of stored RBCs. The resuscitation of the severely injured trauma patient may require what appears to be an inordinate amount of crystalloid resuscitation. Infusion volumes of 10 L during the initial 6 to 12 hours may be required to attain an adequate preload. Although early colloid administration is appealing, evidence to date does not support this concept. In fact, optimizing crystalloid administration is a challenging aspect of early care (i.e., balancing cardiac performance against generation of an abdominal compartment syndrome and generalized tissue edema). Invasive monitoring with pulmonary artery catheters is controversial but may be a critical adjunct in patients with multiple injuries who require advanced inotropic support. Not only do such devices allow minute-to-minute monitoring of the patient, but the added information on the patient's volume status, cardiac function, peripheral vascular tone, and metabolic response to injury permits appropriate therapeutic intervention. With added information on the patient's cardiac function, cardiac indices and oxygen delivery become important variables in the ongoing ICU management. Resuscitation to values of >500 mL/min per square meter for the oxygen delivery index and >3.8 L/min per square meter for the cardiac index are the goals. Pulmonary artery catheters also enable the physician to monitor response to vasoactive agents. Although norepinephrine is the agent of choice for patients with low systemic vascular resistance who are unable to maintain a mean arterial pressure of >60 mmHg, patients may have an element of myocardial dysfunction requiring inotropic support. The role of relative adrenal insufficiency is another controversial area. Optimal early resuscitation is mandatory and determines when the patient can undergo definitive diagnosis as well as when the patient can be returned to the OR after initial damage control surgery. Specific goals of resuscitation before repeated "semielective" transport include a core temperature of >35°C (95°F), base deficit of <6 mmol/L, and normal coagulation indices. Although correction of metabolic acidosis is desirable, how quickly this should be accomplished requires careful consideration. Adverse sequelae of excessive crystalloid resuscitation include increased intracranial pressure, worsening pulmonary edema, and intra-abdominal visceral and retroperitoneal edema resulting in secondary abdominal compartment syndrome. Therefore, it should be the overall trend of the resuscitation rather than a rapid reduction of the base deficit that is the goal. Exogenous bicarbonate, occasionally given to improve cardiovascular function and response to vasoactive agents if the serum pH is below 7.2, obfuscates the base deficit trending, and lactate level is a more reliable indicator of adequate perfusion after the first 12 hours.

Abdominal Compartment Syndrome Abdominal compartment syndrome is classified as intra-abdominal hypertension due to intra-abdominal injury (primary) or splanchnic reperfusion after massive resuscitation (secondary). Secondary abdominal compartment syndrome may result from any condition requiring extensive crystalloid resuscitation, including extremity trauma, chest trauma, or even postinjury sepsis. The sources of increased intra-abdominal pressure include gut edema, ascites, bleeding, and packs, among others. A diagnosis of intraabdominal hypertension cannot reliably be made by physical examination; therefore, it is obtained by measuring the intraperitoneal pressure. The most common technique is to measure a patient's bladder pressure. Fifty milliliters of saline is instilled into the bladder via the aspiration port of the Foley catheter with the drainage tube clamped, and a three-way stopcock and water manometer is placed at the level of the pubic symphysis. Bladder pressure is then measured on the manometer in centimeters of water (Table 7-12) and correlated with the physiologic impact of abdominal compartment syndrome. Conditions in which the bladder pressure is unreliable include bladder rupture, external compression from pelvic packing, neurogenic bladder, and adhesive disease. Table 7-12 Abdominal Compartment Syndrome Grading System Bladder Pressure Grade

mmHg

cm H 2 O

I

10–15

13–20

II

16–25

21–35

III

26–35

36–47

IV

>35

>48

Increased abdominal pressure affects multiple organ systems (Fig. 7-72). Abdominal compartment syndrome, as noted earlier, is defined as intra-abdominal hypertension and frequently manifests via such end-organ sequelae as decreased urine output, increased pulmonary inspiratory pressures, decreased cardiac preload, and increased cardiac afterload. Because any of these clinical symptoms of abdominal compartment syndrome may be attributed to the primary injury, a heightened awareness of this syndrome must be maintained. Organ failure can occur over a wide range of recorded bladder pressures. Generally, no specific bladder pressure prompts therapeutic intervention, except when the pressure is >35 mmHg. Rather, emergent decompression is carried out when intra-abdominal hypertension reaches a level at which endorgan dysfunction occurs. Mortality is directly affected by decompression, with 60% mortality in patients undergoing presumptive decompression, 70% mortality in patients with a delay in decompression, and nearly uniform mortality in those not undergoing decompression. Decompression is performed operatively either in the ICU if the patient is hemodynamically unstable or in the OR. ICU bedside laparotomy is easily accomplished, avoids transport of hemodynamically compromised patients, and requires minimal equipment (e.g., scalpel, suction device, cautery, and dressings for temporary abdominal closure). In patients with significant intra-abdominal fluid as the primary component of abdominal compartment syndrome, rather than bowel or retroperitoneal edema, decompression may be accomplished effectively via a percutaneous drain. This method is particularly applicable for nonoperative management of major liver injuries. These patients are identified by bedside ultrasound, and the morbidity of a laparotomy is avoided. When operative decompression is required with egress of the abdominal contents, temporary coverage is obtained using a subfascial 45 x 60 cm sterile drape and Ioban application (see Fig. 7-50). Fig. 7-72.

Abdominal compartment syndrome is defined by the end organ sequelae of intra-abdominal hypertension. CO = cardiac output; CVP = central venous pressure; ICP = intracranial pressure; PA = pulmonary artery; SV = stroke volume; SVR = systemic vascular resistance; UOP = urine output; VEDV = ventricular end diastolic volume.

The performance of damage control surgery and recognition of abdominal compartment syndrome have dramatically improved patient survival, but at the cost of an open abdomen. Several management points deserve attention. Despite having a widely open abdomen, patients can develop recurrent abdominal compartment syndrome, which increases their morbidity and mortality; therefore, bladder pressure should be monitored every 4 hours, with significant increases in pressures alerting the clinician to the possible need for repeat operative decompression. Patients with an open abdomen lose between 500 and 2500 mL per day of abdominal effluent. Appropriate volume compensation for this albumin-rich fluid remains controversial, with regard to both the amount administered (replacement based on clinical indices vs. routine 1 / 2 mL replacement for every milliliter lost) as well as the type of replacement (crystalloid vs. colloid/blood products). Following resuscitation and management of specific injuries, the goal of the operative team is to close the abdomen as quickly as possible. Multiple techniques have been introduced to obtain fascial closure of the open abdomen to minimize morbidity and cost of care. Historically, for patients who could not be closed at repeat operation, approximation of the fascia with mesh (prosthetic or biologic) was used, with planned reoperation. Another option was split-thickness skin grafts applied directly to the exposed bowel for coverage; removal of the skin grafts was planned 9 to 12 months after the initial surgery, with definitive repair of the hernia by component separation. However, delayed abdominal wall reconstruction was resource invasive, with considerable patient morbidity. The advent of VAC technology has revolutionized fascial closure. The authors currently use a sequential closure technique with the wound VAC device that provides constant fascial tension and return to the OR every 48 hours until closure is complete (Fig. 7-73). The authors' success rate with this approach exceeds 95%. Among patients not attaining fascial closure, 20% suffer GI tract complications that prolong their hospital course. These include intra-abdominal abscess, enteric fistula, and bowel perforations (Fig. 7-74). Management includes operative or percutaneous drainage of abscesses, control of fistulas, and nutritional support for bowel complications. Fig. 7-73.

The authors' sequential closure technique for the open abdomen. A. Multiple white sponges (solid arrow), stapled together, are placed on top of the bowel underneath the

fascia. Interrupted No. 1 polydioxanone sutures are placed approximately 5 cm apart (dashed arrow), which puts the fascia under moderate tension over the white sponge. B. After the sticky clear plastic vacuum-assisted closure (VAC) dressing is placed over the white sponges and adjacent 5 cm of skin, the central portion is removed by cutting along the wound edges. C and D. Black VAC sponges are placed on top of the white sponges and plastic-protected skin with standard occlusive dressing and suction. E. On return to the operating room (OR) 48 hours later, fascial sutures are placed from both the superior and inferior directions until tension precludes further closure; skin is closed over the fascial closure with skin staples. F. White sponges (fewer in number) are again applied and fascial retention sutures are placed with planned return to the OR in 48 hours.

Fig. 7-74.

Complications after split-thickness skin graft closure of the abdomen include enterocutaneous fistulas (intubated here with a red rubber catheter) (A;arrow) and rupture of the graft with exposure of the bowel mucosa (B).

SPECIAL TRAUMA POPULATIONS Pregnant Patients Seven percent of women are injured during their pregnancy. Motor vehicle collisions and falls are the leading causes of injury, accounting for 70% of cases. Fetal death after trauma most frequently occurs after motor vehicle collisions, but only 11% of fetal deaths are due to the death of the mother; therefore, early trauma resuscitation and management is directed not only at the mother but also at the fetus. Domestic violence is also common, affecting between 10 and 30% of pregnant women and resulting in

fetal mortality of 5%. Pregnancy results in physiologic changes that may impact postinjury evaluation (Table 7-13). Heart rate increases by 10 to 15 beats per minute during the first trimester and remains elevated until delivery. Blood pressure diminishes during the first two trimesters due to a decrease in systemic vascular resistance and rises again slightly during the third trimester (mean values: first = 105/60, second = 102/55, third = 108/67). Intravascular volume is increased by up to 8 L, which results in a relative anemia but also a relative hypervolemia. Consequently a pregnant woman may lose 35% of her blood volume before exhibiting signs of shock. Pregnant patients have an increase in tidal volume and minute ventilation but a decreased functional residual capacity; this results in a diminished P CO2 reading and respiratory alkalosis. Also, pregnant patients may desaturate more rapidly, particularly in the supine position and during intubation. Supplemental oxygen is always warranted in the trauma patient but is particularly critical in the injured pregnant patient, because the oxygen dissociation curve is shifted to the left for the fetus compared to the mother (i.e., small changes in maternal oxygenation result in larger changes for the fetus because the fetus is operating in the steep portions of the dissociation curve). Anatomic changes contribute to these pulmonary functional alterations and are relevant in terms of procedures. With the gravid uterus enlarged, diagnostic peritoneal lavage (DPL) should be performed in a supraumbilical site with the catheter directed cephalad. In addition, the upward pressure on the diaphragm calls for caution when placing a thoracostomy tube; standard positioning may result in an intra-abdominal location or perforation of the diaphragm. Table 7-13 Physiologic Effects of Pregnancy Cardiovascular Increase in heart rate by 10–15 bpm Decreased systemic vascular resistance resulting in: (a) Increased intravascular volume (b) Decreased blood pressure during the first two trimesters Pulmonary Elevated diaphragm Increased tidal volume Increased minute ventilation Decreased functional residual capacity Hematopoietic Relative anemia Leukocytosis Hypercoagulability (a) Increased levels of factors VII, VIII, IX, X, XII (b) Decreased fibrinolytic activity Other Decreased competency of lower esophageal sphincter Increased enzyme levels on liver function tests Impaired gallbladder contractions Decreased plasma albumin level Decreased blood urea nitrogen and creatinine levels Hydronephrosis and hydroureter

Other physiologic changes during pregnancy affect the GI, renal, and hematologic systems. The lower esophageal sphincter has decreased competency, which increases the risk for aspiration. Liver function test values increase, with the alkaline phosphatase level nearly doubling. The high levels of progesterone impair gallbladder contractions, which results in bile stasis and an increased incidence of gallstone formation; this may not affect the trauma bay evaluation but becomes important in a prolonged ICU stay. Plasma albumin level decreases from a normal of around 4.3 g/dL to an average of 3.0 g/dL. Renal blood flow increases by 30% during pregnancy, which causes a decrease in serum level of blood urea nitrogen and creatinine. The uterus may also compress the ureters and bladder, causing hydronephrosis and hydroureter. Finally, as noted earlier there is a relative anemia during pregnancy, but a hemoglobin level of <11 g/dL is considered abnormal. Additional hematologic changes include a moderate leukocytosis (up to 20,000 mm 3 ) and a relative hypercoagulable state due to increased levels of factors VII, VIII, IX, X, and XII and decreased fibrinolytic activity. During evaluation in the ED, the primary and secondary surveys commence, with mindfulness that the mother always receives priority while conditions are still optimized for the fetus. This management includes provision of supplemental oxygen (to prevent maternal and fetal hypoxia), aggressive fluid resuscitation (the hypervolemia of pregnancy may mask signs of shock), and placement of the patient in the left lateral decubitus position (or tilting of the backboard to the left) to avoid caval compression. Assessment of the fetal heart rate is the most valuable information regarding fetal viability. Fetal monitoring should be performed with a cardiotocographic device that measures both contractions and fetal heart tones (FHTs). Because change in heart rate is the primary response of the fetus to hypoxia or hypotension, anything above an FHT of 160 is a cause for concern, whereas bradycardia (FHT of <120) is considered fetal distress. Ideally, if possible, a member of the obstetrics team will be present during initial evaluation to perform a pelvic examination using a sterile speculum. Vaginal bleeding can signal early cervical dilation and labor, abruptio placentae, or placenta previa. Amniotic sac rupture can result in prolapse of the umbilical cord with fetal compromise. Strong contractions are associated with true labor and should prompt consideration of delivery and resuscitation of the neonate. Focused prenatal history taking should elicit a history of pregnancy-induced hypertension, gestational diabetes, congenital heart disease, preterm labor, or placental abnormalities. Asking the patient when the baby first moved and if she is currently experiencing movement of

the fetus is important. Determining fetal age is important for considerations of viability. Gestational age may be estimated by noting fundal height, with the fundus approximating the umbilicus at 20 weeks and the costal margin at 40 weeks. Discrepancy in dates and size may be due to uterine rupture or hemorrhage. Initial evaluation for abdominopelvic trauma in pregnant patients should proceed in the standard manner. Ultrasound (FAST) of the abdomen should evaluate the four windows (pericardial, right and left upper quadrant, and bladder) and additionally assess FHTs, fetal movement, and sufficiency of amniotic fluid. DPL can be performed in pregnant women via a supraumbilical, open technique. Trauma radiography of pregnant patients presents a conundrum. Radiation damage has three distinct phases of damage and effec