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.

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.

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.

Obstacles to an Effective Low-Titer O Walking Blood Bank: A Deployed Unit's Experience.

INTRODUCTION: We present the experience of our U.S. Navy Role 2's deployment to the U.S. Central Command area of responsibility in support of Operation Inherent Resolve and serving a multinational, joint-service military base. We detail our efforts to establish a low-titer O (LTO) walking blood bank (WBB) in an effort to prepare for potential combat casualties. MATERIALS AND METHODS: We decided on an LTO WBB based on our available resources and a review of the literature. We collected blood samples from volunteer O-type donors throughout deployment. We conducted some titers locally and sent all samples to the ASBP in San Antonio for confirmatory testing. We conducted internal training on the WBB to improve our efficiency. We conducted monthly base-wide drills and blood drives to increase our donor pool and improve coordination between the multiple units on base. RESULTS: We were able to collect samples from 108 military members during our deployment. Because of cold chain and shipping issues, by the time we departed theater, we had confirmation of 31 LTO donors from the Armed Services Blood Program. Thanks to local titers and units arriving to theater with titers complete; we were able to maintain an LTO donor pool close to our intended target of 50 available donors through most of our deployment. CONCLUSIONS: A WBB based on LTO blood is possible in theater. In order to maximize donor pools, it is imperative that units deploying to forward areas complete titer and transfusion transmissible disease testing before arrival in theater.

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.