Fluid Resuscitation

State of the Science for Treating Combat Casualties and Civilian Injuries

Andrew Pope, Geoffrey French, and David E. Longnecker, Editors

Committee on Fluid Resuscitation for Combat Casualties

Division of Health Sciences Policy

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, DC



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Fluid Resuscitation State of the Science for Treating Combat Casualties and Civilian Injuries Andrew Pope, Geoffrey French, and David E. Longnecker, Editors Committee on Fluid Resuscitation for Combat Casualties Division of Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, DC

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. This work relates to Department of Navy Grant N00014-98-1-0789 issued by the Office of Naval Research. The United States Government has a royalty-free license throughout the world in all copyrightable material contained herein. The views presented in this report are those of the Committee on Fluid Resuscitation for Combat Casualties and are not necessarily those of the funding organization. International Standard Book No. 0-309-06481-3 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's on-line bookstore at www.nap.edu. The full text of this report is available on-line at http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www2.nas.edu/iom. Copyright 1999 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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COMMITTEE ON FLUID RESUSCITATION FOR COMBAT CASUALTIES DAVID E. LONGNECKER (Chair), Robert D. Dripps Professor and Chair, Department of Anesthesia, University of Pennsylvania Health System WILLIAM G. BAXT, Professor and Chair, Department of Emergency Medicine, Chief, Emergency Services, University of Pennsylvania Health System JOSEPH C. FRATANTONI, Vice President, Biologics, C.L. McIntosh & Associates, Rockville, Maryland JURETA W. HORTON, Professor and Core Lab Director, Department of Surgery, University of Texas Southwestern Medical School, Dallas JOHN P. KAMPINE, Professor and Chairman, Department of Anesthesiology, Medical College of Wisconsin HARVEY G. KLEIN, Chief, Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland JOSEPH E. RALL, Senior Scientist, Emeritus, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland GEORGE F. SHELDON, Professor and Chair, Department of Surgery, School of Medicine, University of North Carolina at Chapel Hill BLAINE C. WHITE, Professor, Departments of Emergency Medicine and Physiology, Wayne State University School of Medicine Study Staff ANDREW POPE, Director, Health Sciences Policy Program GEOFFREY FRENCH, Project Officer CHARLES EVANS, Head, Health Sciences Section SARAH PITLUCK, Administrative Assistant GLEN SHAPIRO, Research and Project Assistant MELVIN H. WORTH, Jr., Scholar-in-Residence Consultant KATHI HANNA Copy Editor MICHAEL HAYES

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the Institute of Medicine in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. The committee wishes to thank the following individuals for their participation in the review of this report: H. RICHARD ADAMS, College of Veterinary Medicine, Texas A&M University; RONALD F. BELLAMY, Borden Institute, Walter Reed Army Medical Center, Washington, D.C.; ROBERT W. BERLINER, Yale University School of Medicine; ROBERT E. FORSTER, University of Pennsylvania School of Medicine; LAZAR J. GREENFIELD, University of Michigan School of Medicine; TIBOR J. GREENWALT, Hoxworth Blood Center, University of Cincinnati; RONALD D. MILLER, University of California at San Francisco; HELEN RANNEY, Alliance Pharmaceutical Corp., San Diego, California; PETER ROSEN, University of California at San Diego Medical Center; G. TOM SHIRES, University of Nevada School of Medicine, Trauma Institute, Las Vegas; DONALD D. TRUNKEY, Oregon Health Sciences University; MARY J. VASSAR, San Francisco Injury Center, University of California at San Francisco; and ROBERT M. WINSLOW, Sangart, Inc., San Diego, California. While the individuals listed above have provided constructive comments and suggestions, it must be emphasized that responsibility for the final content of this report rests entirely with the authoring committee and the Institute of Medicine.

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Preface The U.S. military has a long tradition of making the safety of its troops a top priority. This goal is evident in military strategy and tactics and in the development of sophisticated technology that decreases or avoids human risk. This commitment is evident in the fostering and support of biomedical research that is applicable to the military as well. The spectrum of supported research ranges from acute through chronic care of the soldier. The U.S. Department of Veterans Affairs, for example, invests in research on long-term rehabilitation from wounds or military-related disease, whereas the armed services often focus on the acute medical needs of the injured soldier. One of the most important goals involves immediate resuscitation of the wounded soldier in the field, to support life during transport to a field facility, where definitive treatment may be instituted by highly trained medical personnel. The Office of Naval Research asked our committee to focus on this immediate resuscitation to ensure that current care is optimal and that future research is focused in the most fertile areas for advancement. The National Academy of Sciences (NAS) has a long history of assisting the military in the evaluation of methods of resuscitation and shock. NAS volunteered its expertise to President Woodrow Wilson in 1916, and he responded by asking NAS to organize scientific agencies for national defense. At the conclusion of World War I in 1918, the president, by executive order, asked the Academy to perpetuate the National Research Council (NRC) for the government to have a consulting body available for a variety of needs. NRC played an important role in the studies of shock and resuscitation prior to and during World War II and provided advice for research policy and treatment protocols. The challenges associated with the immediate resuscitation of the wounded soldier are daunting and are often unappreciated by civilian medical personnel. Military engagements often take place in mud, rain, snow, heat, or cold, at sea or on beaches, and often at night. The field medics, who are responsible for ini-

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tial resuscitation and treatment, can carry only very limited medical gear, and they are often engaged in battle and under fire while attempting to treat the wounded. Thus, the need for simple, compact, and effective approaches for immediate resuscitation is apparent. Research in this area is extraordinarily challenging. First, there are few, if any, ways in which all aspects of human hemorrhagic shock can be fully reproduced in the laboratory. Various animal models can mimic specific aspects of the shock process, but no single model represents the entire spectrum of human hemorrhagic shock; there remain fundamental differences that apparently cannot be narrowed. Yet the use of unproven treatments in the field is simply unacceptable. The committee had two goals as it thought about research in this area. First, it wanted to indicate to the Office of Naval Research which technologies were best suited for use in the immediate future. Second, it wanted to give some direction for longer-term research by identifying promising areas that might lead to leaps in the knowledge about hemorrhagic shock or care for the combat casualty. As part of the committee's review of the state of the science, the committee held a 2-day conference and heard from more than 40 scientists, medical researchers, and clinicians in the field of resuscitation research. Subsequently, the committee solicited information from several additional scientists and from the scientific community at large. In the end, the committee felt comfortable with its grasp of current research and with its view of the opportunities for future investigation. These conclusions are presented in the text of this report. Finally, the committee wanted its work to have some relevance to the civilian medical community. Although its first responsibility was to the military, the committee understood that there are both similarities and differences between civilian emergency trauma care and acute military medicine. With this in mind, the committee was explicit in describing the similarities and differences between the combat and civilian environments, and it offered suggestions for technologies or approaches that would apply to civilian care as well. The committee hopes that this report will help energize and focus research in both military and civilian emergency medical care and help to save the lives of citizens and soldiers alike. On behalf of the committee, I wish to express our gratitude to all who contributed to the production of this report. First, we appreciate the opportunity that was presented by the Office of Naval Research, which initiated the questions and sponsored the project. Second, a review of the science would not be possible if it were not for the many scientists and experts whose findings formed the scientific basis of this report. Third, the arduous process of conducting the complex task was made easier by the talented staff of the Institute of Medicine, especially Andy Pope, Geoff French, and Glen Shapiro. Most importantly, I want to add my personal gratitude to the rest of this committee who volunteered countless hours of their time and expertise to produce this document.

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If the work that we have done here serves to assist in resuscitating even one casualty that would have otherwise been lost, as we believe it will, then this will have been a successful and worthwhile endeavor. DAVID E. LONGNECKER, M.D. CHAIR

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Photographs Page xii: A bottle of blood plasma hangs on a "wounded" man's rifle during a training exercise in 1943. Photograph by Marjory Collins. Courtesy of the Library of Congress. Page 8: Medics helping a wounded soldier in France, 1944. Courtesy of the National Archives and Records Administration. Page 18: An American soldier receives blood plasma in Sicily, 1943. Courtesy of the National Archives and Records Administration. Page 46: A blood transfusion underway aboard a DUKW during the fighting on Iwo Jima, 1945. Courtesy of the Bureau of Medicine Historical Archives. Page 78: Water and plasma being given to a marine at Eniwetok Atoll. Courtesy of the Bureau of Medicine Historical Archives. Page 96: Soldiers at a battalion aid station await evacuation while being transfused in Korea, 1952. Reprinted with permission of the American Red Cross. All rights reserved. Page 108: Wounded soldiers are evacuated aboard a tank in Vietnam, 1968. Photograph by John Olson. Copyright 1968 by Time, Inc. All rights reserved.

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Contents     Executive Summary   1 1   Introduction   9     History of Fluid Resuscitation   12     Origin, Scope, and Organization of the Report   16 2   Pathophysiology of Acute Hemorrhagic Shock   19     Definitions of Hemorrhagic Shock   19     Organ Involvement in Shock   21     Physiologic Responses To Hemorrhage   23     Shock Decompensation   24     Cellular Responses To Shock   25     Altered Energy Metabolism, Ion Compartmentalization, Lipid Metabolism, and Radical Production and Metabolism   25     Alterations in Macrophage Function   28     Surgical Bleeding Disorders   29     Fundamental Alterations in Transcription and Translation: Apoptosis   29     Alterations in Secretion of and Cellular Responsiveness to Growth Factors   36     Hematologic Abnormalities Associated with Shock and Resuscitation   38     Transfusion of the Patient in Shock   39     Massive Transfusion   40     Risks of Blood Transfusion   41

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    Blood Substitutes and Alternatives to Transfusion   41     Disseminated Intravascular Coagulation   42     Conclusions and Recommendations   43 3   Experience With And Complications of Fluid Resuscitation   47     Overview of Colloid and Crystalloid Resuscitation   47     Complications of Resuscitation In General   51     Effects of Fluid Resuscitation on Coagulation   51     Oxygen Toxicity Associated with Resuscitation   53     Reperfusion-Mediated Injury   54     Complications of Late Resuscitation of Shock   59     Complications of Colloid Resuscitation   60     Complications of Crystalloid Resuscitation   62     Effects of Crystalloid Resuscitation on Immune Function   62     Effects of Crystalloid Resuscitation on Cytokine Response   67     Adverse Effects of Large-Volume Crystalloid Resuscitation   68     Adverse Effects of Lactated Ringer's Solution   69     Safety and Efficacy of Hypertonic Saline Solutions   71     Alternative Resuscitation Approaches   73     Summary   74     Conclusions and Recommendation   75 4   Novel Approaches To Treatment Of Shock   79     Prevention   80     Oxygen Therapeutics   80     First-, Second-, and Third-Generation Therapeutics   82     Perfluorochemicals   83     Liposomes   83     Other Novel Approaches   84     Intervention   84     Targets for Intervention   84     Therapies for Reperfusion-Mediated Free-Radical Damage   86     Hormonal Influences   92     Diagnostic Instrumentation   92     Tolerance   92     Recommendation   93 5   Protocols of Care At The Site Of Injury   97     The Combat Environment   97     Expected Condition of Combatant on the Battlefield   98     Limits of Battlefield Care for the Injured Combatant   98

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    Resuscitation Needs of the Injured Combatant on the Battlefield   99     Current Protocols   100     Conclusions and Recommendations   102     Training First Responders   102     Available Approaches for Treatment of Injury   102     Additional Considerations   106 6   Future Directions   109     Animal Models   109     Effects of Extent of Hypotension and Rates of Hemorrhage on Immune Function in Mouse Models   110     Swine Models of Combined Hemorrhage and Injury   111     Value of Animal Models   112     Technical Models   112     Role of Anesthesia   114     Clinical Trials   115     Role of Clinical Trials in Development of Therapies   115     Endpoints and Indications   116     Unique Problems of Clinical Trials of Trauma   120     Clinical Research and Clinical Trials in Trauma Centers   121     Conclusions and Recommendations   122     References   125     Appendixes         A Acknowledgments   159     B Acronyms   167     C Conference Agenda   171     D Committee and Staff Biographies   179     Index   185

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