The Efficacy of Whole Blood Resuscitation During Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) to Mitigate Post-occlusion Circulatory Collapse: A Translational Model in Large Swine.

INTRODUCTION: Uncontrolled torso hemorrhage is the primary cause of potentially survivable deaths on the battlefield. Zone 1 Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA), in conjunction with damage control resuscitation, may be an effective management strategy for these patients in the prehospital or austere phase of their care. However, the effect of whole blood (WB) transfusion during REBOA on post-occlusion circulatory collapse is not fully understood. MATERIALS AND METHODS: Yorkshire male swine (n = 6 per group, 70-90 kg) underwent a 40% volume-controlled hemorrhage. After a 10-minute hemorrhagic shock period, a REBOA balloon was inflated in Zone 1. Fifteen minutes after inflation, 0, 1, or 3 units (450 mL/unit) of autologous WB was infused through the left jugular vein. Thirty minutes after initial balloon inflation, the balloon was deflated slowly over 3 minutes. Following deflation, normal saline was administered (up to 3,000 mL) and swine were observed for 2 hours. Survival (primary outcome), hemodynamics, and blood gas values were compared among groups. Statistical significance was determined by log-rank test, one-way ANOVA, and repeated measures ANOVA. RESULTS: Survival rates were comparable between groups (P = .345) with 66% of control, 33% of the one-unit animals, and 50% of the 3-unit animals survived until the end of the study. Following WB infusion, both the 1-unit and the 3-unit groups had significantly higher blood pressure (P < .01), pulmonary artery pressure (P < .01), and carotid artery flow (P < .01) compared to the control group. CONCLUSIONS: WB transfusion during Zone 1 REBOA was not associated with increased short-term survival in this large animal model of severe hemorrhage. We observed no signal that WB transfusion may mitigate post-occlusion circulatory collapse. However, there was evidence of supra-normal blood pressures during WB transfusion.

Safety of Bioplasma FDP and Hemopure in rhesus macaques after 30% hemorrhage.

Objectives: Prehospital transfusion can be life-saving when transport is delayed but conventional plasma, red cells, and whole blood are often unavailable out of hospital. Shelf-stable products are needed as a temporary bridge to in-hospital transfusion. Bioplasma FDP (freeze-dried plasma) and Hemopure (hemoglobin-based oxygen carrier; HBOC) are products with potential for prehospital use. In vivo use of these products together has not been reported. This study assessed the safety of intravenous administration of HBOC+FDP, relative to normal saline (NS), in rhesus macaques (RM). Methods: After 30% blood volume removal and 30 minutes in shock, animals were resuscitated with either NS or two units (RM size adjusted) each of HBOC+FDP during 60 minutes. Sequential blood samples were collected. After neurological assessment, animals were killed at 24 hours and tissues collected for histopathology. Results: Due to a shortage of RM during the COVID-19 pandemic, the study was stopped after nine animals (HBOC+FDP, seven; NS, two). All animals displayed physiologic and tissue changes consistent with hemorrhagic shock and recovered normally. There was no pattern of cardiovascular, blood gas, metabolic, coagulation, histologic, or neurological changes suggestive of risk associated with HBOC+FDP. Conclusion: There was no evidence of harm associated with the combined use of Hemopure and Bioplasma FDP. No differences were noted between groups in safety-related cardiovascular, pulmonary, renal or other organ or metabolic parameters. Hemostasis and thrombosis-related parameters were consistent with expected responses to hemorrhagic shock and did not differ between groups. All animals survived normally with intact neurological function. Level of evidence: Not applicable.

Evaluation of hemostatic devices in a randomized porcine model of junctional hemorrhage and 72-hour prolonged field care.

BACKGROUND: Hemorrhage control in prolonged field care (PFC) presents unique challenges that drive the need for enhanced point of injury treatment capabilities to maintain patient stability beyond the Golden Hour. To address this, two hemostatic agents, Combat Gauze (CG) and XSTAT, were evaluated in a porcine model of uncontrolled junctional hemorrhage for speed of deployment and hemostatic efficacy over 72 hours. METHODS: The left subclavian artery and subscapular vein were isolated in anesthetized male Yorkshire swine (70-85 kg) and injured via 50% transection, followed by 30 seconds of hemorrhage. Combat Gauze (n = 6) or XSTAT (n = 6) was administered until bleeding stopped and remained within subjects for observation over 72 hours. Physiologic monitoring, hemostatic efficacy, and hematological parameters were measured throughout the protocol. Gross necropsy and histology were performed following humane euthanasia. RESULTS: Both CG and XSTAT maintained hemostasis throughout the full duration of the protocol. There were no significant differences between groups in hemorrhage volume (CG: 1021.0 ± 183.7 mL vs. XSTAT: 968.2 ± 243.3 mL), total blood loss (CG: 20.8 ± 2.7% vs. XSTAT: 20.1 ± 5.1%), or devices used (CG: 3.8 ± 1.2 vs. XSTAT: 5.3 ± 1.4). XSTAT absorbed significantly more blood than CG (CG: 199.5 ± 50.3 mL vs. XSTAT: 327.6 ± 71.4 mL) and was significantly faster to administer (CG: 3.4 ± 1.6 minutes vs. XSTAT: 1.4 ± 0.5 minutes). There were no significant changes in activated clot time, prothrombin time, or international normalized ratio between groups or compared with baseline throughout the 72-hour protocol. Histopathology revealed no evidence of microthromboemboli or disseminated coagulopathies across evaluated tissues in either group. CONCLUSION: Combat Gauze and XSTAT demonstrated equivalent hemostatic ability through 72 hours, with no overt evidence of coagulopathies from prolonged indwelling. In addition, XSTAT offered significantly faster administration and the ability to absorb more blood. Taken together, XSTAT offers logistical and efficiency advantages over CG for immediate control of junctional noncompressible hemorrhage, particularly in a tactical environment. In addition, extension of indicated timelines to 72 hours allows translation to PFC.

PREHOSPITAL PLASMA IS NONINFERIOR TO WHOLE BLOOD FOR RESTORATION OF CEREBRAL OXYGENATION IN A RHESUS MACAQUE MODEL OF TRAUMATIC SHOCK AND HEMORRHAGE.

ABSTRACT: Introduction: Traumatic shock and hemorrhage (TSH) is a leading cause of preventable death in military and civilian populations. Using a TSH model, we compared plasma with whole blood (WB) as prehospital interventions, evaluating restoration of cerebral tissue oxygen saturation (CrSO 2 ), systemic hemodynamics, colloid osmotic pressure (COP) and arterial lactate, hypothesizing plasma would function in a noninferior capacity to WB, despite dilution of hemoglobin (Hgb). Methods: Ten anesthetized male rhesus macaques underwent TSH before randomization to receive a bolus of O(-) WB or AB(+) plasma at T0. At T60, injury repair and shed blood (SB) to maintain MAP > 65 mm Hg began, simulating hospital arrival. Hematologic data and vital signs were analyzed via t test and two-way repeated measures ANOVA, data presented as mean ± SD, significance = P < 0.05. Results: There were no significant group differences for shock time, SB volume, or hospital SB. At T0, MAP and CrSO 2 significantly declined from baseline, though not between groups, normalizing to baseline by T10. Colloid osmotic pressure declined significantly in each group from baseline at T0 but restored by T30, despite significant differences in Hgb (WB 11.7 ± 1.5 vs. plasma 6.2 ± 0.8 g/dL). Peak lactate at T30 was significantly higher than baseline in both groups (WB 6.6 ± 4.9 vs. plasma 5.7 ± 1.6 mmol/L) declining equivalently by T60. Conclusions: Plasma restored hemodynamic support and CrSO 2 , in a capacity not inferior to WB, despite absence of additional Hgb supplementation. This was substantiated via return of physiologic COP levels, restoring oxygen delivery to microcirculation, demonstrating the complexity of restoring oxygenation from TSH beyond simply increasing oxygen carrying capacity.

Effects of hemodilution on coagulation function during prolonged hypotensive resuscitation in a porcine model of severe hemorrhagic shock.

Background: Although hemorrhage remains the leading cause of survivable death in casualties, modern conflicts are becoming more austere limiting available resources to include resuscitation products. With limited resources also comes prolonged evacuation time, leaving suboptimal prehospital field care conditions. When blood products are limited or unavailable, crystalloid becomes the resuscitation fluid of choice. However, there is concern of continuous crystalloid infusion during a prolonged period to achieve hemodynamic stability for a patient. This study evaluates the effect of hemodilution from a 6-hour prehospital hypotensive phase on coagulation in a porcine model of severe hemorrhagic shock. Methods: Adult male swine (n=5/group) were randomized into three experimental groups. Non-shock (NS)/normotensive did not undergo injury and were controls. NS/permissive hypotensive (PH) was bled to the PH target of systolic blood pressure (SBP) 85±5 mm Hg for 6 hours of prolonged field care (PFC) with SBP maintained via crystalloid, then recovered. Experimental group underwent controlled hemorrhage to mean arterial pressure 30 mm Hg until decompensation (Decomp/PH), followed by PH resuscitation with crystalloid for 6 hours. Hemorrhaged animals were then resuscitated with whole blood and recovered. Blood samples were collected at certain time points for analysis of complete blood counts, coagulation function, and inflammation. Results: Throughout the 6-hour PFC, hematocrit, hemoglobin, and platelets showed significant decreases over time in the Decomp/PH group, indicating hemodilution, compared with the other groups. However, this was corrected with whole blood resuscitation. Despite the appearance of hemodilution, coagulation and perfusion parameters were not severely compromised. Conclusions: Although significant hemodilution occurred, there was minimal impact on coagulation and endothelial function. This suggests that it is possible to maintain the SBP target to preserve perfusion of vital organs at a hemodilution threshold in resource-constrained environments. Future studies should address therapeutics that can mitigate potential hemodilutional effects such as lack of fibrinogen or platelets. Level of evidence: Not applicable-Basic Animal Research.

An Analysis of Head and Neck Surgical Workload During Recent Combat Operations From 2002 to 2016.

INTRODUCTION: In battle-injured U.S. service members, head and neck (H&N) injuries have been documented in 29% who were treated for wounds in deployed locations and 21% who were evacuated to a Role 4 MTF. The purpose of this study is to examine the H&N surgical workload at deployed U.S. military facilities in Iraq and Afghanistan in order to inform training, needed proficiency, and MTF manning. MATERIALS AND METHODS: A retrospective analysis of the DoD Trauma Registry was performed for all Role 2 and Role 3 MTFs, from January 2002 to May 2016; 385 ICD-9 CM procedure codes were identified as H&N surgical procedures and were stratified into eight categories. For the purposes of this analysis, H&N procedures included dental, ophthalmologic, airway, ear, face, mandible maxilla, neck, and oral injuries. Traumatic brain injuries and vascular injuries to the neck were excluded. RESULTS: A total of 15,620 H&N surgical procedures were identified at Role 2 and Role 3 MTFs. The majority of H&N surgical procedures (14,703, 94.14%) were reported at Role 3 facilities. Facial bone procedures were the most common subgroup across both roles of care (1,181, 75.03%). Tracheostomy accounted for 16.67% of all H&N surgical procedures followed by linear repair of laceration of eyelid or eyebrow (8.23%) and neck exploration (7.41%). H&N caseload was variable. CONCLUSIONS: H&N procedures accounted for 8.25% of all surgical procedures performed at Role 2 and Role 3 MTFs; the majority of procedures were eye (40.54%) and airway (18.50%). These data can be used as planning tools to help determine the medical footprint and also to help inform training and sustainment requirements for deployed military general surgeons especially if future contingency operations are more constrained in terms of resources and personnel.

Cerebral Regional Tissue Oxygenation as Surrogate for Blood Loss in Nonhuman Primate Models of Shock.

INTRODUCTION: Hemorrhage is the leading cause of preventable death, with a majority of mortalities in the prehospital setting. Current hemorrhage resuscitation guidelines cannot predict the critical point of intervention to activate massive transfusion (MT) and prevent cardiovascular decompensation. We hypothesized that cerebral regional tissue oxygenation (CrSO2) would indicate MT need in nonhuman primate models of hemorrhagic shock. METHODS: Nineteen anesthetized male rhesus macaques underwent hemorrhage via a volume-targeted (VT) or pressure-targeted (PT) method. VT animals were monitored for 30 min following 30% blood volume hemorrhage. PT animals were hemorrhaged to mean arterial pressure (MAP) of 20 mmHg and maintained for at least 60 min until decompensation. Statistics for MAP, heart rate (HR), end tidal carbon dioxide (EtCO2), and CrSO2 were analyzed via one- or two-way repeated-measures analysis of variance, Pearson's R, and receiver-operator curve. A P < 0.05 is considered significant. RESULTS: Following initial hemorrhage (S0), there were no significant differences between groups. After cessation of hemorrhage in the VT group, MAP and EtCO2 returned to baseline while CrSO2 plateaued. The PT group maintained model-defined low MAP, suppressing EtCO2, and significantly decreased CrSO2 compared to the VT group by S25. Linear regression of CrSO2versus shed blood volume demonstrated R2 = 0.7539. CrSO2 of 47% was able to detect >40% blood loss with an area under the curve of 0.9834 at 92.3% (66.7%-99.6%) sensitivity and 95.5% (84.9%-99.2%) specificity. CONCLUSIONS: Regardless of hemorrhage modality and compensatory response, CrSO2 correlated strongly with shed blood volume. Analysis demonstrated that CrSO2 values below 49% indicate Advanced Trauma Life Support class IV shock (blood loss>40%). CrSO2 at the point of care may help indicate MT need earlier and more accurately than traditional markers.

Advanced bleeding control in combat casualty care: An international, expert-based Delphi consensus.

BACKGROUND: Hemorrhage from truncal and junctional injuries is responsible for the vast majority of potentially survivable deaths in combat casualties, causing most of its fatalities in the prehospital arena. Optimizing the deployment of the advanced bleeding control modalities required for the management of these injuries is essential to improve the survival of severely injured casualties. This study aimed to establish consensus on the optimal use and implementation of advanced bleeding control modalities in combat casualty care. METHODS: A Delphi method consisting of three rounds was used. An international expert panel of military physicians was selected by the researchers to complete the Delphi surveys. Consensus was reached if 70% or greater of respondents agreed and if 70% or greater responded. RESULTS: Thirty-two experts from 10 different nations commenced the process and reached consensus on which bleeding control modalities should be part of the standard equipment, that these modalities should be available at all levels of care, that only trained physicians should be allowed to apply invasive bleeding control modalities, but all medical and nonmedical personnel should be allowed to apply noninvasive bleeding control modalities, and on the training requirements for providers. Consensus was also reached on the necessity of international registries and guidelines, and on certain indications and contraindications for resuscitative endovascular balloon occlusion of the aorta (REBOA) in military environments. No consensus was reached on the role of a wound clamp in military settings and the indications for REBOA in patients with chest trauma, penetrating axillary injury or penetrating neck injury in combination with thoracoabdominal injuries. CONCLUSION: Consensus was reached on the contents of a standard bleeding control toolbox, where it should be available, providers and training requirements, international registries and guidelines, and potential indications for REBOA in military environments.

Therapeutic cardiac arrest as an adjunct to resuscitative endovascular balloon occlusion of the aorta: Bridging the gap from fatal hemorrhage to definitive surgical control in swine.

BACKGROUND: Uncontrolled hemorrhage is the leading cause of potentially survivable combat casualty mortality, with 86.5% of cases resulting from noncompressible torso hemorrhage. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive technique used to stabilize patients with noncompressible torso hemorrhage; however, its application can take an average of 8 minutes to place. One therapeutic capable of bridging this gap is adenosine-lidocaine-magnesium (ALM), which at high doses induces a reversible cardioplegia. We hypothesize by using ALM as an adjunct to REBOA, the ALM-induced cardiac arrest will temporarily halt exsanguination and reduce blood loss, allowing for REBOA placement and control of bleeding. METHODS: Male Yorkshire swine (60-80 kg) were randomly assigned to REBOA only or ALM-REBOA (n = 8/group). At baseline, uncontrolled hemorrhage was induced via a 1.5-cm right femoral arteriotomy, and hemorrhaged blood was quantified. One minute after injury (S1), ALM was administered, and 7 minutes later (T0), zone 1 REBOA inflation occurred. If cardiac arrest ensued, cardiac function either recovered spontaneously or advanced life support was initiated. At T30, surgical hemostasis was obtained, and REBOA was deflated. Animals were resuscitated until they were humanely euthanized at T90. RESULTS: During field care phase, heart rate and end-tidal CO2 of the ALM-REBOA group were significantly lower than the REBOA only group. While mean arterial pressure significantly decreased from baseline, no significant differences between groups were observed throughout the field care phase. There was no significant difference in survival between the two groups (ALM-REBOA = 89% vs. REBOA only = 100%). Total blood loss was significantly decreased in the ALM-REBOA group (REBOA only = 24.32 ± 1.89 mL/kg vs. ALM-REBOA = 17.75 ± 2.04 mL/kg, p = 0.0499). CONCLUSION: Adenosine-lidocaine-magnesium is a novel therapeutic, which, when used with REBOA, can significantly decrease the amount of blood loss at initial presentation, without compromising survival. This study provides proof of concept for ALM and its ability to bridge the gap between patient presentation and REBOA placement.

Noninvasive Cerebral Perfusion and Oxygenation Monitoring Augment Prolonged Field Care in a Non-Human Primate Model of Decompensated Hemorrhage and Resuscitation.

BACKGROUND: Decompensated hemorrhagic shock (DHS) is the leading cause of preventable death in combat casualties. "Golden hour" resuscitation effects on cerebral blood flow and perfusion following DHS in prolonged field care (PFC) are not well investigated. Using an established non-human primate model of DHS, we hypothesized noninvasive regional tissue oxygenation (rSO2) and Transcranial Doppler (TCD) would correlate to the invasive measurement of partial pressure of oxygen (PtO2) and mean arterial pressure (MAP) in guiding hypotensive resuscitation in a PFC setting. METHODS: Ten rhesus macaques underwent DHS followed by a 2 h PFC phase (T0-T120), and subsequent 4 h hospital resuscitation phase (T120-T360). Invasive monitoring (PtO2, MAP) was compared against noninvasive monitoring systems (rSO2, TCD). Results were analyzed using t tests and one-way repeated measures ANOVA. Linear correlation was determined via Pearson r. Significance = P < 0.05. RESULTS: MAP, PtO2, rSO2, and mean flow velocity (MFV) significantly decreased from baseline at T0. MAP and PtO2 were restored to baseline by T15, while rSO2 was delayed through T30. At T120, MFV returned to baseline, while the Pulsatility Index significantly elevated by T120 (1.50 ±â€Š0.31). PtO2 versus rSO2 (R2 = 0.2099) and MAP versus MFV (R2 = 0.2891) shared very weak effect sizes, MAP versus rSO2 (R2 = 0.4636) displayed a low effect size, and PtO2 versus MFV displayed a moderate effect size (R2 = 0.5540). CONCLUSIONS: Though noninvasive monitoring methods assessed here did not correlate strongly enough against invasive methods to warrant a surrogate in the field, they do effectively augment and direct resuscitation, while potentially serving as a substitute in the absence of invasive capabilities.

Resuscitative endovascular balloon occlusion of the aorta for thoracic trauma in the setting of platelet dysfunction: A translational swine study.

BACKGROUND: In patients with noncompressible torso hemorrhage, antiplatelet medications may lead to worse outcomes. Resuscitative endovascular balloon occlusion of the aorta (REBOA) may potentially stabilize these patients, but currently, major thoracic bleeding is a contraindication. The goal of this study was to determine if REBOA use for shock with major thoracic bleeding has worse outcomes in the setting of platelet dysfunction (PD). METHODS: Forty-one male Yorkshire swine (60-80 kg) underwent a 30% hemorrhage and then were randomized to three thoracic injuries, with and without zone 1 REBOA occlusion: pulmonary parenchymal injury (PI), thoracic venous injury (VI), or subclavian artery injury (AI). All animals were given aspirin to produce PD. Following hemorrhage, thoracic injuries were induced (T0) and allowed to bleed freely. Resuscitative endovascular balloon occlusion of the aorta groups had zone 1 occlusion, with deflation at T30. All groups received whole blood resuscitation at T30 and were euthanized at T90. Survival, total blood loss, hemodynamics, and arterial blood gas parameters were analyzed. RESULTS: The PD-VI-REBOA group had 87.5% survival where PD-VI survival was 28.6%. No difference in survival was seen in the PI or AI groups. The PD-VI-REBOA group had total blood loss of 575.0 ± 339.1 mL, which was less than the PD-VI group (1,086.0 ± 532.1 mL). There was no difference in total thoracic blood loss in the PI and AI groups with the addition of REBOA. All groups showed an equivalent decrease in HCO3 and base excess and increase in lactate at the end of the 30-minute prehospital phase. CONCLUSION: In this study, zone 1 REBOA improved survival and decreased blood loss with major VI, where no differences were seen in parenchymal and subclavian artery injuries. For thoracic bleeding without surgical capability, outcomes may be improved with REBOA, and these findings challenge current guidelines stating the contraindication of REBOA use in this setting.

Use of bilobed partial resuscitative endovascular balloon occlusion of the aorta is logistically superior in prolonged management of a highly lethal aortic injury.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a viable technique for management of noncompressible torso hemorrhage. The major limitation of the current unilobed fully occlusive REBOA catheters is below-the-balloon ischemia-reperfusion complications. We hypothesized that partial aortic occlusion with a novel bilobed partial (p)REBOA-PRO would result in the need for less intraaortic balloon adjustments to maintain a distal goal perfusion pressure as compared with currently available unilobed ER-REBOA. METHODS: Anesthetized (40-50 kg) swine randomized to control (no intervention), ER-REBOA, or pREBOA-PRO underwent supraceliac aortic injury. The REBOA groups underwent catheter placement into zone 1 with initial balloon inflation to full occlusion for 10 minutes followed by gradual deflation to achieve and subsequently maintain half of the baseline below-the-balloon mean arterial pressure (MAP). Physiologic data and blood samples were collected at baseline and then hourly. At 4 hours, the animals were euthanized, total blood loss and urine output were recorded, and tissue samples were collected. RESULTS: Baseline physiologic data and basic laboratories were similar between groups. Compared with control, interventions similarly prolonged survival from a median of 18 minutes to over 240 minutes with comparable mortality trends. Blood loss was similar between partial ER-REBOA (41%) and pREBOA-PRO (51%). Partial pREBOA-PRO required a significantly lower number of intraaortic balloon adjustments (10 ER-REBOA vs. 3 pREBOA-PRO, p < 0.05) to maintain the target below-the-balloon MAP. The partial ER-REBOA group developed significantly increased hypercapnia, fibrin clot formation on TEG, liver inflammation, and IL-10 expression compared with pREBOA-PRO. CONCLUSION: In this highly lethal aortic injury model, use of bilobed pREBOA-PRO for a 4-hour partial aortic occlusion was logistically superior to unilobed ER-REBOA. It required less intraaortic balloon adjustments to maintain target MAP and resulted in less inflammation.

Fresh frozen plasma attenuates lung injury in a novel model of prolonged hypotensive resuscitation.

BACKGROUND: Hemorrhagic shock remains a leading cause of early death among severely injured in both civilian and military settings. As future military operations will require strategies allowing prolonged field care of the injured, we sought to develop an in vivo model of prolonged hypotensive resuscitation (PHR) and to evaluate the role of plasma-based resuscitation in this model. We hypothesized that resuscitation with fresh frozen plasma (FFP) would mitigate lung injury when compared with Hextend in a rodent model of PHR. METHODS: Mice underwent laparotomy and hemorrhagic shock (mean arterial blood pressure, 35 ± 5 mm Hg × 90 minutes) followed by PHR with either FFP or Hextend to maintain a mean arterial blood pressure of 55 mm Hg to 60 mm Hg for 6 hours. Sham animals underwent cannulation only. At the end of 6 hours, animals were euthanized, and lung tissue harvested for measurement of histopathologic injury, inflammation and permeability using hematoxylin and eosin staining, myeloperoxidase immunofluorescence staining and Evans Blue dye. Pulmonary syndecan-1 immunostaining was assessed as an indicator of endothelial cell integrity. RESULTS: All animals in the FFP, Hextend, and sham groups survived to the end of resuscitation. Resuscitation with FFP mitigated lung histopathologic injury compared with Hextend (histologic injury score of 4.38 ± 2.07 vs. 7.5 ± 0.93, scale of 0-9, p = 0.002) and was comparable to shams (histologic injury score of 4.0 ± 1.93, scale of 0-9, p = 0.99). Fresh frozen plasma also reduced lung inflammation (0.116 ± 0.044 vs. 0.308 ± 0.054 relative fluorescence of myeloperoxidase, p = 0.002) and restored pulmonary syndecan-1 (0.514 ± 0.061 vs. 0.059 ± 0.021, relative syndecan-1 fluorescence, p < 0.001) when compared with Hextend. Consistently, FFP mitigated lung hyperpermeability compared with Hextend (7.30 ± 1.34 µg vs. 14.91 ± 5.55 µg Evans blue/100 mg lung tissue, p = 0.005). CONCLUSION: We have presented a novel model of PHR of military relevance to the prolonged field care environment. In this model, FFP maintains its pulmonary protective effects using a PHR strategy compared with Hextend, which supports the need for further development and implementation of plasma-based resuscitation in the forward environment. LEVEL OF EVIDENCE: Basic science.

Resuscitative endovascular balloon occlusion of the aorta for thoracic trauma: A translational swine study.

Noncompressible torso hemorrhage in trauma is particularly lethal. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has the potential to stabilize these patients, but currently is contraindicated for major thoracic bleeding. The goal of this study was to evaluate the effect of REBOA on the hemodynamic and metabolic profile as well as its effect on early survival in a porcine model of thoracic hemorrhage and shock. METHODS: Forty-eight male Yorkshire swine (60-80 kg) underwent 30% hemorrhage and were randomized to three thoracic injuries, with and without zone 1 REBOA occlusion: pulmonary parenchymal injury, thoracic venous injury, or subclavian artery injury. Following hemorrhage, thoracic injuries were induced (time of major thoracic injury) and allowed to bleed freely. The REBOA groups had zone 1 occlusion after the thoracic injury, with deflation at the end of prehospital. All groups had whole blood resuscitation at the end of prehospital and were euthanized at end of the hospital care phase. Survival, total blood loss, mean arterial pressure, end-tidal CO2, and arterial blood gas parameters were analyzed. Statistical significance was determined by t tests and two-way repeated-measures analysis of variance. RESULTS: The use of REBOA improved the hemodynamics in all three injury patterns, with no differences observed in the outcomes of short-term survival and thoracic blood loss between the REBOA and non-REBOA groups. All groups showed equivalent changes in markers of shock (pH, HCO3, and base excess) prior to resuscitation. CONCLUSION: In this animal study of hemorrhage and major thoracic bleeding, the addition of zone 1 REBOA did not significantly affect short-term survival or blood loss, while providing hemodynamic stabilization. Therefore, in noncompressible thoracic bleeding, without immediate surgical capability, long-term outcomes may be improved with REBOA, and thoracic hemorrhage should not be considered contraindications to REBOA use.

Evaluation of prolonged 'Permissive Hypotension': results from a 6-hour hemorrhage protocol in swine.

BACKGROUND: Tactical Combat Casualty Care guidelines for hemorrhage recommend resuscitation to systolic blood pressure (SBP) of 85±5 mm Hg during prehospital care. Success depends on transport to definitive care within the 'golden hour'. As future conflicts may demand longer prehospital/transport times, we sought to determine safety of prolonged permissive hypotension (PH). METHODS: Adult male swine were randomized into three experimental groups. Non-shock (NS)/normotensive underwent anesthesia only. NS/PH was bled to SBP of 85±5 mm Hg for 6 hours of prolonged field care (PFC) with SBP maintained via crystalloid, then recovered. Experimental group underwent controlled hemorrhage to mean arterial pressure 30 mm Hg until decompensation (Decomp/PH), followed by 6 hours of PFC. Hemorrhaged animals were then resuscitated with whole blood and observed for 24 hours. Physiologic variables, blood, tissue samples, and neurologic scores were collected. RESULTS: Survival of all groups was 100%. Fluid volumes to maintain targeted SBP in PFC were significantly higher in the hemorrhage group than sham groups. After 24 hours' recovery, no significant differences were observed in neurologic scores or cerebrospinal fluid markers of brain injury. No significant changes in organ function related to treatment were observed during PFC through recovery, as assessed by serum chemistry and histological analysis. CONCLUSIONS: After 6 hours, a prolonged PH strategy showed no detrimental effect on survival or neurologic outcome despite the increased ischemic burden of hemorrhage. Significant fluid volume was required to maintain SBP-a potential logistic burden for prehospital care. Further work to define maximum allowable time of PH is needed. STUDY TYPE: Translational animal model. LEVEL OF EVIDENCE: N/A.

Prehospital whole blood resuscitation prevents coagulopathy and improves acid-base status at hospital arrival in a nonhuman primate hemorrhagic shock model.

BACKGROUND: Hemorrhage remains the primary cause of preventable death in civilian and military trauma. The Committee on Tactical Combat Casualty Care recommends prehospital (PH) resuscitation with whole blood (WB). However, 6% hetastarch in lactated electrolyte (HEX) and crystalloids are more commonly available and used for PH resuscitation in military and civilian environments, respectively. The mechanistic benefits of PH WB resuscitation have not been well studied and remain to be elucidated. STUDY DESIGN AND METHODS: The aim of this study was to evaluate the differences in simulated PH WB and HEX resuscitation, specifically with regards to coagulation, physiologic, and metabolic outcomes to better elucidate the mechanistic benefits of WB. In a randomized study, the physiologic, coagulation, and metabolic responses to simulated PH WB (n = 12) or HEX (n = 12) were evaluated in a nonhuman primate model of severe polytraumatic hemorrhagic shock. RESULTS: Notable findings included 1) equivalence of shock reversal between simulated PH WB and HEX treatment groups as determined by hemodynamics and base deficit and 2) prevention of coagulopathy at simulated hospital arrival with initial WB resuscitation as determined by viscoelastic and plasmatic coagulation assays. CONCLUSION: The major benefit of WB, as compared to HEX, in simulated PH resuscitation appears to be prevention of coagulopathy at hospital arrival. Both fluids effectively reversed shock in this model, implying that efficacious provision preload (cardiac output support and hence oxygen delivery) and coagulation proteins (prevention of coagulopathy) are mechanisms underlying WB's effectiveness in early resuscitation of hemorrhagic shock.

Prehospital adenosine, lidocaine, and magnesium has inferior survival compared with tactical combat casualty care resuscitation in a porcine model of prolonged hemorrhagic shock.

BACKGROUND: Adenosine, lidocaine, and magnesium (ALM) is a cardioplegic agent shown to improve survival by improving cardiac function, tissue perfusion, and coagulopathy in animal models of shock. We hypothesized prehospital ALM treatment in hemorrhagic shock would improve survival compared to current Tactical Combat Casualty Care (TCCC) resuscitation beyond the golden hour. METHODS: Swine were randomized to: (1) TCCC, (2) 2 mL·kg vehicle control (VC), (3) 2 mL·kg ALM + drip, (4) 4 mL·kg ALM + drip, 5) 4 mL·kg ALM + delayed drip at 0.5 mL·kg·h, 6) 4 mL/kg VC, 7) 4 mL·kg ALM for 15 minutes + delayed drip at 3 mL·kg·h. Animals underwent pressure controlled hemorrhage to mean arterial pressure (MAP) of 30 mm Hg (S = 0). Treatment was administered at T = 0. After 120 minutes of simulated prehospital care (T = 120) blood product resuscitation commenced. Physiologic variables were recorded and laboratories were drawn at specified time points. RESULTS: Tactical Combat Casualty Care demonstrated superior survival to all other agents. The VC and ALM groups had lower MAPs and systolic blood pressures compared with TCCC. Except for the VC groups, lactate levels remained similar with correction of base deficit after prehospital resuscitation in all groups. Kidney function and liver function remained comparable across all groups. Compared with baseline values, TCCC demonstrated significant hypocoagulability. CONCLUSION: Adenosine, lidocaine, and magnesium, as administered in this study, are inferior to current Hextend-based resuscitation for survival from prolonged hemorrhagic shock in this model. In survivors, ALM groups had lower systolic blood pressures and MAPs, but provided a protective effect on coagulopathy as compared to TCCC. Adenosine, lidocaine, and magnesium do not appear to be a suitable low volume replacement to current TCCC resuscitation. The reduced coagulopathy compared to TCCC warrants future studies of ALM, perhaps as a therapeutic adjunct.

Cerebral Blood Flow in Polytrauma: Transcranial Doppler Analysis in a Nonhuman Primate Shock Model.

BACKGROUND: In combat-related trauma, resuscitation goals are to attenuate tissue hypoxia and maintain circulation. During hemorrhagic shock, compensatory and autoregulatory mechanisms are activated to preserve cerebral blood flow. Transcranial Doppler (TCD) ultrasonography may be an ideal noninvasive modality to monitor cerebral hemodynamics. Using a nonhuman primate (NHP) model, we attempted to characterize cerebral hemodynamics during polytraumatic hemorrhagic shock using TCD ultrasonography. MATERIALS AND METHODS: The ophthalmic artery was insonated at multiple time points during varying stages of shock. Hemorrhage was controlled and pressure targeted to 20 mmHg to initiate and maintain the shock period. Mean flow velocity (MFV), peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), and resistance index (RI) were recorded. Results represent mean ± standard deviation; statistical significance is P < 0.05; n = 12. RESULTS: Compared to baseline, MFV, PSV, EDV, and RI show significant changes after 60 min of hemorrhagic shock, (9.81 ± 3.60 cm/s; P < 0.01), (21.15 ± 8.59 cm/s; P < 0.01), (5.15 ± 0.21 cm/s; P < 0.01), (0.70 ± 0.11; P < 0.05), respectively. PI did not change during hemorrhagic shock. At end of prehospital care (T30), cerebral flow recovers for MFV, PSV, and RI while EDV remained decreased at T30 (6.15 ± 1.13 cm/s; P < 0.01) and 1 h of simulated transport (T90) (5.87 ± 0.62 cm/s; P < 0.01). Changes in PI at T30 and T90 were not significant. MFV diminished (16.45 ± 3.85 cm/s; P < 0.05) at T90. CONCLUSIONS: This study establishes baseline and hemorrhagic shock values for NHP cerebral blood flow velocities and cerebrovascular indices. TCD ultrasonography may represent an important area of research for targeted resuscitation investigations using a hemorrhagic shock model in NHPs.