Executive Summary

Historically, one fifth of all injured combatants die in battle. Although this number has varied significantly depending on the specific campaign, 20 percent has been the mean mortality rate among injured combatants in all U.S. conflicts since World War II combined. Furthermore, of every 10 combatants who die from battle injuries, 9 die on the battlefield (i.e., are killed in action) before evacuation to a field hospital (Bellamy, 1998). Precise data are not available to verify the percentage of casualties who are potentially salvageable (Bowen and Bellamy, 1998; Koehler et al., 1994), but authorities have estimated this number to be approximately 20 percent (Bellamy, 1984, 1987a,b, 1995). The single major cause of death in potentially salvageable battlefield casualties is hemorrhage, and the greatest opportunity for reducing mortality and morbidity of battlefield casualties involves fluid resuscitation and treatment of hypovolemia (abnormally decreased volume of circulating fluid [plasma] in the body).

Current therapeutic regimens usually specify the use of crystalloid solutions for the treatment of hypovolemia and subsequent shock. However, numerous questions and concerns regarding the concentration, rate, and quantity of resuscitation fluid persist. Additionally, battlefield conditions further constrain the type, quantity, and delivery options of resuscitation fluids that can be administered in far-forward areas. Because of these and other concerns, the Office of Naval Research asked the Institute of Medicine to provide an independent assessment of the current status of resuscitation fluids and resuscitation protocols for combat casualties and to develop a series of findings and recommendations for future research directed at the acute treatment of massive blood loss on the battlefield. The Institute of Medicine committee reviewed the published literature, conducted an international conference, and interviewed numerous authorities to formulate an evidence-based response.



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Executive Summary Historically, one fifth of all injured combatants die in battle. Although this number has varied significantly depending on the specific campaign, 20 percent has been the mean mortality rate among injured combatants in all U.S. conflicts since World War II combined. Furthermore, of every 10 combatants who die from battle injuries, 9 die on the battlefield (i.e., are killed in action) before evacuation to a field hospital (Bellamy, 1998). Precise data are not available to verify the percentage of casualties who are potentially salvageable (Bowen and Bellamy, 1998; Koehler et al., 1994), but authorities have estimated this number to be approximately 20 percent (Bellamy, 1984, 1987a,b, 1995). The single major cause of death in potentially salvageable battlefield casualties is hemorrhage, and the greatest opportunity for reducing mortality and morbidity of battlefield casualties involves fluid resuscitation and treatment of hypovolemia (abnormally decreased volume of circulating fluid [plasma] in the body). Current therapeutic regimens usually specify the use of crystalloid solutions for the treatment of hypovolemia and subsequent shock. However, numerous questions and concerns regarding the concentration, rate, and quantity of resuscitation fluid persist. Additionally, battlefield conditions further constrain the type, quantity, and delivery options of resuscitation fluids that can be administered in far-forward areas. Because of these and other concerns, the Office of Naval Research asked the Institute of Medicine to provide an independent assessment of the current status of resuscitation fluids and resuscitation protocols for combat casualties and to develop a series of findings and recommendations for future research directed at the acute treatment of massive blood loss on the battlefield. The Institute of Medicine committee reviewed the published literature, conducted an international conference, and interviewed numerous authorities to formulate an evidence-based response.

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The committee found that there are at least theoretical disadvantages to existing resuscitation fluids (although these fluids are rarely questioned in clinical practice) and that many have not been modified for several decades. Still, both laboratory and clinical information demonstrated that some new protocols may reduce the rate of mortality among injured combatants on the battlefield. The committee concluded that new protocols for the fluid resuscitation of battlefield casualties should be implemented immediately and makes the following re-commentation: Recommendation: The initial fluid resuscitation of the hemorrhaging battlefield casualty should be a 250 ml bolus of 7.5 percent hypertonic saline delivered by a rapid-infusion system. (Recommendation 5.2) Systemic administration of hypertonic saline solution would take place via an intraosseous needle placed in the anterior tibia, even through the uniform if necessary. The fluid bag would be placed under manual low pressure or attached to a simple and durable pump, which could be mechanical or electric. The option for intravenous access should also be provided, but the committee felt that it would be easier to teach nonmedical combatants the intraosseous route. The committee also noted that fluid resuscitation is only one component of the immediate care of the battlefield casualty. Fluid resuscitation is predicated on the control of bleeding and improvements in fluid therapy will be most effective when they are accompanied by improvements in management of the airway and ventilation in the field, and by rapid evacuation of the injured individual to a site where definitive care can be initiated by trained clinicians. Even though the administration of hypertonic saline would be an improvement over current protocols, new resuscitation fluids should be developed and tested. Such fluids should address the metabolic and cellular consequences of traumatic shock and the potential disadvantages of existing fluid formulations. Future research directed at acute treatment of massive blood loss on the battlefield should explore the development of an improved resuscitation fluid. Ideally, such a fluid would provide adequate control of pH, partial CO2 pressure/bicarbonate ratio, the phosphorylate potential, the redox state, and osmotic pressure; adequate control of sodium chloride, calcium, and potassium levels; and adequate control of the lactate and pyruvate ratio. Although the large volume of lactated Ringer's solution that is required for resuscitation in the field is simply not currently compatible with the expected functions of the first responder, who is both combatant and medic in most situations, evidence from a variety of sources suggests that modifications to lactated Ringer's solution might be of value, and the committee proposes that these be explored. Recommendation: Research involving modifications of existing lactated Ringer's solutions could include:

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1.   elimination of D-lactate, 2.   reduction of total L-lactate load, 3.   addition of ketones as an energy source, and 4.   addition of free-radical scavengers and antioxidants (vitamins E and C, glutathione, or iron chelators). (Recommendation 3.1) At present, there is insufficient evidence that proposed fluids, such as parenteral saline containing normochloremic carbonate/carbon dioxide: (1) restore blood volume effectively; (2) produce the desired hemodynamic, hematologic, cellular, and immunologic-related advantages; or (3) do not cause adverse events. The ideal solution for fluid resuscitation—one that addresses all of the physiologic and cellular aspects of hemorrhagic shock and that is easy to carry and use in the battlefield—is not apparent at this time. To hasten the development of such a fluid, several changes in the conduct, focus, and direction of resuscitation fluid research will have to take place. Proper clinical evaluation of resuscitation fluids and protocols is hampered by the inevitably uncontrolled conditions that accompany clinical trauma and hemorrhage. These include variations in the site and extent of injuries, the duration of hypotension and hypoperfusion, the extent of hypothermia, and the interval before access to definitive care. Much laboratory research has been done with animal models that lack either reproducibility or clear relevance to the clinical scenario, or both. Some fluid resuscitation research has been limited by protocols that did not adequately distinguish or address (1) the differences between pure hemorrhagic shock and traumatic shock associated with tissue injury, (2) the need to standardize the animal models with regard to anesthesia and general care, and (3) the need to observe the subjects for longer-term survival. Clinical research specifically has been hampered by the lack of an organized national approach to trauma research that takes advantage of the considerable clinical material and research expertise among the regional trauma centers. Furthermore, approaches to both current treatment and future research are hampered by inadequate methods for classification of the severity of clinical trauma; such classifications are essential to evaluations of the efficacies of new treatment protocols that involve modifications in fluid formulations or novel therapies. Current trauma indexing systems are inadequate for use in future trauma research. Recommendation: A national study group should be convened to develop and implement clinical research, including multicenter clinical trials on selected topics at existing regional trauma centers. Federal agencies, including the U.S. Department of Defense, the U.S. Department of Veterans Affairs, and the National Institutes of Health, and national professional organizations, should collaborate with each other and with the private sector in this activity. (Recommendation 6.2)

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Recommendation: A new system for categorizing injury in trauma care should be developed. (Recommendation 6.3) For these reasons, among others, the considerable research on fluid resuscitation for hypovolemia has not led to the implementation of new clinical approaches that improve hemodynamics or significantly reduce the rate of mortality among injured combatants on the battlefield. Furthermore, the key to improved care may not involve hemodynamics alone but likely requires an understanding of the molecular and cellular responses that are triggered by massive blood loss and shock. The goals of volume replacement therapy therefore include not only hemodynamic stabilization but also amelioration of the chain of events that lead to irreversibility in severe prolonged shock. Major therapeutic advances are most likely to result from new approaches that address the metabolic and cellular consequences of shock, many of which are triggered by the impaired oxygen delivery to tissue that accompanies hemorrhage and ischemia. Resuscitation approaches that enhance oxygen delivery to tissue deserve further evaluation. Recommendation: Evaluate the applicability of small-volume, stable oxygen (O2)-carrying and O2-facilitating agents that improve and sustain O2 delivery in the wounded subject for 24 to 48 hours. (Recommendation 4.1) Finally, the complex events that result from the initial insult, tissue injury, and resuscitative attempts provide numerous potential therapeutic targets for novel interventions. Novel therapeutic strategies might be conveniently, if somewhat artificially, categorized as those that prevent the early complications of the shock syndrome (prevention), those that treat the complications of shock syndrome and reperfusion injury (intervention), and those that render the subject less vulnerable to hypoxia and its consequences (tolerance). The military should maintain a research interest, if not research support, in each of these areas, recognizing that some are approaching sufficient maturity for clinical trials, whereas others are still at an investigative, basic science stage. The committee found that much of the research on hemorrhagic shock has remained focused on hemodynamics or has been directed toward the correction of a single biochemical abnormality that accompanies hemorrhage. Such strategies are unlikely to be successful, because multiple pathways lead to the cell death that results from severe hemorrhagic shock. Rather, novel therapies should be aimed at the multiple metabolic and cellular derangements that accompany traumatic shock. These approaches should take advantage of advances in other related fields (such as ischemia-reperfusion research on specific organs) and should be approached in a systematic manner that involves prophylaxis, immediate intervention, or the development of tolerance to global ischemia. The committee's recommendations are listed in their entirety in Box 1.

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Box 1. The Committee's Recommendations Pathophysiology of Acute Hemorrhagic Shock Recommendation 2.1 Develop and validate diagnostic assays for substances in serum that Indicate the specific mechanisms involved in the molecular processes of cellular injury and cell death induced by shock and resuscitation. Recommendation 2.2 Expand the use of transgenic experimental animals to further evaluate the role of specific proteins and enzymes in cellular injury and death induced by shock and resuscitation. Recommendation 2.3 Study and rigorously evaluate polypharmaceutical approaches directed against the multiple and independent mechanisms of cellular injury and death induced by shock and resuscitation. Experience with and Complications of Fluid Resuscitation Recommendation 3.1 Research involving modifications of existing lactated Ringer's solutions could include: 1.   elimination of D-lactate; 2.   reduction of total L-lactate load, 3.   addition of ketones as an energy source, and 4.   addition of free-radical scavengers and antioxidants (vitamins E and C, glutathione, or iron chelators). Recommendation 3.2 Studies examining modifications of the existing lactated Ringer's solution formula must include examining the effects of the modified solution on: 1.   immunologic-related function, 2.   cellular apoptosis, 3.   intravascular retention, and 4.   specific end-organ function such as pulmonary, renal, and cardiac function (i.e., the presence or absence of arrhythmias) Recommendation 3.3 Previous concerns regarding the detrimental effects of aggressive fluid resuscitation with large volumes of crystalloids suggested the need to examine both the immunologic as well as hemodynamic consequences of small-volume lactated Ringer's resuscitation. Studies examining reduced volume of lactated Ringer's solution should examine the effects of this volume on: 1.   hemodynamic function, 2.   immunologic-related function, 3.   cellular apoptosis, 4.   specific end-organ function such as pulmonary, renal, and cardiac function.

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Novel Approaches to Treatment of Shock Recommendation 4.1 Evaluate the applicability of small-volume, stable oxygen (O2)-carrying and O2-facilitating agents that improve and sustain O2 delivery in the wounded subject for 24 to 48 hours. Recommendation 4.2 Therapeutic agents that target the toxic effects of hypoxic injury (e.g., antioxidants, chelating agents, hormones, and nitric oxide inhibitors) should be studied with animal models and subsequently in clinical trials. Combinations of several therapeutic agents should also be investigated. Recommendation 4.3 Mechanisms that may induce tolerance to ischemia and cellular hypoxia (e.g., hibernation, ischemic preconditioning, and hypothermia) should be explored with appropriate preclinical models. Protocols of Care at the Site of Injury Recommendation 5.1 The number of trained first responders in the combat environment should be increased through development of a Military Trauma Life Support course. Recommendation 5.2 The initial fluid resuscitation of the hemorrhaging battlefield casualty should be a 250 ml bolus of 7.5 percent saline delivered by a rapid-infusion system. Recommendation 5.3 Efforts should be made to ensure that the airway of a battlefield casualty is patent and that ventilation is adequate. Recommendation 5.4 If accessible, all severely injured battlefield casualties should be evacuated to a front-line high-echelon care site in less than an hour. Future Directions Recommendation 6.1 Laboratory research should be reproducible and relevant to the clinical scenario. For fluid resuscitation research, the experimental design of animal research should be guided by the following principles. when feasible, the experimental model should include soft-tissue injury in addition to hemorrhage; controlled hemorrhage protocols are preferred over uncontrolled hemorrhage models; when feasible, protocols that do not require anesthesia are preferred. If anesthesia is required, the depth of anesthesia should be reproducible, and the anesthetic agent should be selected to minimize alterations in the physiologic responses to hemorrhage;

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experimental animal species should be selected on the basis of clinical relevance, and will vary depending on the research question; if survival is an endpoint, mortality should be measured for at least 5 days; and the experimental design should establish a reliable 50 percent lethal dose (LD50) for the control group. Any and all animal research should be conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NRC, 1996). Recommendation 6.2 A national study group should be convened to develop and implement clinical research, including multicenter clinical trials on selected topics at existing regional trauma centers. Federal agencies, including the U.S. Department of Defense, the U.S. Department of Veterans Affairs, and the National Institutes of Health, and national professional organizations, should collaborate with each other and with the private sector in this activity. Recommendation 6.3 A new system for categorizing injury in trauma care should be developed.

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