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Current concepts in fluid resuscitation for prehospital care of combat casualties.

INTRODUCTION

It is reported that acute hemorrhage consistently accounts for about 50% of battlefield deaths in conventional warfare, and for 30% of casualties who die from wounds. (1) In addition, lessons learned by the British, the Israelis and the Indians in their various conflicts and skirmishes confirmed that prompt resuscitation improves survival. (2,3) Also, results of a consensus conference and studies of pulse status concluded that fluid resuscitation was necessary for any casualty with a change in mental status or who was unconscious, suggesting a systolic blood pressure less than 50 mm Hg. (4,5)

It is well recognized that limitations exist in providing sufficient fluid for resuscitation in far-forward combat environments. Weight and cube limitations restrict the availability of large volumes of crystalloid resuscitation fluids for far-forward use. In addition, the combat medic has limited training, and long evacuation times or delayed transport to forward surgical facilities can be expected. Future combat scenarios imply that delays of 24 hours before evacuation of casualties could be more common, particularly if evacuation is from urban environments, as was experienced in Somalia. (6) The implication is that several hours may pass before any surgical intervention is possible to treat the injured Soldier. As indicated by Bellamy, (1) mortality increased from 20% to 32% when evacuation of casualties was delayed from immediately to 24 hours. Yet, evidence from experimental animals suggests that interventions to reestablish homeostasis may need to be initiated within 30 minutes after injury to assure survival, (7) offering additional challenges to attempts to improve resuscitation on the battlefield and at higher echelons of care.

Addressing the need for improved prehospital fluid resuscitation for treating traumatic hemorrhage was the topic of an ISR-sponsored symposium held in January 2010. The current tactical combat casualty care guidelines were evaluated along with the goals that an ideal resuscitation fluid should expand and maintain circulating blood volume, and thus vital organ perfusion, while having a positive effect on hemostasis. The current state-of-the-art use of crystalloids, colloids, and oxygen carriers were discussed. The discussion led to the conclusion that current fluid resuscitation guidelines are not optimal and further research was needed for prehospital resuscitation.

DAMAGE CONTROL RESUSCITATION

Autopsy data from about 1000 casualties in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) have identified hemorrhage as a cause of death in 85% of potentially survivable casualties, and bleeding could only have been controlled in 32% of these casualties by means presently available to the field medic, such as tourniquets and hemostatic dressings. (8) For the remaining 68% with noncompressible hemorrhage, the medic has few options at present, other than fluid to maintain blood pressure until the casualty can get to a surgeon. In addition, it is well recognized that trauma patients can develop coagulopathy. For years it has been reported that trauma patients can become hypothermic and acidotic which, along with the development of a coagulopathy, forms a triad known as the "bloody viscious cycle" with a high mortality rate. (9) Routine care has been to warm these patients and reverse their acidosis, which has been successful. (10,11) However, little has been done to address their bleeding abnormalities until the patient went to the operating room. In addition, it has recently been recognized that traumatic injury can early induce a bleeding disorder that is independent of the development of hypothermia or a result of hemodilution, and is commonly seen in the most severely injured patients who require a massive transfusion. (12-14) This observation initially seen in the civilian community was also recognized in a military population, (15) representing about 38% of casualties requiring a transfusion. Data show that coagulopathy is related to severity of injury and markedly increases mortality rates at similar levels of injury severity. Improving survival at all echelons of care in these patients requires hemorrhage control and resuscitation to restore normal blood clotting capabilities and metabolic processes, while providing volume. Current guidelines provided by the Committee on Tactical Combat Casualty Care advocate the control of bleeding and limited fluid resuscitation with Hextend (Hospira, Inc, Lake Forest, IL), allowing the systolic blood pressure to rise to around 80 mm HG. Over the past 40 to 50 years, the treatments commonly used for resuscitation of hemorrhagic shock in both the civilian and military sector, including crystalloid solutions and packed red blood cells, actually dilute the remaining coagulation factors and platelets further which may increase the tendency for more bleeding.

An evaluation of patients at Combat Support Hospitals from January 2004 to December 2006 revealed that 90% suffered from penetrating trauma, with hemorrhage being the number one problem. (15,16) Of these patients, 22% required a transfusion and over 8% required a massive transfusion, defined as 10 or more units of packed red blood cells (RBCs) in a 24-hour period. In comparison, at a major trauma center in the United States, 11% required a transfusion and only 2.7% of those required a massive transfusion. Considering the much greater magnitude of injuries and the over 3 times higher need for massive transfusion encountered in OIF and OEF compared to civilian trauma, (17) the requirement for more effective treatment is more of an urgent problem for the military. Since patients who require massive transfusion generally comprise the majority of in-hospital trauma deaths, there was a need for a revolutionary strategy to treat such severe injuries.

To address the above problems, the concept of damage control resuscitation (DCR) was introduced as a resuscitation strategy primarily for the most seriously injured patient. It is a structured intervention that consists of 2 goals and was endorsed Army-wide in January 2007 for optimal resuscitation of severely injured Soldiers. The first goal is to limit fluid resuscitation to keep the patient's systolic blood pressure at about 80 mm HG to minimize renewed bleeding from recently formed blood clots. (18) The second goal is to restore the blood volume using plasma as the primary resuscitation fluid in a ratio close to 1:1 with RBCs to provide hemostatic resuscitation. Other blood products reserved for massive transfusion protocols, such as platelets, cryoprecipitate, and, possibly, recombinant activated Factor VII and fibrinogen which are available and could be used as needed.

PERMISSIVE HYPOTENSION

Permissive hypotension, or fluid resuscitation to a blood pressure lower than normal, was recognized as a reasonable approach in the care of combat casualties in both World Wars I and II. (19,20) Adaptation of permissive hypotension as a far-forward treatment strategy was renewed by US Special Operations Forces after a 1998 conference. (5)

Today, fluid resuscitation practices to normalize the blood pressure rapidly after traumatic hemorrhage are no longer recommended, especially in patients with penetrating injuries. (21,22) Rapid volume infusion even for blunt trauma patients is also being questioned. (23) It has been argued that resuscitation to baseline or normal blood pressure can increase bleeding and worsen outcome because of severe hemodilution of remaining coagulation factors and hemoglobin, as well as disruption of newly forming blood clots. Thus, it is suggested that permissive hypotensive resuscitation can improve outcome, yet avoid these adverse hemostatic and metabolic effects. (21,22,24,25) As an example, studies in both rodents and swine have shown that in the treatment of uncontrolled hemorrhage from a vascular injury, restoring mean arterial pressure to 40 mm HG or 60 mm HG, resulted in longer survival compared to animals resuscitated to the baseline mean arterial pressure of 80 mm HG, as well as animals that received no fluid. (26,27) In addition, the provision of some fluid even before surgical repair of the injury is performed also appeared to be better than delaying all fluid until after surgery. (26) Also, our own work observed that lactated Ringer's (LR) infusion to a mean arterial pressure (MAP) of 70 mm HG improved hemorrhage-induced vascular hyporeactivity to norepinephrine better than LR resuscitation to baseline MAP during the 4-hour study period. (28) Resuscitation to baseline MAP with LR resulted in severe hemodilution and deterioration of vascular responsiveness to norepinephrine. The medical literature contains several studies reporting on adverse immunologic effects of LR or normal saline, (29,30) so efforts to reduce the volumes used seem prudent. However, the adequacy of hypotensive fluid resuscitation is not well delineated as some studies have suggested that hypotensive crystalloid resuscitation to a MAP of 60 mm HG to 70 mm HG may be inadequate to prevent metabolic derangements associated with hemorrhagic shock. (31,32) It should be noted that over the last decade of research into hypotensive resuscitation, the majority of studies have only monitored animals for a few hours, and LR or normal saline has been the primary fluid examined. (33,34) Since not all animals in the hypotensive resuscitation groups survived in some of the studies, research into better resuscitation strategies and improved fluids seems warranted.

BLOOD AND BLOOD COMPONENTS

As mentioned, the second major aspect of damage control resuscitation recommends a judicious use of blood products in more favorable ratios to improve outcome in the severely injured, particularly in patients requiring a massive transfusion. This aspect of DCR is focused on addressing the coagulopathy associated with traumatic injury through hemostatic resuscitation. Adverse effects of RBC transfusion are well described, (35-39) so determining which patients need blood is another area of research at the US Army Institute of Surgical Research (USAISR).

Damage control resuscitation practices in theater were implemented through a Joint Theater Trauma System Clinical Practice Guideline * (last updated February 2009) for the use of blood products at level IIb/III. Of course, the use of blood by the US military is not a new idea and transfusion practices date back to World War I. Blood use in World War II, (40) the Korean conflict, (41) and in Vietnam (42) have been described. This history has also been extensively reviewed by Hess and Thomas. (43)

Several retrospective reviews have analyzed military casualty data from combat support hospitals and have concluded that use of plasma, including plasma to RBC ratios that approached 1:1, improved the coagulopathy and reduced 30-day mortality compared to the use of more RBCs or ratios of plasma to RBCs greater than 1:4. (44-46) Prospective studies in swine polytrauma models have also shown that plasma alone could improve coagulopathy. (47) Other studies observed improved survival with greater use of platelets and the benefits of higher fibrinogen to RBC ratios. (48,49) Also of interest is the successful use of warm, fresh, whole blood in theater where over 6000 units have been transferred over a 4 to 5 year period. (16) Retrospective studies have seen improved 30-day survival with warm, fresh, whole blood compared to casualties who received component therapy, as well as acceptable benefit-to-risk ratios under situations where blood components are unavailable or not available in sufficient amounts for transfusion requirements. (16,50,51)

Retrospective reviews of greater use of plasma and higher plasma to RBC ratios have also been assessed in civilian trauma patients. More aggressive use of plasma seems to be beneficial in improving coagulopathy. (11,52) Further evaluation suggested that achieving near a 1:1:1 ratio of plasma, RBC, and platelets improved the coagulopathy and had a positive impact on survival. (53-57) However, the optimal ratios remain controversial. (58,59) Taken together, the data suggest that DCR practices improve outcomes in coagulopathic trauma patients by using more plasma and other blood components in ratios closer to whole blood, and by reducing the use of large volumes of crystalloids in the resuscitation.

As the current use of blood products for treating severely injured trauma patients has occurred in medical treatment facilities, interest has been generated regarding having plasma available in the prehospital or far-forward setting. It is well known that freeze-dried plasma was extensively used for resuscitation in forward areas during World War II, but was withdrawn due to high transmission rates of hepatitis. (40) Efforts are currently underway to redevelop a freeze-dried plasma product for use in the United States. Recent studies in a swine polytrauma model showed that freeze-dried plasma was similar to fresh-frozen plasma in its coagulation factor levels and could improve the coagulopathy in this model. (60,61) Currently, freeze-dried plasma is available through the German Red Cross and the French Military, and both products are available for use by coalition medical personnel in Operation Enduring Freedom (Afghanistan).

CONCLUDING REMARKS

Prehospital resuscitation practices and the use of crystalloids for fluid resuscitation have not changed significantly in the past 40 to 50 years in either the military or civilian sector. Through research funded primarily by the US Army Combat Casualty Care Research Program, efforts in the past 20 years have been directed on improving far-forward resuscitation. Current investigations on fluid resuscitation strategies at USAISR are now focused under the concept of damage control resuscitation. Despite efforts to provide small volume resuscitation through development of hypertonic fluids such as hypertonic 7.5% saline without or with Dextran-70 (hypertonic saline/dextran) over the past 20 years, these products have yet to achieve FDA approval, although a 5% saline solution is FDA approved for hyponatremia. Consequently, for the past decade the Tactical Combat Casualty Care committee recommended Hextend, a hetastarch based product in a balanced salt solution, as the fluid of choice for small volume resuscitation, with guidance to limit the total infusion to one liter based on the casualty's mental status or pulse character. (4) No fluid is recommended if the casualty is not in shock.

As noted, to date most fluid resuscitation studies evaluating this permissive hypotension have generally used crystalloids such as LR or normal (physiologic) saline. Our own studies in a swine hemorrhage model have indicated that similar hemodynamic and metabolic responses can be achieved with about a third of the volume using colloids compared to crystalloids in swine resuscitated to 80 mm HG systolic pressure. (62) However, the limits of this hypotensive resuscitation strategy, such as whether permissive hypotension would worsen the incidence of late complications that could arise from incomplete resuscitation, are unknown. Also, evidence does suggest that resuscitation to a systolic blood pressure of 80 mm HG would be inadequate to improve cerebral perfusion after head injury. Thus, a component of DCR research at USAISR investigates adjuncts that can be used in small volume resuscitation (<2 ml/kg). This work is in conjunction with the Defense Advanced Research Projects Agency Surviving Blood Loss Program. Preliminary studies in a swine severe hemorrhage model have show some benefit associated with small volume estrogen infusion. (63) An overview of research projects at the USAISR under the damage control resuscitation program is presented in the Table.

At present, the clinical practice guidelines for use of warm, fresh, whole blood or plasma and other blood components as part of a damage control resuscitation regimen are designed for level IIb/III echelons of care. As mentioned, the approach is to treat the most severely injured who present with a coagulopathy and have the greatest chance of dying. Typically, these are the patients who require a massive transfusion. However, efforts are underway to move this DCR strategy to more forward echelons of care, and current research efforts focus on the development of freeze-dried plasma and platelet-like substances, as well as other components derived from plasma such as fibrinogen concentrates and recombinant activated factor VII. The consensus of discussants at the USAISR-sponsored symposium on prehospital fluid resuscitation overwhelmingly favored the development of a dried plasma product that could expand and maintain blood volume while providing lost coagulation factors resulting from the traumatic injury. Thus, this further supports expanding DCR capabilities to the prehospital arena. Damage control resuscitation guidelines emerged from a recognized medical problem and are being addressed by preclinical and clinical studies to develop an evidence-based best practice for treating these severely injured Soldiers. It is hoped that early implementation of far-forward damage control resuscitation will result in fewer early deaths from hemorrhage and fewer medical complications, such as development of multiorgan failure and related sequelae, as well as overall reduction in blood product use.

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(49.) Stinger HK, Spinella PC, Perkins JG, et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an Army combat support hospital. J Trauma. 2008;64 (suppl2):S79-S85.

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Michael A. Dubick, PhD

* Internal military document not normally accessible by the general public.

Dr Dubick is Supervisory Research Pharmacologist and Task Area Manager, Damage Control Resuscitation Research Program, US Army Institute of Surgical Research, Fort Sam Houston, Texas.
Damage control resuscitation research areas at the US Army Institute
of Surgical Research

General Resuscitation
  Adequate Volume
    Hypotensive resuscitation
    Temperature of fluid
    Choice of fluid
  Metabolic derangements
    Adjuncts (metabolic substrates, antioxidants, sex hormones, etc)
  Immune Modulation
    As related to standard therapy in patients
    Interactions with coagulation system (animals/trauma patients)
    Complement components

Hemostatic Resuscitation
  Blood products including coagulation factors
  Blood product ratios
  Age of blood products

Acquired Coagulopathy
  Acidosis
  Hypothermic
  Anemia
  Trauma Induced coagulopathy (joint program with Blood Research)

Endothelial cell function, interactions, effect of laminar flow

Hemostatic Agents
  Dressing for external wounds
  Tourniquets and junctional devices
  Intracavitary bleeding

Biomarker of Resuscitation
  Hypoxia signals and cellular susceptibility
  Improvement by resuscitation?

Newer Blood products (in collaboration with Blood Research program)
  Freeze dried plasma
  Refrigerated/frozen/freeze-dried/spray-dried platelets
  Dried/freeze-dried red blood cells
  Freeze-dried/recombinant fibrinogen
  Hemoglobin-based oxygen carriers

JTTR retrospective review (outcome data)
  Use of blood products
  Coagulopathy

Clinical Studies
  Assessment of blood product use in trauma patients
  Resuscitation Outcomes Consortium (Joint effort of Department of
    Defense and National Institutes of Health)
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Author:Dubick, Michael A.
Publication:U.S. Army Medical Department Journal
Article Type:Report
Geographic Code:1USA
Date:Apr 1, 2011
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