Damage Control Resuscitation Supplemented with Vasopressin in a Severe Polytrauma Model with Traumatic Brain Injury and Uncontrolled Internal Hemorrhage

Damage Control Resuscitation Supplemented with Vasopressin in a Severe Polytrauma Model with... Abstract Introduction Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of traumatic death worldwide and particularly on the battlefield. They are especially challenging when present simultaneously (polytrauma), and clear blood pressure end points during fluid resuscitation are not well described for this situation. The goal of this study is to evaluate for any benefit of increasing blood pressure using a vasopressor on brain blood flow during initial fluid resuscitation in a swine polytrauma model. Materials and Methods We used a swine polytrauma model with simultaneous TBI, femur fracture, and HS with uncontrolled noncompressible internal bleeding from an aortic tear injury. Five animals were assigned to each of three experimental groups (hydroxyethyl starch only [HES], HES + 0.4 U/kg vasopressin, and no fluid resuscitation [No Fluids]). Fluids were given as two 10 mL/kg boluses according to tactical field care guidelines. Primary outcomes were mean arterial blood pressure (MAP) and brain blood flow at 60 min. Secondary outcomes were blood flows in the heart, intestine, and kidney; arterial blood lactate level; and survival at 6 hr. Organ blood flow was measured using injection of colored microspheres. Results Five animals were tested in each of the three groups. There was a statistically significant increase in MAP with vasopressin compared with other experimental groups, but no significant increase in brain blood flow during the first 60 min of resuscitation. The vasopressin group also exhibited greater total internal hemorrhage volume and rate. There was no difference in survival at 6 hours. Conclusion In this experimental swine polytrauma model, increasing blood pressure with vasopressin did not improve brain perfusion, likely due to increased internal hemorrhage. Effective hemostasis should remain the top priority for field treatment of the polytrauma casualty with TBI. Introduction Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of traumatic death worldwide and particularly on the battlefield. When combined, known as polytrauma, they are associated with a significant increase in mortality compared with either one alone.1,2 The increased mortality from polytrauma stems from simultaneous hypovolemia and tissue ischemia from HS and increased intracranial pressure (ICP) from TBI that further impairs blood flow to the brain and a compromised ability to compensate and respond to hemorrhagic shock. For HS, standard US military tactical combat casualty care (TCCC) training recommends damage control resuscitation (DCR), which consists of permissive hypotension with systolic blood pressure (SBP) of 70–90 mmHg or mean arterial pressure (MAP) of 65 mmHg.3 This minimizes blood loss and promotes clot formation at sites of vascular injury. In contrast, for a patient with TBI with elevated ICP, an increased blood pressure goal of SBP ≥ 120, or MAP ≥ 105 mmHg, is recommended in order to maintain cerebral perfusion.4 Aggressive large-volume fluid resuscitation to support blood pressure can cause coagulopathy, hypothermia, and even hyperchloremic acidosis, all elements of the “lethal triad” associated with increased bleeding and mortality.4–7 Additionally, an animal model of polytrauma with TBI and uncontrolled hemorrhage demonstrated improved outcome when animals were managed with a protocol of permissive hypotension as compared with those aggressively resuscitated.8 However, it is also clear that even transient episodes of hypotension after brain injury lead to irreversible secondary brain damage in a time- and dose-dependent manner.4,9 Furthermore, TBI can interfere with resuscitation of HS due to autonomic nervous system insult, which blunts systemic neurovascular responses that normally support physiological compensation to shock.1,2,10–18 To further confound these observations, recent studies using polytrauma animal models determined that even hemostatic resuscitation given aggressively using blood products may not be sufficient when TBI is also present.19 These concerns fuel the ongoing debate as to whether a limited or aggressive resuscitation approach is appropriate during initial fluid resuscitation of the polytrauma patient. The question of the optimal resuscitation approach for the polytraumatized casualty is even more critical when considering the challenges and limitations of battlefield medicine. Special Operations Forces (SOF) medics are charged with the care of polytraumatized casualties independently for up to 72 hr without evacuation or resupply.20 Moreover, the SOF medic’s resources are finite and often limited to what can be carried on his person or distributed among team members. Thus, polytrauma patients rapidly consume medical resources under the best of conditions. Blast injuries from improvised explosive devices (IED) are commonplace, oftentimes incurring multiple casualties.21,22 Thus, it is often the case that a single SOF medic is responsible for the care of multiple polytraumatized patients, in an austere environment, and likely while still engaged by hostile forces. To further complicate matters, current medical evacuation (MEDEVAC) times are expected to increase while SOF’s continue to operate and sustain casualties in this environment.23 In short, multiple casualties, relative lack of resources, prolonged MEDEVAC times, and the fact that TCCC guidelines are not designed for such prolonged care all contribute to the circumstances in which the current prehospital battlefield treatment of polytraumatized patients often falls short. Given the logistical limitations associated with SOF operations in austere locations, alternative strategies for blood pressure support in polytraumatized casualties with HS should be considered. An attractive, low-volume solution that could support vital organ perfusion is vasopressor support using vasopressin. Blood vasopressin concentration is increased acutely after polytrauma.24 Vasopressin infusion can also prolong survival during severe hemorrhagic shock and improve brain perfusion when given after initial resuscitation in animal models.25,26 However, such vasoactive infusions may also be associated with more specific detrimental effects on brain circulation as well as an increase in hemorrhage from uncontrolled sites of injury, and hence, its potential value during polytrauma resuscitation remains unknown.27 The goal of this study is to evaluate whether there is benefit to raising systemic blood pressure using vasopressin during initial fluid resuscitation in the presence of TBI and HS with uncontrolled internal hemorrhage. To accomplish this goal, we used a swine polytrauma model with simultaneous TBI, femur fracture, and HS with uncontrolled noncompressible internal bleeding from an aortic tear injury. We hypothesized that adding vasopressin to increase MAP during the first 60 min of fluid resuscitation would improve both blood pressure and brain perfusion. Materials and Methods Anesthesia and Instrumentation This study was approved and abided by a protocol approved by the University of Washington Office of Animal Welfare. Domestic female Yorkshire swine weighing 20–30 kg were used for this study and were housed in a local vivarium and provided full veterinary care. On the morning of the study, animals were sedated with 0.2 ml/kg of intramuscular ketamine and xylazine mixed in 7:1 (v:v) ratio, endotracheally intubated, and fully anesthetized to a surgical plane with a mixture of isoflurane (1–5%), and oxygen (33%) delivered via nose cone. Animals were also given one intramuscular dose (0.01 mg/kg) of buprenorphine for analgesia. Animals remained intubated for the duration of the experiment and were allowed to breath spontaneously with supplemental mechanical ventilation as needed while end-tidal CO2 was monitored continuously (Datex Capnomac Ultima; Datex Instrumentarium Corp). Arterial blood gas measurements were used to titrate oxygenation and ventilation settings as needed to maintain normal blood pH, pO2, and pCO2 parameters during the baseline equilibration period before onset of hemorrhage. After anesthesia induction, the right side of the neck, both femoral areas including the site of the femur fracture, and the anterior abdominal wall were shaved and widely prepared with povidone-iodine. Right femoral artery and venous catheters were placed for blood sampling and fluid/drug administration. The right femoral artery catheter was premeasured by anatomical landmarks and was advanced into the infrarenal aorta for pressure monitoring and to ensure patency for blood draws during periods of hypotension. The left midshaft femur was exposed using sharp incision of the skin and blunt dissection to the bone. Adjacent nerve and vascular structures were mobilized away from the bone to avoid injury. A right carotid artery introducer catheter was placed and a 5-French pig-tail catheter was placed via the right carotid into the left ventricle for pressure monitoring and colored microsphere injection for regional blood flow measurements. A pulmonary artery thermodilution catheter was inserted via the right external jugular vein and advanced into the pulmonary artery for central venous pressure (CVP), mean pulmonary artery pressure (MPAP), cardiac output (CO), core temperature monitoring, and mixed venous blood (SvO2) sampling. The pulmonary artery catheter position was confirmed by characteristic pressure waveform tracing. A laparotomy was then performed via midline abdominal incision for splenectomy and placement of a 4.0 monofilament stainless steel surgical wire spanning 4 mm on the ventral wall of the aorta for creation of an aortic tear injury. The bladder was also cannulated for drainage. The wire ends were then exteriorized through the abdominal incision and the incision will be closed in single-layer manner with surgical staples. After the above instrumentation, pigs were then placed in the prone position with their head placed in a stabilizer. The scalp was widely prepared with povidone-iodine. A circumferential incision and the cranium exposed for a 16-mm diameter craniotomy in the right parietal region adjacent to the sagittal suture and anterior to the coronal suture. A T-shaped bolt was screwed into the craniotomy to abut the intact dura. This bolt was connected to the fluid percussion TBI device. All craniotomy sites were then sealed with dental cement. Electrocardiographic (ECG) leads were then placed on the anterior thorax of the animal and were connected to a Biopac MP150 monitoring and data acquisition system (Biopac System, Inc. Santa Barbara, CA, USA) in addition to arterial and Swan Ganz catheters for continuous hemodynamic pressure monitoring. Experimental Injury and Hemorrhage Following baseline measurements, fluid percussion injury (FPI) was induced by applying a 3–4 atmosphere fluid wave directly to the dura using a pendulum fluid percussion device. The FPI device consists of a saline-filled tube, which connects to the craniotomy bolt. On the opposite end of the device is a pendulum arm with a weight at its distal end. The pendulum is pulled back a standard distance and allowed to fall, striking a plexiglass piston, which in turn strikes a rubber seal at the end of the fluid filled cylinder. The resulting fluid wave that is generated in this closed system transmits a 15-ms pressure pulse to the intact dura. A high-pressure transducer recorded the delivered pressure. Animals were then immediately placed in the supine position and a percussive femur fracture was induced using a captive bolt gun (Schermer Stunner Model MKL; Karl Schermer and Co., Karlsruhe, Germany) using a 0.22 caliber blank load was fired to induce an open displaced, comminuted midshaft femur fracture with surrounding soft tissue injury. Hemorrhage was then started from the femoral artery catheter connected to a computer-driven roller pump programmed to bleed the animal at a rate of 35 ml/kg over 30 min. To duplicate more closely the physiology and kinetics of hemorrhagic hypotension, the computer was programmed to withdraw blood at a rate that decreases exponentially over time. This model mimics traumatic hemorrhage in that the initial bleed rate is rapid but decreases with the fall in blood pressure. Once the animal’s mean arterial pressure (MAP) reached 50 mmHg, the aortic wire was pulled, creating a fixed internal aortic tear injury allowing for free intraperitoneal hemorrhage. When the animal’s MAP decreased to 30 mmHg, the catheter hemorrhage was discontinued and the pressure held at 30–35 mmHg and titrated with short intervals of additional catheter hemorrhage for 15 min (S0–S15) to achieve a state of hemorrhagic shock indicated by an increased arterial lactate level above baseline. At the end of the shock period, resuscitation time 0 (R0), animals were randomized to one of the following experimental groups: No Fluid: Negative control, no resuscitation fluids given. 6% Hydroxyethyl starch in balanced saline solution (Hextend; Hospira Inc., Lake Forest, IL, USA) (HES): Given as 7 ml/kg with 3 ml/kg normal saline volume control given at R0 minutes and infused over 10 min. A second bolus was given 30 min later at R40 minutes. HES+Vasopressin: HES given as 7 ml/kg with 3 ml/kg normal saline containing 0.4 U/kg vasopressin, (Pitressin; Parke-Davis/Pfizer, Karlsruhe, Germany) given at R0 minutes and infused over 10 min. A second bolus was given 30 min later at R40 minutes. No other fluid resuscitation was provided and animals were observed for up to 6 hr. Arterial blood was sampled serially for blood gas measurements and colored microspheres (Dye-Trak Microspheres; Triton Inc., Seattle, WA, USA) were injected into the left ventricle serially at baseline before hemorrhage, and again at 30 and 60 min after the onset of fluid resuscitation for measurement of vital organ blood flow. The polystyrene microspheres of prespecified uniform diameter are dyed with one of several possible colors. Simultaneous injection of the microspheres into the left ventricle and measurement of cardiac output at the time of injection enables measurement of organ-specific blood flow by recovery of spheres in tissue biopsies. The spheres are recovered from tissue and blood samples by digestion and subsequent micro-filtration. The dyes are then recovered from the spheres within a known volume of a solvent and their organ flow-dependent concentrations determined by spectrophotometry. Spontaneous animal death was defined by a decrease in mean arterial pressure to <10 mmHg for at least 1 min and confirmed by loss of arterial pressure waveform. Upon spontaneous death, or at 6 hr, euthanasia was performed by pentobarbital overdose while under anesthesia. After euthanasia, the peritoneum was reopened and all internal blood loss was collected and measured using preweighed sponges. Organs including brain, lung, heart, liver, intestine, and kidney were also biopsied for colored microsphere measurement of organ-specific blood flow. Statistical Analysis Outcomes and physiological data were presented as means and standard deviations. One-way ANOVA was used to compare single-outcome variables between groups after adjusting for multiple comparisons using Tukey’s adjustment. For physiological data measured serially over time, two-way repeated measures ANOVA (rmANOVA) with interaction was used to evaluate for significant effects of treatment group and time. A significant interaction effect would indicate that the variable of interest was significantly different between treatment groups at a particular time during the hemorrhage or resuscitation protocol. Tukey adjustment for multiple comparisons was used to examine individual differences between treatment groups if a significant treatment effect was present. Simple Pearson rank correlation was used to examine for significant associations between MAP, blood loss, and survival time. Significance was defined at the p < 0.05 level of confidence for all effects. All statistical analyses were performed using JMP-12 statistical software (SAS, Cary, NC, USA). Results Five animals with a mean weight of 21.8 kg (SD ± 1.7 kg) completed the protocol in each of the three treatment groups. Fluid percussion induced a mean intracranial pressure spike of 3.4 (0.3) atmospheres. No animals in any group survived to 6 hr. The longest surviving animal lived to 327 of 360 min and was in the HES group. This particular animal appeared survived 1.3 times longer than any other animal. However, there was no significant difference in total blood loss in this particular animal (29.6 ml/kg) and no protocol deviations identified, so it was included in the overall analysis. Survival outcomes and blood loss are given in Table I. Mean survival time was longest in the HES group, but this difference was not statistically different than other groups. Intraperitoneal hemorrhage volume was greatest in the HES+vasopressin group and was significantly greater than the negative control No Fluids group. Table I. Effect of Hextend (7 ml/kg per Bolus) and Hextend with Vasopressin (0.4 U/kg per Bolus) on Intraperitoneal Blood Loss and Survival Time.   No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007    No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007  *ANOVA p < 0.02 vs. No Fluids group with Tukey HSD for individual comparisons. HES = 6% hyroxyethyl starch. Table I. Effect of Hextend (7 ml/kg per Bolus) and Hextend with Vasopressin (0.4 U/kg per Bolus) on Intraperitoneal Blood Loss and Survival Time.   No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007    No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007  *ANOVA p < 0.02 vs. No Fluids group with Tukey HSD for individual comparisons. HES = 6% hyroxyethyl starch. Mean (SD) MAP averaged over 60 min of resuscitation was 44.1 (17.4) mmHg in the HES+vasopressin group and was significantly higher than both the negative control No Fluids group at 28.6 (10.6) mmHg, p < 0.001, and the HES group at 34.3 (18.0) mmHg, p = 0.01. There was no single time point within the first 60 min of resuscitation at which the MAP was significantly different between groups (rmANOVA interaction, p = 0.8) (Fig. 1). Lactate concentration averaged over the first 60 min was significantly increased in the HES+vasopressin group at 5.5(3.3) mmol/L compared with the negative control No Fluids group at 3.4(1.0) mmol/L, p = 0.036, but was not different than the HES group at 4.3 (1.4)mmol/L, p = 0.3. There was no individual time point in the first 60 min at which lactate was different between groups (rmANOVA interaction, p = 0.7) (Fig. 1). Figure 1. View largeDownload slide Mean arterial pressure (MAP, top panel) and arterial lactate concentration (bottom panel) during fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. Fluid boluses were given at R0 and R40. Error bars represent standard deviation. Figure 1. View largeDownload slide Mean arterial pressure (MAP, top panel) and arterial lactate concentration (bottom panel) during fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. Fluid boluses were given at R0 and R40. Error bars represent standard deviation. There was no difference between brain blood flow measured in all areas of the brain (all rmANOVA treatment group, p > 0.15), and there were no significant interactions present (Fig. 2). There was also no difference between treatment groups when examining blood flow in other vital organs (kidneys rmANOVa treatment, p > 0.055; Ileum rmANOVA treatment, p = 0.4; heart rmANOVA treatment, p = 0.22) (Fig. 3). Figure 2. View largeDownload slide Mean regional brain hemispheric blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Figure 2. View largeDownload slide Mean regional brain hemispheric blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Figure 3. View largeDownload slide Mean vital organ blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Figure 3. View largeDownload slide Mean vital organ blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Intraperitoneal blood loss and survival time did not correlate significantly (R = −0.5, p = 0.056). There was also no significant correlation between survival time and mean MAP during the first 60 min of resuscitation (R = −0.37, p = 0.17). However, there were significant positive correlations between the mean MAP over the first 60 min of resuscitation and intraperitoneal blood loss (R = 0.66, p = 0.006) and total hemorrhage volume (R = 0.76, p < 0.001). Discussion Our hypothesis that adding vasopressin to initial fluid resuscitation during the first 60 min of polytrauma resuscitation would improve both systemic MAP and local brain perfusion was not supported using this pig polytrauma model. An increase in MAP was seen when compared with the No Fluids and HES groups. However, there was no significant increase in brain or vital organ perfusion, likely due to increased internal blood loss. In the casualty having hemorrhagic shock, DCR calls for limited fluid resuscitation to maintain a SBP < 90 mmHg to prevent coagulopathy and reduce blood loss. This study showed that raising blood pressure with vasopressin did not improve cerebral perfusion but did increase hemorrhage volume. This observation is consistent with DCR teaching that a higher MAP in HS with uncontrolled bleeding leads to clot disruption, continued hemorrhage, and decreased survival. With this in mind, DCR protocols for polytrauma require refinement with greater emphasis placed upon achieving hemostasis in a dynamic physiologic setting. Due to logistical requirements and austere environment encountered by SOF, it is important that medical supplies are lightweight, durable, and require minimal logistical support.20 HES was chosen as the resuscitation fluid in this study due to its wide use in SOF medicine. Comparing crystalloids, colloids, and fresh frozen plasma (FFP) in similar polytrauma models, Jin et al found that normal saline exacerbated cerebral edema while both HES and FFP decreased swelling.28 Jin also found that FFP actually reduced brain lesion size when compared with both normal saline and HES. FFP’s increasing use in SOF medicine warrants further study as resuscitation fluid in polytrauma given its additional contribution to hemostasis but would prove costlier and perhaps less favorable due to logistical requirements. Gibson et al found that fresh whole blood was also superior to normal saline in another similar polytrauma model.29 The practice of fresh whole blood transfusion in the field has shown promise to address the needs of the polytrauma casualty by providing oxygen delivery, volume expansion, and coagulation support and has made a recent comeback into SOF medicine, yet remains less logistically feasible than a shelf-stable resuscitation fluid. Alternatively, vasopressin requires no refrigeration and could be deployed by adding directly to a bag of resuscitation fluid. It is lightweight and could easily be carried in the SOF medic’s aid bag. It could be administered as fluid bolus or infusion over time. However, our finding of increased blood loss with vasopressin necessitates the need for increased hemorrhage control efforts, new hemostatic adjuncts, and possibly closer blood pressure monitoring if vasopressin were to be used. Retesting vasopressin in the presence of hemostatic therapies capable of addressing internal noncompressible hemorrhage including tranexamic acid, lyophilized plasmas, and fibrinogen concentrates that have shown efficacy in animal models should be considered a research priority.30 In addition, the liberal use of standard hemostatic maneuvers such as tourniquets or hemostatic bandages should be further prioritized. Limitations of this study include the small number of experiments as well as outliers in particular groups causing an increase in variability. Each group was limited to five animals, and while some trends in physiologic measurements were observed, it is difficult to definitively draw clear conclusions without having more data. There was also an outlier in the HES group in respect to key physiologic measurements to include MAP. Coupled with the small numbers, this outlier has great effect on the variability of these primary outcomes as well as other secondary outcomes. Although this pig did demonstrate a marked deviation from the others in its respective group in these measured outcomes, there was no appropriate reason for study exclusion. The use of general anesthesia before injury, including xylazine, may also exert effects that are not seen in the clinical situation such as blunting of adrenergic outflow. Caution should also be applied when generalizing these data to human experience. This and the effects of other vasopressors that induce positive inotropic effects should also be studied in future work. These data were obtained under strict experimental conditions under full anesthesia and in a species with several dissimilarities to humans. 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Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government. © Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Military Medicine Oxford University Press

Damage Control Resuscitation Supplemented with Vasopressin in a Severe Polytrauma Model with Traumatic Brain Injury and Uncontrolled Internal Hemorrhage

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Abstract

Abstract Introduction Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of traumatic death worldwide and particularly on the battlefield. They are especially challenging when present simultaneously (polytrauma), and clear blood pressure end points during fluid resuscitation are not well described for this situation. The goal of this study is to evaluate for any benefit of increasing blood pressure using a vasopressor on brain blood flow during initial fluid resuscitation in a swine polytrauma model. Materials and Methods We used a swine polytrauma model with simultaneous TBI, femur fracture, and HS with uncontrolled noncompressible internal bleeding from an aortic tear injury. Five animals were assigned to each of three experimental groups (hydroxyethyl starch only [HES], HES + 0.4 U/kg vasopressin, and no fluid resuscitation [No Fluids]). Fluids were given as two 10 mL/kg boluses according to tactical field care guidelines. Primary outcomes were mean arterial blood pressure (MAP) and brain blood flow at 60 min. Secondary outcomes were blood flows in the heart, intestine, and kidney; arterial blood lactate level; and survival at 6 hr. Organ blood flow was measured using injection of colored microspheres. Results Five animals were tested in each of the three groups. There was a statistically significant increase in MAP with vasopressin compared with other experimental groups, but no significant increase in brain blood flow during the first 60 min of resuscitation. The vasopressin group also exhibited greater total internal hemorrhage volume and rate. There was no difference in survival at 6 hours. Conclusion In this experimental swine polytrauma model, increasing blood pressure with vasopressin did not improve brain perfusion, likely due to increased internal hemorrhage. Effective hemostasis should remain the top priority for field treatment of the polytrauma casualty with TBI. Introduction Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of traumatic death worldwide and particularly on the battlefield. When combined, known as polytrauma, they are associated with a significant increase in mortality compared with either one alone.1,2 The increased mortality from polytrauma stems from simultaneous hypovolemia and tissue ischemia from HS and increased intracranial pressure (ICP) from TBI that further impairs blood flow to the brain and a compromised ability to compensate and respond to hemorrhagic shock. For HS, standard US military tactical combat casualty care (TCCC) training recommends damage control resuscitation (DCR), which consists of permissive hypotension with systolic blood pressure (SBP) of 70–90 mmHg or mean arterial pressure (MAP) of 65 mmHg.3 This minimizes blood loss and promotes clot formation at sites of vascular injury. In contrast, for a patient with TBI with elevated ICP, an increased blood pressure goal of SBP ≥ 120, or MAP ≥ 105 mmHg, is recommended in order to maintain cerebral perfusion.4 Aggressive large-volume fluid resuscitation to support blood pressure can cause coagulopathy, hypothermia, and even hyperchloremic acidosis, all elements of the “lethal triad” associated with increased bleeding and mortality.4–7 Additionally, an animal model of polytrauma with TBI and uncontrolled hemorrhage demonstrated improved outcome when animals were managed with a protocol of permissive hypotension as compared with those aggressively resuscitated.8 However, it is also clear that even transient episodes of hypotension after brain injury lead to irreversible secondary brain damage in a time- and dose-dependent manner.4,9 Furthermore, TBI can interfere with resuscitation of HS due to autonomic nervous system insult, which blunts systemic neurovascular responses that normally support physiological compensation to shock.1,2,10–18 To further confound these observations, recent studies using polytrauma animal models determined that even hemostatic resuscitation given aggressively using blood products may not be sufficient when TBI is also present.19 These concerns fuel the ongoing debate as to whether a limited or aggressive resuscitation approach is appropriate during initial fluid resuscitation of the polytrauma patient. The question of the optimal resuscitation approach for the polytraumatized casualty is even more critical when considering the challenges and limitations of battlefield medicine. Special Operations Forces (SOF) medics are charged with the care of polytraumatized casualties independently for up to 72 hr without evacuation or resupply.20 Moreover, the SOF medic’s resources are finite and often limited to what can be carried on his person or distributed among team members. Thus, polytrauma patients rapidly consume medical resources under the best of conditions. Blast injuries from improvised explosive devices (IED) are commonplace, oftentimes incurring multiple casualties.21,22 Thus, it is often the case that a single SOF medic is responsible for the care of multiple polytraumatized patients, in an austere environment, and likely while still engaged by hostile forces. To further complicate matters, current medical evacuation (MEDEVAC) times are expected to increase while SOF’s continue to operate and sustain casualties in this environment.23 In short, multiple casualties, relative lack of resources, prolonged MEDEVAC times, and the fact that TCCC guidelines are not designed for such prolonged care all contribute to the circumstances in which the current prehospital battlefield treatment of polytraumatized patients often falls short. Given the logistical limitations associated with SOF operations in austere locations, alternative strategies for blood pressure support in polytraumatized casualties with HS should be considered. An attractive, low-volume solution that could support vital organ perfusion is vasopressor support using vasopressin. Blood vasopressin concentration is increased acutely after polytrauma.24 Vasopressin infusion can also prolong survival during severe hemorrhagic shock and improve brain perfusion when given after initial resuscitation in animal models.25,26 However, such vasoactive infusions may also be associated with more specific detrimental effects on brain circulation as well as an increase in hemorrhage from uncontrolled sites of injury, and hence, its potential value during polytrauma resuscitation remains unknown.27 The goal of this study is to evaluate whether there is benefit to raising systemic blood pressure using vasopressin during initial fluid resuscitation in the presence of TBI and HS with uncontrolled internal hemorrhage. To accomplish this goal, we used a swine polytrauma model with simultaneous TBI, femur fracture, and HS with uncontrolled noncompressible internal bleeding from an aortic tear injury. We hypothesized that adding vasopressin to increase MAP during the first 60 min of fluid resuscitation would improve both blood pressure and brain perfusion. Materials and Methods Anesthesia and Instrumentation This study was approved and abided by a protocol approved by the University of Washington Office of Animal Welfare. Domestic female Yorkshire swine weighing 20–30 kg were used for this study and were housed in a local vivarium and provided full veterinary care. On the morning of the study, animals were sedated with 0.2 ml/kg of intramuscular ketamine and xylazine mixed in 7:1 (v:v) ratio, endotracheally intubated, and fully anesthetized to a surgical plane with a mixture of isoflurane (1–5%), and oxygen (33%) delivered via nose cone. Animals were also given one intramuscular dose (0.01 mg/kg) of buprenorphine for analgesia. Animals remained intubated for the duration of the experiment and were allowed to breath spontaneously with supplemental mechanical ventilation as needed while end-tidal CO2 was monitored continuously (Datex Capnomac Ultima; Datex Instrumentarium Corp). Arterial blood gas measurements were used to titrate oxygenation and ventilation settings as needed to maintain normal blood pH, pO2, and pCO2 parameters during the baseline equilibration period before onset of hemorrhage. After anesthesia induction, the right side of the neck, both femoral areas including the site of the femur fracture, and the anterior abdominal wall were shaved and widely prepared with povidone-iodine. Right femoral artery and venous catheters were placed for blood sampling and fluid/drug administration. The right femoral artery catheter was premeasured by anatomical landmarks and was advanced into the infrarenal aorta for pressure monitoring and to ensure patency for blood draws during periods of hypotension. The left midshaft femur was exposed using sharp incision of the skin and blunt dissection to the bone. Adjacent nerve and vascular structures were mobilized away from the bone to avoid injury. A right carotid artery introducer catheter was placed and a 5-French pig-tail catheter was placed via the right carotid into the left ventricle for pressure monitoring and colored microsphere injection for regional blood flow measurements. A pulmonary artery thermodilution catheter was inserted via the right external jugular vein and advanced into the pulmonary artery for central venous pressure (CVP), mean pulmonary artery pressure (MPAP), cardiac output (CO), core temperature monitoring, and mixed venous blood (SvO2) sampling. The pulmonary artery catheter position was confirmed by characteristic pressure waveform tracing. A laparotomy was then performed via midline abdominal incision for splenectomy and placement of a 4.0 monofilament stainless steel surgical wire spanning 4 mm on the ventral wall of the aorta for creation of an aortic tear injury. The bladder was also cannulated for drainage. The wire ends were then exteriorized through the abdominal incision and the incision will be closed in single-layer manner with surgical staples. After the above instrumentation, pigs were then placed in the prone position with their head placed in a stabilizer. The scalp was widely prepared with povidone-iodine. A circumferential incision and the cranium exposed for a 16-mm diameter craniotomy in the right parietal region adjacent to the sagittal suture and anterior to the coronal suture. A T-shaped bolt was screwed into the craniotomy to abut the intact dura. This bolt was connected to the fluid percussion TBI device. All craniotomy sites were then sealed with dental cement. Electrocardiographic (ECG) leads were then placed on the anterior thorax of the animal and were connected to a Biopac MP150 monitoring and data acquisition system (Biopac System, Inc. Santa Barbara, CA, USA) in addition to arterial and Swan Ganz catheters for continuous hemodynamic pressure monitoring. Experimental Injury and Hemorrhage Following baseline measurements, fluid percussion injury (FPI) was induced by applying a 3–4 atmosphere fluid wave directly to the dura using a pendulum fluid percussion device. The FPI device consists of a saline-filled tube, which connects to the craniotomy bolt. On the opposite end of the device is a pendulum arm with a weight at its distal end. The pendulum is pulled back a standard distance and allowed to fall, striking a plexiglass piston, which in turn strikes a rubber seal at the end of the fluid filled cylinder. The resulting fluid wave that is generated in this closed system transmits a 15-ms pressure pulse to the intact dura. A high-pressure transducer recorded the delivered pressure. Animals were then immediately placed in the supine position and a percussive femur fracture was induced using a captive bolt gun (Schermer Stunner Model MKL; Karl Schermer and Co., Karlsruhe, Germany) using a 0.22 caliber blank load was fired to induce an open displaced, comminuted midshaft femur fracture with surrounding soft tissue injury. Hemorrhage was then started from the femoral artery catheter connected to a computer-driven roller pump programmed to bleed the animal at a rate of 35 ml/kg over 30 min. To duplicate more closely the physiology and kinetics of hemorrhagic hypotension, the computer was programmed to withdraw blood at a rate that decreases exponentially over time. This model mimics traumatic hemorrhage in that the initial bleed rate is rapid but decreases with the fall in blood pressure. Once the animal’s mean arterial pressure (MAP) reached 50 mmHg, the aortic wire was pulled, creating a fixed internal aortic tear injury allowing for free intraperitoneal hemorrhage. When the animal’s MAP decreased to 30 mmHg, the catheter hemorrhage was discontinued and the pressure held at 30–35 mmHg and titrated with short intervals of additional catheter hemorrhage for 15 min (S0–S15) to achieve a state of hemorrhagic shock indicated by an increased arterial lactate level above baseline. At the end of the shock period, resuscitation time 0 (R0), animals were randomized to one of the following experimental groups: No Fluid: Negative control, no resuscitation fluids given. 6% Hydroxyethyl starch in balanced saline solution (Hextend; Hospira Inc., Lake Forest, IL, USA) (HES): Given as 7 ml/kg with 3 ml/kg normal saline volume control given at R0 minutes and infused over 10 min. A second bolus was given 30 min later at R40 minutes. HES+Vasopressin: HES given as 7 ml/kg with 3 ml/kg normal saline containing 0.4 U/kg vasopressin, (Pitressin; Parke-Davis/Pfizer, Karlsruhe, Germany) given at R0 minutes and infused over 10 min. A second bolus was given 30 min later at R40 minutes. No other fluid resuscitation was provided and animals were observed for up to 6 hr. Arterial blood was sampled serially for blood gas measurements and colored microspheres (Dye-Trak Microspheres; Triton Inc., Seattle, WA, USA) were injected into the left ventricle serially at baseline before hemorrhage, and again at 30 and 60 min after the onset of fluid resuscitation for measurement of vital organ blood flow. The polystyrene microspheres of prespecified uniform diameter are dyed with one of several possible colors. Simultaneous injection of the microspheres into the left ventricle and measurement of cardiac output at the time of injection enables measurement of organ-specific blood flow by recovery of spheres in tissue biopsies. The spheres are recovered from tissue and blood samples by digestion and subsequent micro-filtration. The dyes are then recovered from the spheres within a known volume of a solvent and their organ flow-dependent concentrations determined by spectrophotometry. Spontaneous animal death was defined by a decrease in mean arterial pressure to <10 mmHg for at least 1 min and confirmed by loss of arterial pressure waveform. Upon spontaneous death, or at 6 hr, euthanasia was performed by pentobarbital overdose while under anesthesia. After euthanasia, the peritoneum was reopened and all internal blood loss was collected and measured using preweighed sponges. Organs including brain, lung, heart, liver, intestine, and kidney were also biopsied for colored microsphere measurement of organ-specific blood flow. Statistical Analysis Outcomes and physiological data were presented as means and standard deviations. One-way ANOVA was used to compare single-outcome variables between groups after adjusting for multiple comparisons using Tukey’s adjustment. For physiological data measured serially over time, two-way repeated measures ANOVA (rmANOVA) with interaction was used to evaluate for significant effects of treatment group and time. A significant interaction effect would indicate that the variable of interest was significantly different between treatment groups at a particular time during the hemorrhage or resuscitation protocol. Tukey adjustment for multiple comparisons was used to examine individual differences between treatment groups if a significant treatment effect was present. Simple Pearson rank correlation was used to examine for significant associations between MAP, blood loss, and survival time. Significance was defined at the p < 0.05 level of confidence for all effects. All statistical analyses were performed using JMP-12 statistical software (SAS, Cary, NC, USA). Results Five animals with a mean weight of 21.8 kg (SD ± 1.7 kg) completed the protocol in each of the three treatment groups. Fluid percussion induced a mean intracranial pressure spike of 3.4 (0.3) atmospheres. No animals in any group survived to 6 hr. The longest surviving animal lived to 327 of 360 min and was in the HES group. This particular animal appeared survived 1.3 times longer than any other animal. However, there was no significant difference in total blood loss in this particular animal (29.6 ml/kg) and no protocol deviations identified, so it was included in the overall analysis. Survival outcomes and blood loss are given in Table I. Mean survival time was longest in the HES group, but this difference was not statistically different than other groups. Intraperitoneal hemorrhage volume was greatest in the HES+vasopressin group and was significantly greater than the negative control No Fluids group. Table I. Effect of Hextend (7 ml/kg per Bolus) and Hextend with Vasopressin (0.4 U/kg per Bolus) on Intraperitoneal Blood Loss and Survival Time.   No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007    No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007  *ANOVA p < 0.02 vs. No Fluids group with Tukey HSD for individual comparisons. HES = 6% hyroxyethyl starch. Table I. Effect of Hextend (7 ml/kg per Bolus) and Hextend with Vasopressin (0.4 U/kg per Bolus) on Intraperitoneal Blood Loss and Survival Time.   No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007    No Fluids  HES  HES+Vasopressin  ANOVA p-value  Mean  Std Dev  Mean  Std Dev  Mean  Std Dev  Survival time (min)  137.4  39.7  208.2  82.5  145.8  94.0  0.3  Catheter hemorrhage volume (ml/kg)  15.3  4.5  17.1  3.8  16.0  7.3  0.9  Intraperitoneal hemorrhage (mL/kg)  5.4  2.8  13.5  10.7  25.8*  13.6  0.02  Total hemorrhage volume (ml/kg)  20.7  2.2  30.6  10.3  41.8*  10.2  0.007  *ANOVA p < 0.02 vs. No Fluids group with Tukey HSD for individual comparisons. HES = 6% hyroxyethyl starch. Mean (SD) MAP averaged over 60 min of resuscitation was 44.1 (17.4) mmHg in the HES+vasopressin group and was significantly higher than both the negative control No Fluids group at 28.6 (10.6) mmHg, p < 0.001, and the HES group at 34.3 (18.0) mmHg, p = 0.01. There was no single time point within the first 60 min of resuscitation at which the MAP was significantly different between groups (rmANOVA interaction, p = 0.8) (Fig. 1). Lactate concentration averaged over the first 60 min was significantly increased in the HES+vasopressin group at 5.5(3.3) mmol/L compared with the negative control No Fluids group at 3.4(1.0) mmol/L, p = 0.036, but was not different than the HES group at 4.3 (1.4)mmol/L, p = 0.3. There was no individual time point in the first 60 min at which lactate was different between groups (rmANOVA interaction, p = 0.7) (Fig. 1). Figure 1. View largeDownload slide Mean arterial pressure (MAP, top panel) and arterial lactate concentration (bottom panel) during fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. Fluid boluses were given at R0 and R40. Error bars represent standard deviation. Figure 1. View largeDownload slide Mean arterial pressure (MAP, top panel) and arterial lactate concentration (bottom panel) during fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. Fluid boluses were given at R0 and R40. Error bars represent standard deviation. There was no difference between brain blood flow measured in all areas of the brain (all rmANOVA treatment group, p > 0.15), and there were no significant interactions present (Fig. 2). There was also no difference between treatment groups when examining blood flow in other vital organs (kidneys rmANOVa treatment, p > 0.055; Ileum rmANOVA treatment, p = 0.4; heart rmANOVA treatment, p = 0.22) (Fig. 3). Figure 2. View largeDownload slide Mean regional brain hemispheric blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Figure 2. View largeDownload slide Mean regional brain hemispheric blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Figure 3. View largeDownload slide Mean vital organ blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Figure 3. View largeDownload slide Mean vital organ blood flow as a percentage of baseline blood flow during the first 60 min of fluid resuscitation (R) in minutes. HES+vasopressin (diamond), HES alone (X), and No Fluids (closed circle) were compared. There were no statistically significant differences between groups. Intraperitoneal blood loss and survival time did not correlate significantly (R = −0.5, p = 0.056). There was also no significant correlation between survival time and mean MAP during the first 60 min of resuscitation (R = −0.37, p = 0.17). However, there were significant positive correlations between the mean MAP over the first 60 min of resuscitation and intraperitoneal blood loss (R = 0.66, p = 0.006) and total hemorrhage volume (R = 0.76, p < 0.001). Discussion Our hypothesis that adding vasopressin to initial fluid resuscitation during the first 60 min of polytrauma resuscitation would improve both systemic MAP and local brain perfusion was not supported using this pig polytrauma model. An increase in MAP was seen when compared with the No Fluids and HES groups. However, there was no significant increase in brain or vital organ perfusion, likely due to increased internal blood loss. In the casualty having hemorrhagic shock, DCR calls for limited fluid resuscitation to maintain a SBP < 90 mmHg to prevent coagulopathy and reduce blood loss. This study showed that raising blood pressure with vasopressin did not improve cerebral perfusion but did increase hemorrhage volume. This observation is consistent with DCR teaching that a higher MAP in HS with uncontrolled bleeding leads to clot disruption, continued hemorrhage, and decreased survival. With this in mind, DCR protocols for polytrauma require refinement with greater emphasis placed upon achieving hemostasis in a dynamic physiologic setting. Due to logistical requirements and austere environment encountered by SOF, it is important that medical supplies are lightweight, durable, and require minimal logistical support.20 HES was chosen as the resuscitation fluid in this study due to its wide use in SOF medicine. Comparing crystalloids, colloids, and fresh frozen plasma (FFP) in similar polytrauma models, Jin et al found that normal saline exacerbated cerebral edema while both HES and FFP decreased swelling.28 Jin also found that FFP actually reduced brain lesion size when compared with both normal saline and HES. FFP’s increasing use in SOF medicine warrants further study as resuscitation fluid in polytrauma given its additional contribution to hemostasis but would prove costlier and perhaps less favorable due to logistical requirements. Gibson et al found that fresh whole blood was also superior to normal saline in another similar polytrauma model.29 The practice of fresh whole blood transfusion in the field has shown promise to address the needs of the polytrauma casualty by providing oxygen delivery, volume expansion, and coagulation support and has made a recent comeback into SOF medicine, yet remains less logistically feasible than a shelf-stable resuscitation fluid. Alternatively, vasopressin requires no refrigeration and could be deployed by adding directly to a bag of resuscitation fluid. It is lightweight and could easily be carried in the SOF medic’s aid bag. It could be administered as fluid bolus or infusion over time. However, our finding of increased blood loss with vasopressin necessitates the need for increased hemorrhage control efforts, new hemostatic adjuncts, and possibly closer blood pressure monitoring if vasopressin were to be used. Retesting vasopressin in the presence of hemostatic therapies capable of addressing internal noncompressible hemorrhage including tranexamic acid, lyophilized plasmas, and fibrinogen concentrates that have shown efficacy in animal models should be considered a research priority.30 In addition, the liberal use of standard hemostatic maneuvers such as tourniquets or hemostatic bandages should be further prioritized. Limitations of this study include the small number of experiments as well as outliers in particular groups causing an increase in variability. Each group was limited to five animals, and while some trends in physiologic measurements were observed, it is difficult to definitively draw clear conclusions without having more data. There was also an outlier in the HES group in respect to key physiologic measurements to include MAP. Coupled with the small numbers, this outlier has great effect on the variability of these primary outcomes as well as other secondary outcomes. Although this pig did demonstrate a marked deviation from the others in its respective group in these measured outcomes, there was no appropriate reason for study exclusion. The use of general anesthesia before injury, including xylazine, may also exert effects that are not seen in the clinical situation such as blunting of adrenergic outflow. Caution should also be applied when generalizing these data to human experience. This and the effects of other vasopressors that induce positive inotropic effects should also be studied in future work. These data were obtained under strict experimental conditions under full anesthesia and in a species with several dissimilarities to humans. Conclusion In this swine model of combined polytrauma with TBI, HS, and free internal bleeding, the addition of vasopressin to HES increased systemic blood pressure but failed to improve brain blood flow. The lack of effect was likely due to increased internal blood loss in the presence of vasopressin. Hemostasis should be prioritized when resuscitating the polytrauma casualty. Funding This work was supported by grant W81XWH-141-0020 from USAMRMC-SOCOM. References 1 Mcmahon CG, Yates DW, Campbell FM, Hollis S, Woodford M: Unexpected contribution of moderate traumatic brain injury to death after major trauma. J Trauma Acute Care Surg  1999; 47( 5): 891– 5. Google Scholar CrossRef Search ADS   2 Mcmahon CG, Kenny R, Bennett K, Little R, Kirkman E: Effect of acute traumatic brain injury on baroreflex function. Shock  2011; 35( 1): 53– 8. Google Scholar CrossRef Search ADS PubMed  3 Jansen JO, Thomas R, Loudon MA, Brooks A: Damage control resuscitation for patients with major trauma. 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Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government. © Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Military MedicineOxford University Press

Published: Mar 14, 2018

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