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Home , Polytrauma, Resuscitation

Cerebrovascular after and Fluid Restriction

Steven A Earle, MD,MarcAdeMoya,MD, Jennifer E Zuccarelli, BA, Michael D Norenberg, MD, Kenneth G Proctor, MD, PhD

BACKGROUND: There are few reproducible models of blast , so it is difficult to evaluate new or existing therapies. We developed a clinically relevant polytrauma model to test the hypothesis that cerebrovascular resuscitation is optimized when intravenous fluid is restricted. STUDY DESIGN: Anesthetized swine (42 Ϯ 5 kg, n ϭ 35) received blasts to the head and bilateral chests with captive bolt ϭ guns, followed by hypoventilation (4 breaths/min; FiO2 0.21). After 30 minutes, resuscitation was divided into phases to simulate typical prehospital, emergency room, and ICU care. For 30 to 45 minutes, group 1, the control group (n ϭ 5), received 1L of normal saline (NS). For 45 to 120 minutes, additional NS was titrated to mean arterial pressure (MAP) Ͼ 60 mmHg. After 120 minutes, mannitol (1g/kg) and phenylephrine were administered to manage cerebral pressure (CPP) Ͼ 70 mmHg, plus addi- tional NS was given to maintain central venous pressure (CVP) Ͼ 12 mmHg. In group 2 (n ϭ 5), MAP and CPP targets were the same, but the CVP target was Ͼ 8 mmHg. Group 3 (n ϭ 5) received1LofNS followed only by CPP management. Group 4 (n ϭ 5) received Hextend (Abbott Laboratories), instead of NS, to the same MAP and CPP targets as group 2. RESULTS: Polytrauma caused 13 deaths in the 35 animals. In survivors, at 30 minutes, MAP was 60 Ͼ Ͻ to 65 mmHg, was 100 beats/min, PaO2 was 50 mmHg, and lactate was Ͼ 5 mmol/L. In two experiments, no fluid or pressor was administered; the and persisted. The first liter of intravenous fluid partially corrected these variables, and

also partially corrected mixed venous O2, gastric and portal venous O2, , renal blood flow, and urine output. Additional NS (total of 36 Ϯ 1 mL/kg/h and 17 Ϯ 6 mL/kg/h, in groups 1 and 2, respectively) correlated with increased intracranial pressure to 38 Ϯ 4 mmHg (group 1) and 26 Ϯ 4 mmHg (group 2) versus 22 Ϯ 4 mmHg in group 3 (who received 5 Ϯ 1 mL/kg/h). CPP was maintained only after mannitol and phenylephrine. By 5 hours, Ͼ Ϯ brain tissue PO2 was 20 mmHg in groups 1 and 2, but only 6 1 mmHg in group 3. In contrast, minimal Hextend (6 Ϯ 3 mL/kg/h) was needed; the corrections in MAP and CPP were immediate and sustained, intracranial pressure was lower (14 Ϯ 2 mmHg), and brain Ͼ tissue PO2 was 20 mmHg. Neuropathologic changes were consistent with , but there were no statistically significant differences between groups. CONCLUSIONS: After polytrauma and resuscitation to standard MAP and CPP targets with mannitol and pressor therapy, we concluded that intracranial hypertension was attenuated and brain oxygenation was maintained with intravenous fluid restriction; cerebrovascular resuscitation was optimized with Hextend versus NS; and longer term studies are needed to determine neuropathologic consequences. (J Am Coll Surg 2007;204:261–275. © 2007 by the American College of Surgeons)

Almost every day, for as long as the wars in Iraq and fer polytrauma, maiming, or death from improvised ex- Afghanistan continue, our soldiers and marines will suf- plosive devices (IED). In fact, the majority of combat

Competing Interests Declared: None. Received October 13, 2006; Revised November 16, 2006; Accepted Novem- Supported by grant N000140210339, from the Office of Naval Research. ber 16, 2006. Abstract presented at the American College of Surgeons 92nd Annual Clinical From the Dewitt-Daughtry Family Department of , Divisions of Traumaand Congress, Surgical Forum, Chicago, IL, October 2006. Surgical Critical Care (Earle, de Moya, Zuccarelli, Proctor) and the Department of Dr de Moya’s current address is: Massachusetts General , Division of Pathology (Norenberg), University of Miami Miller School of , Miami, FL. Trauma, Emergency Surgery, and Surgical Critical Care, 165 Cambridge St, Correspondence address: Kenneth G Proctor, PhD, Divisions ofTraumaand Surgical Suite 810, Boston, MA 02114. Critical Care, Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Ryder , 1800 NW 10th Ave, Miami, FL 33136.

© 2007 by the American College of Surgeons ISSN 1072-7515/07/$32.00 Published by Elsevier Inc. 261 doi:10.1016/j.jamcollsurg.2006.11.014 262 Earle et al Cerebrovascular Resuscitation after Polytrauma J Am Coll Surg

tion has devastating neurologic consequences after Abbreviations and Acronyms blast-induced neurotrauma. BIS EEG ϭ bispectral electroencephalogram ϭ CPP cerebral perfusion pressure METHODS CVP ϭ central venous pressure ICP ϭ intracranial pressure Animals were housed in a facility approved by the Amer- IED ϭ improvised explosive device ican Association of Laboratory Animal Care, with veter- ϭ IVF intravenous fluid inarians available at all times. All procedures were per- MAP ϭ mean arterial pressure NS ϭ normal saline formed according to National Institutes of Health TBI ϭ traumatic brain injury Guidelines for Use of Laboratory Animals and were preap- proved by our Institutional Animal Care and Use Com- mittee. Animals were anesthetized in all surgical inter- casualties are now caused by IEDs.1 The recent upsurge ventions, and all efforts were made to minimize the in urban terrorist bombings2-6 suggests that number of animals involved and to alleviate their pain will become a disturbing reality at both military and and distress. civilian trauma centers in the 21st century.7 General instrumentation There are few reproducible animal models of blast Farm-raised crossbred fasted swine of both genders injury.8 Most existing models for resuscitation research (42 Ϯ 2 kg, n ϭ 35) were sedated with an intramuscu- are inadequate because there is minimal (if any) soft lar injection of 30 mg/kg ketamine and 3.5 mg/kg tissue injury; trauma is usually equated with hemor- xylazine. The animals underwent orotracheal intubation rhagic , and resuscitation is based on blood volume and (Impact Portable Adult Ven- loss in a controlled laboratory setting. In contrast, blast tilator Model 754, Impact Systems), with tidal vol- victims can have multiple soft-tissue , with or umes ϭ 10 mL/kg and 8 to 16 breaths/min to maintain without active hemorrhage, and resuscitation is directed PaCO ϭ 40 Ϯ 5 mmHg. The FiO was 0.4 except 9,10 2 2 at restoring rather than blood volume. where otherwise noted. Anesthesia was initiated with Associated compartment syndromes can confound com- continuous intravenous infusions of 10 mg/kg/h ket- pensatory responses. With no valid models, it is difficult amine, 0.5 mg/kg/h xylazine, and 50 g/kg/h fentanyl. to evaluate new or existing therapies, and it is virtually Pulse oximetry (Nellcor Pulse Oximeter) was continu- impossible to develop specific evidence-based guidelines ously monitored. for treatment. With the animal in the supine position, Recent data from Walter Reed Army Hospital suggest were placed in the femoral artery for continuous ar- that occult traumatic brain injury (TBI) is common in terial blood pressure (Zoll Hemodynamic many soldiers exposed to blast, even when there are no Monitor) and in the external jugular vein for IVF obvious external signs or loss of consciousness.10-12 Blast administration. Additional catheters were placed in overpressure might also produce lung injuries that re- the urinary bladder to measure urine output, in the semble .9,10 The resultant hypox- pulmonary artery to measure mixed venous pulmo- emia can potentiate secondary damage after TBI.13,14 nary artery oxygen saturation, pulmonary artery pres- One goal of this study was to develop a clinically relevant sures, and cardiac output, and in the portal vein to model of blast-induced polytrauma. measure oxygen saturation (Abbott Critical Care Sys- The other major goal of this study was to test the tems, Abbott Laboratories). Gastric tissue oxygen sat- hypothesis that resuscitation after polytrauma is opti- uration was measured by suturing a surface probe mized with IV fluid (IVF) restriction. Cerebrovascular (InSpectra Tissue Spectrometer, Hutchinson Tech- resuscitation in a combat environment can be com- nologies Inc) to the outer surface of the anterior gas- plicated by a lack of basic monitoring capability, lim- tric wall. Laser Doppler blood flow probes were su- ited resources, and prolonged evacuation.15-17 On one tured to the inferior pole of the kidney and to the hand, the ability to achieve adequate resuscitation outer surface of the anterior wall of the stomach to with minimal IVF offers considerable logistic advan- measure microcirculatory blood flow (BPM 402, tages for the military. On the other hand, IVF restric- Vasamedics). Vol. 204, No. 2, February 2007 Earle et al Cerebrovascular Resuscitation after Polytrauma 263

The animal was then rotated into the prone posi- that would mimic the apnea that might accompany TBI tion for the remainder of the experiment. Brain tissue in real life.

PO2 and intracranial pressure (ICP) were continu- ously monitored through an intraparenchymal oxy- Resuscitation and treatment groups gen electrode and fiber optic pressure transducer The remainder of the experiment was divided into (LICOX MCB Oxygen Monitor, Integra Neuro- phases that were intended to simulate the types of sciences) that was placed through a small left frontal medical care that would occur in the prehospital craniotomy. In addition, leads were placed so that a phase or during emergency medical transport (30 to bispectral electroencephalogram (BIS EEG) was contin- 45 minutes postinjury; 0 to 15 minutes of first aid), uously recorded (Model A-1050 monitor, Aspect Med- emergency room (ER, 45 to 120 minutes postinjury; ical Systems). The suppression ratio of the BIS EEG is 15 to 90 minutes of medical treatment), and intensive defined as the percentage of isoelectric EEG activity in care unit (ICU, 120 to 300 minutes postinjury; 90 to the last minute, and is consistent with cerebral ischemia. 270 minutes of medical treatment). For 300 to So, BIS monitoring allows precise evaluation of second- 330 minutes after polytrauma, anesthesia and other ary injury to the brain, as we18,19 and others have IVFs were turned off, and the ventilator was switched reported.20,21 to the “assist-control” mode so that a minimal inspira- During a 60-minute postinstrumentation stabiliza- tory effort would trigger a full breath. There were four tion period, 1L of normal saline (NS) was administered treatment groups, and the protocol is outlined in to all animals. All IVF was stopped and the FiO2 was Figure 1. reduced to 0.21 for 15 minutes before injury. In group 1, the standard of care or control group (n ϭ 5), “prehospital” resuscitation consisted of imme- ϭ ϭ Improvised explosive device polytrauma simulation diate ventilatory support (FiO2 0.4; rate 12 to 20 Anesthetized, fully instrumented, and ventilated swine breaths/min) and a 1-L bolus of NS. In the “emergency in the prone position received blunt TBI, bilateral lung room phase,” PEEP was increased to 5 cm H20, and contusions, and hypoventilation for 30 minutes. additional NS was infused to a resuscitation target of The blunt TBI was produced with a commercially mean arterial pressure (MAP) Ͼ 60 mmHg. In the “ICU available power actuated tool or “nail gun” (Remington phase,” prophylactic mannitol (1 g/kg) was adminis- PowerTrigger, Model 479, Desa Specialty Products) that tered for intracranial hypertension (ICP Ͼ 20 mmHg), was activated by a 22-caliber #1 cartridge. and phenylephrine was titrated along with additional Within a minute of blunt TBI, bilateral blunt chest NS to maintain a cerebral perfusion pressure (CPP) injuries were produced by firing a captive bolt gun Ͼ 70 mmHg at a CVP Ͼ12 mmHg. (model ME, Karl Schermer & Co), first against the right Mannitol, rather than hypertonic saline, was chosen and then the left chest. The location was the midaxillary for ICP control based on current evidence-based guide- line at the level of the fourth intercostal space with a lines for managing severe brain trauma.14 The consensus 45-degree cephalad trajectory. The gun was activated statement is that “mannitol is effective for the control of with a #21 10-mm cartridge. Landmarks were the pos- raised ICP after severe ...Effective doses terior axillary line at the angular scapular groove, as de- range from 0.25 to 1 g/kg body weight.” The use of scribed in several previous studies.22-24 mannitol for ICP control after severe brain injury is Kinetic energy from each of the guns was calculated supported at the level of a guideline because there are by determining the mass of the captive bolt and by mea- insufficient data to support a treatment standard on this suring its velocity with high speed digital photography. topic. These measurements were made at Vision Research Inc The remaining three groups were fluid restricted. in the Allan Carlisle Photography laboratory with a Group 2 (NS, CVP ϭ 8 mmHg, n ϭ 5) received NS to Phantom Digital High Speed Camera, Analysis System, the same MAP targets, and NS ϩ phenylephrine ϩ and CineViewer 606 (Photosonics). mannitol to the same CPP target, but the filling pressure For 30 minutes after this insult, animals were me- was 8 mmHg. ϭ ϭ chanically ventilated at 4 breaths/min on FiO2 0.21. Group3(NS1L,n 5) received a total of only This superimposed a hypoxic or hypercapnic stimulus 1 L of NS and then mannitol and phenylephrine to 264 Earle et al Cerebrovascular Resuscitation after Polytrauma J Am Coll Surg

Figure 1. Experimental design. CPP, cerebral perfusion pressure; ER, emergency room; MAP, mean arterial pressure; NS, normal saline; PE, phenylephrine; TBI, traumatic brain injury.

the CPP targets, without regard for filling pressure or ration, portal venous O2 saturation, gastric tissue O2 MAP. saturation, gastric laser Doppler blood flow, renal laser

Group 4 received Hextend (HEX, 6% hydroxyethyl Doppler blood flow, brain tissue PO2, ICP, BIS EEG, starch in lactated electrolyte injection; Abbot Laborato- and urine output. Blood gases (PaO2, PaCO2, pH, base ries), instead of NS, to the group 2 targets (HEX, excess, and arterial O2 saturation), lactate and electro- ϩ ϩ CVP ϭ 8 mmHg, n ϭ 5). In two additional experiments, lytes (Na ,K , , and osmolarity) were recorded no fluid or pressor was administered after polytrauma. at 15- to 30-minute intervals on a Nova Stat Profile Ultra. At 360 minutes, an overdose of anesthesia was Test of cerebrovascular reactivity and compliance administered for euthanasia. Before injury, and at hourly intervals thereafter, cerebro- vascular reactivity and compliance were evaluated. This Histologic specimens technique has been previously described in detail.18,19,25 The brain was weighed. The presence and size of surface Briefly, inhaled CO2 was maintained at 7.5% for 5 min- lesions (measured and contrecoup contusions, hemor- utes, which produced an average end-tidal CO2 of 65 to rhages including epidural and subdural hemorrhages) 70 mmHg. The degree of the CO2-evoked ICP and brain were documented, measured, and photographed. The tissue oxygenation changes depends on cerebral compli- brain was suspended in 10% buffered formalin for ance and vascular reactivity in animals and . 1 week. The cerebral hemispheres, brainstem, and cere- bellum were coronally cut into 5-mm thick sections. Physiologic data Tissue blocks were obtained of all gross lesions and from The following were monitored continuously for representative areas of the neocortex, hippocampus, 60 minutes before and 360 minutes after polytrauma: basal ganglia, thalamus, hemispheric white matter, mid- core temperature, end tidal CO2, heart rate, MAP, brain, and cerebellar hemisphere. Three-millimeter CVP,pulmonary artery pressure, pulmonary capillary thick sections were processed routinely for histology (de- wedge pressure, cardiac output, mixed venous O2 satu- hydration in graded alcohol, clearing in xylene, then Vol. 204, No. 2, February 2007 Earle et al Cerebrovascular Resuscitation after Polytrauma 265

Figure 2. The gross appearance of a typical brain injury at autopsy: before durotomy in situ (A) showing epidural hemorrhage, after durotomy in situ (B) showing subdural hemorrhage. Subarachnoid hemorrhage and contusion (C) and contrecoup injury at the base of the brain (D) were grossly evident. Scale in cm. paraffin embedding). Paraffin sections (8 ␮m) were the SPSS for Windows release 14.0 program (SPSS Inc). stained routinely with hematoxylin and eosin to exam- A two-tailed p Ͻ 0.05 was considered significant. ine for neuronal shrinkage (early ischemia), neuronal eosinophilia (evidence of neuronal necrosis), neuropil spongiosis (edematous changes), microglial nuclear RESULTS enlargement and pallor (microglial activation), endo- Description of polytrauma model thelial nuclear pallor and enlargement (endothelial Blunt TBI was produced by a power actuated piston or activation), and presence of neutrophils (evidence of captive bolt (mass ϭ 103 g) striking a 4-cm (diameter) acute inflammation). Darkened neurons reflected early aluminum disk at 30 m/s (kinetic energy ϭ 0.5 [0.103 ischemic injury.26 Alzheimer type II astrocytosis re- kg] [30 m/s]2 ϭ 46.4 joules). The disk was taped to flected early damage to astrocytes after trauma.27 Semi- the skin overlying the occipital bone along the mid- quantitative assessment of histologic changes were per- line. This blast produced no skull fracture or obvious formed “blindly” and graded on a crude 0-to-3 scale, damage to the head (other than mild erythema). The where 0 ϭ no changes, 1 ϭ slight changes, 2 ϭ moder- gross appearance of a typical injury on autopsy is shown ate changes, and 3 ϭ marked changes. in Figure 2. After craniectomy, a subdural hematoma was obvious (Figs. 2A [before durotomy] and 2B [after Statistics durotomy]), and the contusion (Fig. 2C) and contre- Treatments were applied in random order in two cohorts coup injury at the base of the brain (Fig. 2D) were (groups 1 versus 3; and groups 2 versus 4). Data are grossly evident. expressed as mean Ϯ SEM. Student t-test and one-way Bilateral blunt chest trauma was produced by a power ANOVA for multiple comparisons were calculated with actuated piston with a mushroom head (mass ϭ 352 g) 266 Earle et al Cerebrovascular Resuscitation after Polytrauma J Am Coll Surg

and tachycardia.The and corrected

with ventilatory support and supplemental O2, but car- diac output, mixed venous O2 saturation, and lactate clearance were all depressed. There was no urine output. One animal survived only 60 minutes, and the other survived 300 minutes in these premorbid conditions. This untreated control arm clearly demonstrated that some fluid resuscitation was necessary for survival. Every animal that survived to resuscitation survived to the end of observation with at least some neurologic function, as judged by spontaneous respiratory efforts during venti- lator weaning. This suggests the adequacy of resuscita- tion with the four fluid combinations in these experi- mental conditions. Figure 3. The gross appearance of the lungs at autopsy. Scalpel handle is reference. Physiologic changes with “standard of care” or three different fluid restriction strategies striking the right and then the left chest at 26 m/s (kinetic Figure 4 shows MAP and CPP as a function of time. The energy ϭ 0.5 [0.352 kg] [26 m/s]2 ϭ 119.0 joules). left panel shows that baseline MAP ranged from 85 to The most common pattern was a bruise on 100 mmHg and fell to 60 to 65 mmHg by 30 minutes the chest, but there was no other obvious deformity. after polytrauma. The first liter of IVF transiently in- Tubethoracostomy was usually not required. At autopsy, creased MAP 10 to 19 mmHg in the three NS groups, multiple nondislocated rib fractures were common, but but the increase was Ͼ 35 mmHg (p ϭ 0.059 versus the parietal pleura was not often violated. Lung contu- control) and more sustained in the Hextend group. In sions were obvious on gross examination. Figure 3 shows all groups, MAP increased at 120 minutes, when the typical appearance of the lungs. Gross changes in- mannitol was administered and pressor therapy be- clude diffuse contusions with stiffened heavy tissue, gun. From that point until the end of observation, pleural rents, , or mediastinal extrava- CPP was maintained at the Ͼ 70 mmHg target in all sation of air. Despite these sequelae, PaO2 usually re- groups (right panel). But in the Hextend group, CPP Ͼ ϭ Ͼ mained 200 mmHg on FiO2 0.4 for at least 5 was 70 mmHg immediately on resuscitation hours with standard supportive care. (p ϭ 0.023 versus control). There were 13 (37%) deaths after polytrauma (Fig. 1), Figure 5 shows the IVF required to maintain the MAP which defines the severity of the combined insult. About and CPP targets. Each animal received a bolus of1Lof half of these deaths occurred within 30 minutes, ie, be- NS (approximately 25 mL/kg) during the instrumenta- fore resuscitation. The other half occurred within tion period and before injury. After polytrauma, each 120 minutes; typically, there were two patterns. One was animal received1Lofeither NS or Hextend, plus man- minimal response to the resuscitation fluid, but there nitol (1 g/kg), which partly explains the brisk diuresis. were still signs of life; this was judged as intractable Altogether, group 1 required a total of 161 Ϯ 6 mL/kg hypotension. The other was ICP Ͼ 30 mmHg, which NS for resuscitation, administered as a continuous infu- was judged as a nonsurvivable surgical lesion. sion of 36 Ϯ 1 mL/kg/h plus 0.18 Ϯ 0.04 mg/kg phen- Animals who survived 30 minutes after polytrauma ylephrine. Group 2 required about half as much IVF with ICP Ͻ 30 mmHg typically manifested hypoten- (75 Ϯ 29 mL/kg; 17 Ϯ 6 mL/kg/h, p ϭ 0.002 versus sion, hypoxia, hypercapnia, and tachycardia. On initial control) and also less phenylephrine (0.13 Ϯ 0.03 mg/kg; resuscitation (fluid bolus, ventilatory support, supple- p ϭ 0.34 versus control). Group 3 received a single Ϯ mental O2) followed later by CPP management (includ- 1-L bolus of NS at resuscitation (22 1 mL/kg; ing mannitol and pressor therapy), most physiologic 4.8 Ϯ 0.2 mL/kg/h; p Ͻ 0.001 versus control), then variables corrected in all groups. With no fluid at phenylephrine only for the remainder of the experiment 30 minutes (n ϭ 2), there was persistent hypotension (0.25 Ϯ 0.07 mg/kg; p ϭ 0.20 versus control). Group 4 Vol. 204, No. 2, February 2007 Earle et al Cerebrovascular Resuscitation after Polytrauma 267

Figure 4. Mean arterial pressure (MAP) and cerebral perfusion pressure (CPP), right, as a function of time with standard of care (group 1) and three fluid-restricted groups. After blast-induced polytrauma, MAP and CPP were partially corrected with1Lofnormal saline (NS), but additional NS was needed to fully restore and sustain the benefits. One liter of Hextend (Hex) immediately restored MAP and CPP and only minimal supplemental intravenous fluid was needed to sustain the effects. CVP, central venous pressure; PE, phenylephrine. received 28 Ϯ 13 mL/kg Hextend (6 Ϯ 3 mL/kg/h; p Ͻ volume was similar with 6 mL/kg/h Hextend or 36 mL/ 0.001 versus control) and the least amount of phenyl- kg/h NS, but was slightly reduced with either 5 or ephrine (0.07 Ϯ 0.02 mg/kg; p ϭ 0.06 versus control). 17 mL/kg/h NS. Groups 3 and 4 were in relative fluid balance because the Figure 7 suggests that at least some IVF was probably IVF infusion almost exactly matched the urine output. third spacing into the brain and lungs. The left panel In contrast, urine output was less than half of the IVF shows that ICP progressively increased to 35 to rate in groups 1 and 2. 40 mmHg in group 1, and ICP was 25% to 40% lower Figure 6 shows other markers of vascular volume. In in groups 2 and 3 (p ϭ 0.019 and 0.007, respectively, the control group, CVP was maintained at about versus control). With Hextend, ICP remained near 12 mmHg and hematocrit remained near the baseline 15 mmHg for the entire posttrauma observation (p Ͻ value of about 25, suggesting euvolemia. With Hextend, 0.001 versus control), except during the brief tests of CVP was maintained at 8 mmHg (p ϭ 0.003 versus cerebrovascular reactivity each hour (data not shown). In control), but hematocrit was also consistent with euvol- all groups, increased FiCO2 for 5 minutes provoked a emia. In group 2, CVP was 8 mmHg (p ϭ 0.024 versus 2- to 3-mmHg ICP increase before injury and a 6- to control), but there was a progressive hemoconcentration 10-mmHg increase after injury. This is consistent with to 30 (p ϭ 0.071 versus control), suggesting relative hy- reduced cerebrovascular compliance, but the changes povolemia. In group 3, hematocrit was similarly in- were similar in all groups, so the data are not shown. ϭ creased (p 0.027 versus control) and CVP was Except during the CO2 challenges, PaCO2 was tightly 4 mmHg (p Ͻ 0.001 versus control), also consistent regulated at 40 Ϯ 5 mmHg by varying the respiratory with . In all groups, plasma Naϩ,Kϩ, and rate; there were no differences between groups (data not osmolarity changes were variable and not considerably shown). different between groups (data not shown). So, the com- The right panel of Figure 7 shows that in the three NS bined data in Figures 6 and 7 suggest that intravascular groups, peak inspiratory pressure on constant tidal vol- 268 Earle et al Cerebrovascular Resuscitation after Polytrauma J Am Coll Surg

Figure 5. Total intravenous fluid (IVF) mL/kg/h, (including the first liter) required to maintain the mean arterial pressure cerebral perfusion pressure targets. The associated urine output reflects the osmotic diuresis caused by mannitol. CUP, central venous pressure; NS, normal saline. ume (10 mL/kg/breath) increased from about 20 cm There was a clear trend to diminished EEG activity

H20 in baseline conditions to about 25 cm H20 after and also a trend to increases in EEG burst suppres- 5 hours. In the Hextend group, peak inspiratory pressure sion, indicating ischemic EEG changes. But these was about 5 cm H20 higher throughout the posttrauma changes were highly variable and not statistically dif- resuscitation period (p ϭ 0.01 versus control). ferent between groups, so the data are not shown.

Figure 6. Other markers of vascular volume status (central venous pressure [CVP], left and arterial hematocrit, right) in the four groups. Hex, Hextend; NS, normal saline; PE, phenylephrine. Vol. 204, No. 2, February 2007 Earle et al Cerebrovascular Resuscitation after Polytrauma 269

Figure 7. Intracranial pressure (mmHg), left, and peak inspiratory pressure ECM H2O; right, reflect possible third spacing of intravenous fluid in the four groups. CVP, central venous pressure; Hex, Hextend; NS, normal saline; PE, phenylephrine.

Figure 8 shows that brain tissue PO2 decreased from a there were no differences between groups, so those data baseline value of about 12 mmHg to Ͻ 2 mmHg after are not shown. injury and before resuscitation in all groups (left panel).

The first liter of IVF corrected brain tissue PO2 back to Semiquantitative neuropathologic changes baseline in all groups. But in group 3, brain tissue PO2 Figure 10 shows representative histologic specimens was not maintained. It slowly decreased to about stained with hematoxylin and eosin from the cerebral 6 mmHg and stabilized at that value until the end of the cortex from an uninjured animal (panel A), and cor- observation period (p ϭ 0.045 versus control). In the responding sections after injury and treatment with other three groups, brain tissue PO2 stabilized standard of care (panel B) and with Hextend (panel Ͼ at 20 mmHg. The right panel shows that PaO2 de- C). With standard of care (group 1), there was a strik- creased from a baseline value of about 225 mmHg to ing degree of neuronal shrinkage (arrows) and neuro- about 50 mmHg and then corrected to Ͼ 200 mmHg pil vacuolization (edema). With Hextend (group 4), with resuscitation. There was no PaO2 difference be- there were several dark, slightly shrunken neurons, tween treatments. with prominent perineuronal spaces (arrows). The All other markers of resuscitation and tissue oxygen- scale bar ϭ 120 ␮m. ation were similar between groups. Figure 9 shows that In an attempt to quantitate the neuropathologic mixed venous O2 saturation fell from a baseline value of changes within and between groups, sections from the about 70% to about 25% before resuscitation, and lac- cerebral cortex were evaluated in a blinded fashion. Table 1 tate increased to Ͼ 6 mmol/L. Both of these variables shows that every animal had evidence of severe TBI, but corrected with resuscitation and there was no difference there was large variability within and between individu- between groups. als. Changes included subarachnoid hemorrhage, pete- There were quantitatively similar changes in cardiac chiae, ischemia, neutrophil infiltrates with focal areas of output, renal blood flow, and portal venous and gastric necrosis, shrunken, darkened neurons, Alzheimer type II oxygenation with injury and with resuscitation, and astrocytosis, or spongiosis (neurophil edema). No apop- 270 Earle et al Cerebrovascular Resuscitation after Polytrauma J Am Coll Surg

Figure 8. Brain tissue PO2 (mmHg), left, and PaO2 (mmHg), right, versus time in four groups. Note that brain tissue Ͼ PO2 was not maintained in group 3, but was 20 mmHg in the other three groups. Hex, Hextend; NS, normal saline; PE, phenylephrine. tosis or spheroids and, or retraction balls were noted, but ing to this system, the overall damage was judged as that is not surprising at this early time point. Within follows: group 2 ϭ group 3 Ͼ group 1 Ͼ group 4. One each group, the mean (Ϯstandard error) was calculated specimen was not analyzed in group 3 because of tech- from unweighted averages from each category. Accord- nical reasons.

Figure 9. Systemic markers of resuscitation. Mixed venous O2 saturation (%), left, and arterial lactate (mm), right, corrected in all four groups. Hex, Hextend; NS, normal saline; PE, phenylephrine. Vol. 204, No. 2, February 2007 Earle et al Cerebrovascular Resuscitation after Polytrauma 271

Figure 10. Representative histologic specimens stained with hematoxylin and eosin from the cerebral cortex from an uninjured animal (A), and corresponding sections after injury and treatment with standard of care, group 1 (B) and with Hextend, group 4 (C).

DISCUSSION NS bolus followed by judicious IVF administration to Our soldiers suffer blast injuries almost every day in Iraq maintain MAP Ͼ 60 mmHg at a moderate filling and Afghanistan.28-32 In the best case, if medical re- pressure (CVP Ͼ 12 mmHg), brain oxygenation was sources are available, blood loss can be approximated, restored (Fig. 8), but ICP reached dangerous lev- and resuscitation is targeted to end points such as blood els Ͼ 35 mmHg within the 6-hour observation pe- pressure, heart rate, or urine output. In the worst case, in riod (Fig. 7), even with mannitol and pressor therapy. field situations, emergency care is delayed, there is no Reducing IVF by about half (group 2) reduced ICP by monitoring capability, or resuscitation is limited to the 30% (to 25 mmHg); this ICP value remained danger- fluids carried by the first responder. In either case, it is ously high, according to current evidence-based man- difficult to evaluate which therapeutic modality is best agement guidelines for severe TBI.14 Brain oxygenation because there are no reproducible large animal models to was maintained, but there was evidence of hemoconcen- test the ideas. To our knowledge, this is the first con- tration and a volume deficit (Fig. 6). If IVF was addi- trolled laboratory study to compare fluid restriction re- tionally restricted to a single 1-L bolus of NS (group 3), suscitation strategies after the type of complicated severe brain oxygenation was not maintained. In all three NS polytrauma that might result from a blast injury on the groups, CPP was maintained at Ͼ 70 mmHg only battlefield. after mannitol and pressor therapy. In striking con- In this study, the severity of the polytrauma is re- trast, an initial 1-L bolus of Hextend immediately flected by the 37% (13 of 35) mortality before random- corrected CPP Ͼ 70 mmHg, which is important be- ization (Fig. 1). Animals that survived to the point of cause CPP maintenance is the cornerstone of TBI man- emergency medical care lived at least 6 hours with at agement.33,34 In addition, in group 4, brain oxygenation least some neurologic function, which compares favor- was maintained, and overall IVF requirements were re- ably to reports of casualties evacuated alive from the duced by one-sixth relative to group 1 (Fig. 5). Taken battlefield.7,9-12,15-17,28-32 In all survivors, MAP and CPP together, these observations are consistent with the con- were stable (Fig. 4), there was adequate urine output clusion that intracranial hypertension was acutely atten- (Fig. 5), and lactate was cleared (Fig. 9), which, at first uated, and brain oxygenation was acutely maintained glance, suggests that all four resuscitation strategies only when IVF was restricted and that resuscitation was yielded satisfactory results. optimized when Hextend was used instead of NS.This is The major new findings are that with a reasonable consistent with accumulating evidence that Hextend of- “standard of care” (group 1), which includes an initial fers unique advantage, relative to crystalloid, for combat 272 Earle et al Cerebrovascular Resuscitation after Polytrauma J Am Coll Surg

Table 1. Distribution of Neuropathologic Changes Dark PMN Alzheimer type II Focal Focal Score (Specimen neurons Spongiosi infiltration change necrosis ischemia Petechia SAH (mean؎SE Group 1 #12 ϩϩ ϩ ϩ #14 ϩϩ ϩ ϩ ϩ #15 ϩϩ ϩϩϩ ϩϩϩ ϩϩ #17 ϩϩϩ ϩ #19 ϩϩ ϩ ϩϩϩ ϩϩ Average 1.0 0.2 1.4 0.0 0.8 1.6 0.8 0.4 0.9 Ϯ 0.2 Group 2 #3 ϩϩϩ ϩϩϩ ϩϩϩ ϩ ϩϩϩ ϩϩϩ ϩϩ #5 ϩϩϩ ϩϩϩ ϩϩ ϩ ϩ ϩϩ ϩ #6 ϩϩϩϩϩϩ #9 ϩϩϩ ϩ #11 ϩ ϩ ϩϩ ϩϩ ϩ Average 1.6 1.2 1.0 1.4 0.8 1.4 1.0 1.2 1.2 Ϯ 0.1 Group 3 #13 ϩ ϩϩ ϩϩϩ ϩ ϩϩ #16 ϩϩ ϩϩ ϩϩ ϩϩ ϩ #18 ϩϩϩ ϩ ϩ ϩϩϩ ϩϩϩ ϩϩϩ ϩ #20 ϩϩ ϩ ϩϩ ϩ Average 0.8 0.2 1.8 1.8 0.8 1.5 1.8 1.2 1.2 Ϯ 0.2 Group 4 #2 ϩϩ ϩϩ ϩ ϩϩ ϩϩ #4 ϩϩ ϩ ϩ #7 ϩϩ ϩ #8 ϩ ϩ #10 ϩϩ ϩ ϩ Average 1.0 0.4 0.8 0.4 0.8 0.4 0.0 0.6 0.6 Ϯ 0.1 Each specimen was graded on a 0–3 scale with 0 as normal and ϩϩϩ as severe. PMN, polymorphonuclear leukocyte; SAH, subarachnoid hemorrhage. resuscitation and other situations in which resources are components.9,10 Primary blast injury is caused by the limited, such as emergency medical transport or during pressure wave and occurs almost exclusively in gas- a mass casualty event.16,17 containing organs, such as the lung, ear, and gastrointes- Current military doctrine for treating combat injuries tinal tract. The ear is the most sensitive to this pressure allows permissive hypotensive resuscitation, based on wave, but damage to the lung is responsible for the most the assumption that aggressive normalization of hemo- morbidity and mortality. Gross lung changes include dynamics might exacerbate .17,35 There are am- diffuse contusions with stiffened heavy tissue, pleural ple theoretic data to support this concept.36-38 Because rents, pneumothorax, or mediastinal extravasation of air bleeding extremity wounds have been the most common (eg, Fig. 3). Microscopic lung changes include intraal- combat injury throughout history,15 the importance veolar hemorrhage with perivascular or peribronchial cannot be overstated. On the other hand, permissive disruption and leukocyte infiltration. Secondary blast hypotensive resuscitation could be catastrophic after injury results from blunt or caused concussion from an IED because even brief episodes of by energized objects. Tertiary blast injury occurs when hypotension or hypoxia can double morbidity and mor- the whole body collides with fixed objects. Quaternary tality after TBI.13,14,33,34 blast injury results from and exposure to toxic In the current war in Iraq, the majority of casualties inhalants.7,9 are caused by IEDs,1 and TBI is common.11 In theory, The whole body polytrauma caused by an IED de- the injury caused by an IED can be divided into four pends on several factors, including blast kinetic energy, Vol. 204, No. 2, February 2007 Earle et al Cerebrovascular Resuscitation after Polytrauma 273 fragments and projectiles loaded in the bomb or there have been no randomized clinical trials evaluating launched by the explosion, proximity of the to the use of Hextend for trauma resuscitation. Relative to the blast, barriers that partially deflect the energy, and of hetastarch in saline, Hextend has a beneficial coagula- course, biologic variability in the patient. So no two tion profile, less antigenicity, and some antioxidant injuries or compensatory responses are exactly alike. properties.42,43 Hextend prevents hyperchloremic meta- Nevertheless, if the injury is survivable, there are com- bolic and improves gastric mucosal perfusion mon patterns and general principles that can serve as the versus saline solutions.44 The potential value of Hextend basis for model development. has been recognized in a review of special issues faced by Our IED model was based on three assumptions. battlefield medics.17 But it should be emphasized that First, we reasoned that blast overpressure would likely the use of Hextend in trauma patients is off-label, its cause some structural lung damage, but have no obvious effects are transient, and there is a potential for coagu- 45 functional consequence. This reasoning is based on lopathy. It is regarded as a temporizing measure only after-action reports that confirm that refractory hypox- and is not recommended for those with TBI. Before our emia from the blast is relatively uncommon in a venti- work, there was no evidence that Hextend was safe and lated patient evacuated from the battlefield.10,15,28-31 In effective for resuscitation after trauma with or without any case, the pathophysiology and treatment of blast TBI. In three different trauma models, we showed that injury to the lung are almost exactly the same as the fluid requirements were reduced by at least half, pulmo- pathophysiology and treatment for blunt chest trauma nary and cerebrovascular function were improved, and 39 there was no adverse effect on the coagulation profile and pulmonary contusion. In our model, and in real 19,23,46 life, symptomatic treatment includes judicious IVF ad- with Hextend relative to crystalloid. The results from this study affirm those results. ministration, supplemental O and appropriate ventila- 2, There are at least four major limitations to this study. tory support with positive end expiratory pressure. If any First, for ethical reasons, all animals were anesthetized at one of these conditions is not met, then a progressive the time of injury and throughout the experiment. The develops. Second, we reasoned that in ketamine or fentanyl anesthesia could impart either a most cases, penetrating TBI after an IED is lethal. It protective or a deleterious effect that may differ from the follows that the most common pattern of survivable TBI real-life nonanesthetized trauma patient. Although an after IED is caused by either energized anesthesia artifact may have existed, it was imposed objects striking the head or the head striking a fixed equally on all groups. Second, the magnitude of the lung object. Of course, survivability depends also on the di- injury in this study was somewhat less than that in our rection of the blast and anatomic location of the injury. several previous studies,22-24 even though the kinetic en- In our model, the blast was applied in the occipital re- ergy delivered to the chest wall was similar. The exact gion and in an anterocaudal direction perpendicular to explanation for this difference was not rigorously pur- the spinal cord. Third, we reasoned that neurotrauma sued, but the animals were about 15% to 20% larger, the victims in real life would receive current standards of injury was delivered in the prone rather than supine trauma care, which would include CPP management, if position, there was no superimposed hemorrhage, and necessary. We have a unique perspective on current resuscitation IVF was guided by MAP targets rather than problems related to combat casualty care because the US blood volume lost. Third, there was no longterm fol- Army has selected the University of Miami as the train- lowup, and it is possible that the short-term physiologic ing site for its forward surgical teams. Whenever our differences between groups have no neurologic or other soldiers are in battle, these teams are near the front clinical consequence. There were also no obvious histo- lines. Since September 11, 2001, most of the army’s logic differences after 6 hours (Table 1), so longterm teams deployed in Iraq and Afghanistan have trained studies are clearly indicated. Fourth, the model did not in our laboratory.40 Feedback and after-action reports mimic the shrapnel, heat, or electromagnetic radiation from these teams have grounded our research firmly in that can be caused by an IED. Also, the captive bolt guns reality. produced injuries to the brain and lungs that varied be- Hextend is an FDA-approved hetastarch solution in- tween individuals. On the other hand, relative to an dicated for hypovolemia during elective surgery,41 but actual explosion, recreating the polytrauma with captive 274 Earle et al Cerebrovascular Resuscitation after Polytrauma J Am Coll Surg bolt guns was relatively inexpensive in terms of equip- REFERENCES ment and manpower, and the contribution and direc- 1. Coalition casualties in Iraq and Afghanistan. Available at: http:// tionality of the various injury components could be eas- icasualties.org/oif/default.aspx. Accessed December 6, 2006. 2. Mallonee S, Shariat S, Stennies G, et al. Physical injuries and ily manipulated. fatalities resulting from the Oklahoma City bombing. JAMA In summary, we described a new model of blast injury 1996;276:382–387. polytrauma using captive bolt guns in anesthetized pigs. 3. Gutierrez de Ceballos JP, Turegano Fuentes F, Perez Diaz D, et al. 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