The Journal of TRAUMA Injury, Infection, and Critical Care

Trauma Fluid Resuscitation in 2010

Samuel A. Tisherman, MD
Key Words: Trauma, Fluid, Resuscitation, 2010.
J Trauma. 2003;54:S231S234.

hen considering trauma resuscitation in the year 2010, it would be nice to believe that trauma can be prevented. If the efforts of Mothers Against Drunk Driving could help prevent car crashes from drunk drivers and the beauty pageant contestants who always wish for world peace and brotherly love had an impact, trauma resuscitation in 2010 would not be a major issue. Because this is unlikely, it is worth considering a number of issues for the future of resuscitation. This article discusses the issues of limited fluid resuscitation, optimized resuscitation fluids, pharmacologic therapies, hypothermia, and monitoring during hemorrhagic shock. When considering early deaths from hemorrhage, there are two major scenarios to discuss. First, there is the patient who has uncontrolled hemorrhage leading to, and continuing during, hypovolemic shock. Both penetrating and blunt trauma can lead to uncontrolled hemorrhage. For this scenario, one could envision the use of mild hypothermia and pharmacologic approaches to decrease oxygen demand, along with limited fluid resuscitation, to maintain a pulse (prevent cardiac arrest) until one can perform resuscitative surgery for hemostasis and resuscitate the patient fully in a delayed fashion. The second scenario is the patient with exsanguinating hemorrhage who is losing a pulse. In this scenario, one could envision the use of profound hypothermic and pharmacologic preservation (i.e., suspended animation) to preserve the trauma victim during a period of circulatory arrest followed by resuscitative surgery and delayed resuscitation.

However, several questions remain. The optimal blood pressure and maximal safe duration are two critical questions. Clinically, there are a significant number of civilian and military trauma victims who, because of distance or tactical situations, must survive in a hypovolemic state for a long period of time between injury and surgical intervention. Prolonged limited fluid resuscitation has not been explored. There are issues related to combinations of hemorrhagic shock and head trauma, and issues related to comorbid conditions. In terms of protocols, many studies have used bolus fluid therapy. It would seem that titration would be physiologically more rational. Appropriate methods for titration to specific endpoints need to be determined. The overall goal of limited fluid resuscitation should not be to avoid fluid administration but to prevent cardiac arrest until hemostasis can be achieved. An additional goal of limited fluid resuscitation is to prevent an increase in bleeding.

OPTIMAL FLUIDS
The main objective of fluid resuscitation from hypovolemia is to increase oxygen delivery to vital organs to maintain viability yet not increase bleeding before surgical hemostasis. The optimal fluid for this limited (i.e., hypotensive) fluid resuscitation still needs to be determined. The crystalloid versus colloid debate is not discussed in depth here. The optimal fluid should have certain characteristics. The fluid should rapidly restore plasma volume, microcirculatory flow, and oxygen delivery, without significant side effects, such as a deleterious immune response. It should be readily stored and transported, and it should be inexpensive. Standard plasma substitutes increase volume and flow, but may actually decrease oxygen delivery because of hemodilution. Oxygen-carrying blood substitutes should be considered for limited fluid resuscitation. These solutions should have the ability to carry an appropriate amount of oxygen but should also be able to release this oxygen to tissues. They should have a prolonged half-life, but should not have significant toxicity, such as vasopressor effects, renal dysfunction, and local damage if leaked into traumatized or normal tissues. Storage and cost issues also need to be considered. Combinations of all of these types of fluids need to be considered. One can envision an advantage to using a hypertonic/hyperoncotic solution, coupled with an oxygen-carrying solution, that would rapidly restore blood volume and imS231

LIMITED FLUID RESUSCITATION

Limited fluid resuscitation has been shown to have benefit in multiple animal studies1 4 and one clinical trial.5
Submitted for publication August 5, 2002. Accepted for publication October 23, 2002. Copyright 2003 by Lippincott Williams & Wilkins, Inc. From the Safar Center for Resuscitation Research, and Departments of Surgery and Anesthesiology/Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Presented at Combat Fluid Resuscitation 2001, July 19, 2001, Bethesda, Maryland. Address for reprints: Samuel A. Tisherman, MD, Safar Center for Resuscitation Research, Departments of Surgery and Anesthesiology/Critical Care Medicine, University of Pittsburgh, 638 Scaife Hall, 200 Lothrop Street, Pittsburgh, PA 15213; email: tishermansa@msx.upmc.edu. DOI: 10.1097/01.TA.0000047229.56582.0A

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The Journal of TRAUMA Injury, Infection, and Critical Care

prove oxygen delivery. Different fluids might be used in different clinical situations, such as for patients with head injuries versus those without. Despite proprietary issues, all fluids considered (including new ones developed by industry, in addition to combinations) should be compared with regard to their physiologic and long-term outcome effects in clinically relevant trauma-hemorrhagic shock models in large animals with long-term intensive care. This will require significant funding. improved survival and moderate hypothermia. Because hypothermia tends to increase blood pressure during hemorrhagic shock in rats, Prueckner et al.12 looked at mild hypothermia (34C) during pressure-controlled hemorrhagic shock. Survival was significantly increased, particularly when the mild hypothermia was continued to 12 hours. In the previous studies, hypothermia had been initiated during the period of hemorrhagic shock. Wu et al.13 found that hypothermia was still beneficial even when it was delayed until full fluid resuscitation was initiated. Given the consistent improvement in outcome with mild hypothermia in animal models, it seems appropriate to consider a clinical trial. Before initiating such a trial, possible coagulopathy caused by mild hypothermia needs to be evaluated in a clinically relevant animal model. Moderate hypothermia does appear to cause significant clotting problems,14 but most studies have not found significant changes above 34C. A preclinical study in pigs that was just completed preliminarily shows no early increase in bleeding from a liver injury with mild hypothermia during hemorrhagic shock. There was a delayed small increase in bleeding that needs to be further investigated. Standard blood studies of platelets and the coagulation system were also not different between normothermic and mildly hypothermic animals.15

PHARMACOLOGIC STRATEGIES
Pharmacologic and hypothermic strategies may add significant benefit to limited fluid resuscitation. The targets for the pharmacologic therapies might include oxygen free radicals, nitric oxide, various cytokines, and possibly gene expression. Drugs might also be able to enhance the bodys ability to clot at the site of injury. Some investigators have looked at the addition of drugs to resuscitation fluids. If one assumes that the more severely injured patient will receive more fluid, this approach will then lead to the more severely injured patient also receiving more of the drug. This may be beneficial, but may also lead to toxicities.

HYPOTHERMIA
Before discussing resuscitative hypothermia in more detail, it is important to recognize that therapeutic, controlled hypothermia (which can be beneficial during and after ischemia, trauma, and inflammation) differs significantly from spontaneous, uncontrolled, exposure hypothermia that occurs frequently in trauma patients (which may be deleterious and has been associated with increased mortality). Thus, extrapolating from clinical studies of spontaneous hypothermia in trauma patients to potential detrimental effects of therapeutic hypothermia is inappropriate. It is also important to define temperature levels. For the purpose of this discussion, mild hypothermia is defined as 33 to 36C; moderate, 28 to 32C; deep, 15 to 27C; profound, 5 to 14C; and ultraprofound, 5C. Multiple potential mechanisms of benefit from hypothermia have been documented. The benefit is not purely from a decrease in metabolic demands. Multiple laboratory studies have found benefit of hypothermia during hemorrhagic shock. Meyer and Horton6 and Mizushima et al.7 found that moderate hypothermia during hemorrhagic shock was beneficial for the heart. During volume-controlled hemorrhagic shock in awake rats, Crippen et al. found that moderate hypothermia increased survival time.8 Using a model of uncontrolled hemorrhagic shock by tail cut in a rat, Kim et al.4 found that both limited fluid resuscitation and moderate hypothermia (30C) improved survival. The best survival was with the combination of limited fluid resuscitation and moderate hypothermia. In a lethal model of uncontrolled hemorrhagic shock without fluid resuscitation, Kim et al.9 found that moderate hypothermia doubled survival time. Takasu et al.10,11 found that mild hypothermia S232

SUSPENDED ANIMATION
As has been noted in other presentations, most soldiers killed in action die within 30 minutes, and have so far been considered not salvageable.16 For those who die of exsanguination, a new approach, possibly suspended animation, should be considered. Suspended animation has been defined as protection and preservation of the organism during for up to 2 hours of total circulatory arrest (clinical death) to enable transport and control of bleeding followed by delayed resuscitation. The initial studies to explore this concept of suspended animation were performed in dogs using a model of hemorrhagic shock, rapid cooling, and hemodilution using closedchest cardiopulmonary bypass, up to 2 hours of total circulatory arrest, reperfusion and rewarming with bypass, and intensive care for up to 72 hours. These initial studies by Tisherman et al.17 found that the safe limit (i.e., to allow normal recovery) of deep (15C) hypothermic circulatory arrest after 30 minutes of pressure-controlled hemorrhagic shock is 60 minutes. Neurologic outcome can be improved after 2 hours of circulatory arrest using profound (10C) hypothermia.18 The University of Wisconsin solution, use for solid organ preservation, has no benefit.19 Two hours of circulatory arrest and resuscitation can be accomplished without systemic anticoagulation using a heparin-bonded cardiopulmonary bypass system.20 There was a hint that hematocrit of 20% during circulatory arrest is better than 5%. To explore how severe the hemorrhagic shock period can be before induction of suspended animation, Capone et al.21 examined hemorrhagic shock at a mean arterial pressure of 40 May Supplement 2003

Trauma Fluid Resuscitation in 2010

mm Hg versus 30 mm Hg with or without the addition of 1 hour of profound hypothermic circulatory arrest. They found that the addition of 1 hour of circulatory arrest did not alter the outcome if the hemorrhagic shock period was otherwise survivable. They found deaths only when the mean arterial pressure was 30 mm Hg during the period of shock. These deaths were the result of multiple organ system failure. The animals that survived had normal neurologic function and no histopathologic brain damage. Even though cardiopulmonary bypass systems have become much smaller and more portable, initiation of bypass still requires at least 15 to 20 minutes. A different approach for the initial induction of suspended animation is needed. External cooling, even with immersion, is impractical and too slow. Consequently, a new approach, using an intra-aortic flush of ice-cold fluid to rapidly cool the heart and brain, the most vulnerable organs, is being explored in dogs.2225 These studies have used a model of exsanguination cardiac arrest in dogs, with the intra-aortic flush being administered very shortly after the onset of cardiac arrest. Arrest periods of 15 to 120 minutes have been explored. Behringer et al.22 have found that 60 minutes of cardiac arrest can be survived with normal neurologic function if the brain temperature is decreased to 15C or less. At 10C, 90 minutes of cardiac arrest can be reversed to normality, and with 120 minutes of arrest, some neurologic dysfunction is seen, although two animals had normal function.23 From a clinical standpoint, induction of suspended animation will likely take more time. This is a concern because Behringer et al. (personal communication), found that delay of the flush beyond 5 minutes of the onset of cardiac arrest may be too late for cerebral preservation. To attempt to improve outcome beyond what can be achieved with mild cerebral hypothermia (induced by a small flush volume that could be carried in the field), a large number of drugs have been studied based on known mechanisms of neuronal damage after ischemia. So far, the only drug that Behringer et al. have found to have potential benefit is the antioxidant Tempol.24 Induction of suspended animation (possibly in the field) will require significant improvements in techniques for accessing the aorta and for rapidly infusing cold fluids. Access may be achieved via the femoral route or via a thoracotomy25 or parasternal route. These technical issues are being explored. For mild hypothermia during prolonged hemorrhagic shock and for suspended animation, there may be additional pharmacologic methods to decrease metabolic demands. Hibernating mammals are able to decrease metabolism; however, they are not suffering from tissue anoxia during hibernation, nor are they necessarily more able to tolerate shock. There is no method available yet for inducing hibernationlike changes in nonhibernating mammals. There are also animal species that are able to tolerate profound levels of tissue hypoxia for prolonged periods of time. Although the mechanisms for this tolerance are becoming better underVolume 54 Number 5 stood, it is not clear that this type of tolerance could be induced in other species.

MONITORING
Better monitoring systems will be critical in the future for optimizing the choices of fluid and for titration of fluid therapy. Online measurements of cytokines and other parameters might be able to give clinicians a better overall picture of homeostatic derangements than the standard clinical parameters. Some methods for monitoring vital organ wellness will be needed for optimizing the titration of therapies. Studies need to be performed to determine the optimal tissue and the optimal parameter. In the meantime, the ability to at least monitor arterial pressure accurately in the field during severe hypotension, with use of a miniaturized noninvasive device, would enable titrated therapies for shock. Other monitoring devices may help with diagnosing intrathoracic or intra-abdominal hemorrhage and intracranial injuries. These monitoring systems will greatly enhance our abilities to appropriately triage patients and treat individual patients. The new monitoring systems should be able to help us differentiate four types of patients: the trauma victims who will do well no matter what is done for early resuscitation, those for whom appropriate immediate therapy can make a difference, those for whom suspended animation should be used, and those with injuries that remain lethal no matter what is done.

CONCLUSION
Looking toward the future, it seems reasonable to consider that the medic of the future will carry optimized fluids for limited fluid resuscitation or induction of suspended animation, some type of cooling device, a drug cocktail, and instruments for a thoracotomy or cut-down. The use of new monitoring devices will allow the titrated use of limited fluid resuscitation with optimized fluids, possibly including an oxygen-carrying blood substitute. Pharmacologic strategies could be added and titrated appropriately. Hypothermia, either mild for prolonged hemorrhagic shock or profound for suspended animation, will become potent additions to our therapeutic armamentarium for victims of severe trauma.

ACKNOWLEDGMENTS
We thank Peter Safar, MD, for his valuable suggestions and Christine Henderson for assistance with preparation of the article.

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