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The use of whole blood in the prehospital setting is increasing. Currently available intraosseous and peripheral venous catheters limit the flow of blood products and fluid during resuscitation. Central venous catheters can be effectively placed in the prehospital environment. Rapid, high-volume infusion of blood products can be lifesaving., (© 2024 AABB. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Abstract: Battlefield lessons learned are forgotten; the current name for this is the Walker Dip. Blood transfusion and the need for a Department of Defense Blood Program are lessons that have cycled through being learned during wartime, forgotten, and then relearned during the next war. The military will always need a blood program to support combat and contingency operations. Also, blood supply to the battlefield has planning factors that have been consistent over a century. In 2024, it is imperative that we codify these lessons learned. The linchpins of modern combat casualty care are optimal prehospital care, early whole blood transfusion, and forward surgical care. This current opinion comprised of authors from all three military Services, the Joint Trauma System, the Armed Services Blood Program, blood SMEs and the CCC Research Program discuss two vital necessities for a successful military trauma system: (1) the need for an Armed Services Blood Program and (2) Planning factors for current and future deployed military ere is no effective care for wounded soldiers, and by extension there is no effective military medicine., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “œwork of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Damage-control resuscitation has come full circle, with the use of whole blood and balanced components. Lack of platelet availability may limit effective damage-control resuscitation. Platelets are typically stored and transfused at room temperature and have a short shelf-life, while cold-stored platelets (CSPs) have the advantage of a longer shelf-life. The US military introduced CSPs into the battlefield surgical environment in 2016. This study is a safety analysis for the use of CSPs in battlefield trauma., Methods: The Department of Defense Trauma Registry and Armed Services Blood Program databases were queried to identify casualties who received room-temperature-stored platelets (RSPs) or both RSPs and CSPs between January 1, 2016, and February 29, 2020. Characteristics of recipients of RSPs and RSPs-CSPs were compared and analyzed., Results: A total of 274 patients were identified; 131 (47.8%) received RSPs and 143 (52.2%) received RSPs-CSPs. The casualties were mostly male (97.1%), similar in age (31.7 years), with a median Injury Severity Score of 22. There was no difference in survival for recipients of RSPs (88.5%) versus RSPs-CSPs (86.7%; p = 0.645). Adverse events were similar between the two cohorts. Blood products received were higher in the RSPs-CSPs cohort compared with the RSPs cohort. The RSPs-CSPs cohort had more massive transfusion (53.5% vs. 33.5%, p = 0.001). A logistic regression model demonstrated that use of RSPs-CSPs was not associated with mortality, with an adjusted odds ratio of 0.96 (p > 0.9; 95% confidence interval, 0.41-2.25)., Conclusion: In this safety analysis of RSPs-CSPs compared with RSPs in a combat setting, survival was similar between the two groups. Given the safety and logistical feasibility, the results support continued use of CSPs in military environments and further research into how to optimize resuscitation strategies., Level of Evidence: Therapeutic/Care Management; Level IV., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting., Methods: We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation., Results: The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time., Conclusions: This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings., (© 2024. The Author(s).)

Introduction: In recent conflicts, the Joint Theater Trauma System (JTTS) led the systematic approach to improve battlefield trauma care, substantially contributing to the unprecedented survival of combat casualties. The Joint Trauma System (JTS) was codified in 2016 to preserve the lessons learned and functions of the JTTS, including the Department of Defense Trauma Registry. Concurrently, Combatant Commands (CCMD) were directed to establish CCMD Trauma Systems (CTS) "modeled after the JTTS" and to maintain a baseline of core functions intended to rapidly scale as needed. The complex nature of both CCMDs and the military trauma system has challenged the full implementation of the CTS. Analyzing the historical experiences of the JTTS, JTS, and CTS within a military doctrinal framework might enable the further success of the military trauma system., Methods: The strategic, operational, and tactical levels of warfare, in accordance with Joint Publication 1-0, Doctrine of the Armed Forces of the United States, and Joint Publication 3-0, Joint Operations, established the analytic framework for this study. The literature regarding the JTTS, CTS, and JTS was reviewed for relevant information concerning organizational structure and functions of trauma system performance improvement (PI) capabilities. A comprehensive analysis was performed using a thematic approach to evaluating descriptive data contained within the collected data set. Deployed trauma system PI tasks, functions, and responsibilities were identified, defined, and correlated according to the respective levels of warfare., Results: The comprehensive analysis revealed both discrete and overlapping tasks, functions, and responsibilities of the trauma system PI capabilities at each of the three levels of warfare. Strategic-level actions were categorized according to 12 distinct themes: reduce mortality; strategic reporting; centralized trauma registry; strategic communications; centralized organization; direct support to CCMDs; Department of Defense policy and doctrine; strategic-level PI; clinical practice guidelines; training and readiness standards; force structure, standardization, and interoperability; and research and development. Operational-level actions were categorized according to seven distinct themes: theater trauma system policies and requirements; theater trauma system leadership; stakeholder coordination; theater communication; theater standards for readiness and skill sustainment; trauma system planning; and medical logistics support. Tactical-level actions were categorized according to seven distinct themes: trauma system personnel; PI; documentation enforcement and patient care data collection; tactical planning recommendations for employing medical assets; research support; communication and reporting; and training and skills sustainment., Conclusion: The deployed U.S. military trauma system requires a robust PI capability to optimize combat casualty care. Policy updates, a joint military trauma system doctrine, and force design updates are necessary for deployed military trauma system PI capabilities to function optimally across all levels of warfare., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Tactical Combat Casualty Care (TCCC) guidelines recognize low-titer group O whole blood (LTOWB) as the resuscitative fluid of choice for combat wounded. Utilization of prescreened LTOWB in a walking blood bank (WBB) format has been well described by the Ranger O low-titer blood (ROLO) and the United States Marine Corps Valkyrie programs, but it has not been applied to the maritime setting., Methods: We describe three WBB experiences of an expeditionary resuscitative surgical system (ERSS) team, attached to three nontraditional maritime medical receiving platforms, over 6 months., Results: Significant variations were identified in the number of screened eligible donors, the number of LTOWB donors, and the timely arrival at WBB activation sites between the platforms. Overall, 95% and 84% of the screened eligible group O blood donors on the Arleigh Burke Class Destroyer (DDG) and Nimitz Class Aircraft Carrier (CVN), respectively, were determined to be LTOWB. However, only 37% of the eligible screened group O blood donors aboard the Harper's Ferry Class Dock Landing Ship (LSD) were found to be LTOWB. Of the eligible donors, 66% did not complete screening, with 52% citing a correctable reason for nonparticipation., Conclusion: LTOWB attained through WBBs may be the only practical resuscitative fluid on maritime platforms without inherent blood product storage capabilities to perform remote damage control resuscitation. Future efforts should focus on optimizing WBBs through capability development, education, and training efforts.

In rural settings worldwide, many people live in effective blood deserts without access to any blood transfusion. The traditional system of blood banking is logistically complex and expensive for many resource-restricted settings and demands innovative and multidisciplinary solutions. 17 international experts in medicine, industry, and policy participated in an exploratory process with a 2-day hybrid seminar centred on three promising innovative strategies for blood transfusions in blood deserts: civilian walking blood banks, intraoperative autotransfusion, and drone-based blood delivery. Participant working groups conducted literature reviews and interviews to develop three white papers focused on the current state and knowledge gaps of each innovation. Seminar discussion focused on defining blood deserts and developing innovation-specific implementation agendas with key research and policy priorities for future work. Moving forward, advocates should prioritise the identification of blood deserts and address the context-specific challenges for these innovations to alleviate the ongoing crisis in blood deserts., Competing Interests: Declaration of interests We note that YEA works from the WHO Regional Office for the Eastern Mediterranean, and his views expressed in this Viewpoint are personal. We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Pre-hospital potentially preventable trauma related deaths are mainly due to hypoperfusion-induced tissue hypoxia leading to irreversible organ dysfunction at or near the point of injury or during transportation prior to receiving definitive therapy. The prolyl hydroxylase domain (PHD) is an oxygen sensor that regulates tissue adaptation to hypoxia by stabilizing hypoxia inducible factor (HIF). The benefit of PHD inhibitors (PHDi) in the treatment of anemia and lactatemia arises from HIF stabilization, which stimulates endogenous production of erythropoietin and activates lactate recycling through gluconeogenesis. The results of this study provide insight into the therapeutic roles of MK-8617, a pan-inhibitor of PHD-1, 2, and 3, in the mitigation of lactatemia in anesthetized rats with polytrauma and hemorrhagic shock. Additionally, in an anesthetized rat model of lethal decompensated hemorrhagic shock, acute administration of MK-8617 significantly improves one-hour survival and maintains survival at least until 4 h following limited resuscitation with whole blood (20% EBV) at one hour after hemorrhage. This study suggests that pharmaceutical interventions to inhibit prolyl hydroxylase activity can be used as a potential pre-hospital countermeasure for trauma and hemorrhage at or near the point of injury., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rationale: Early post injury mitigation strategies in ARDS are in short supply. Treatments with allogeneic stromal cells are administered after ARDS develops, require specialized expertise and equipment, and to date have shown limited benefit. Objectives: Assess the efficacy of immediate post injury intravenous administration of autologous or allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of acute respiratory distress syndrome (ARDS) due to smoke inhalation and burns. Methods: Yorkshire swine ( n  = 32, 44.3 ± 0.5 kg) underwent intravenous anesthesia, placement of lines, severe smoke inhalation, and 40% total body surface area flame burns, followed by 72 hours of around-the-clock ICU care. Mechanical ventilation, fluids, pressors, bronchoscopic cast removal, daily lung computed tomography scans, and arterial blood assays were performed. After injury and 24 and 48 hours later, animals were randomized to receive autologous concentrated bone marrow aspirate ( n  = 10; 3 × 10 6 white blood cells and a mean of 56.6 × 10 6 platelets per dose), allogeneic MSCs ( n  = 10; 6.1 × 10 6 MSCs per dose) harvested from healthy donor swine, or no treatment in injured control animals ( n  = 12). Measurements and Main Results: The intravenous administration of MSCs after injury and at 24 and 48 hours delayed the onset of ARDS in swine treated with autologous MSCs (48 ± 10 h) versus control animals (14 ± 2 h) ( P  = 0.004), reduced ARDS severity at 24 ( P  < 0.001) and 48 ( P  = 0.003) hours, and demonstrated visibly diminished consolidation on computed tomography (not significant). Mortality at 72 hours was 1 in 10 (10%) in the autologous group, 5 in 10 (50%) in the allogeneic group, and 6 in 12 (50%) in injured control animals (not significant). Both autologous and allogeneic MSCs suppressed systemic concentrations of TNF-α (tumor necrosis factor-α). Conclusions: The intravenous administration of three doses of freshly processed autologous bone marrow-derived MSCs delays ARDS development and reduces its severity in swine. Bedside retrieval and administration of autologous MSCs in swine is feasible and may be a viable injury mitigation strategy for ARDS.

Platelet transfusions are essential for managing bleeding and hemostatic dysfunction and could be expanded as a cell therapy due to the multifunctional role of platelets in various diseases. Creating these cell therapies will require modifying transfusable donor platelets to express therapeutic proteins. However, there are currently no appropriate methods for genetically modifying platelets collected from blood donors. Here, we describe an approach using platelet-optimized lipid nanoparticles containing mRNA (mRNA-LNP) to enable exogenous protein expression in human and rat platelets. Within the library of mRNA-LNP tested, exogenous protein expression did not require nor correlate with platelet activation. Transfected platelets retained hemostatic function and accumulated in regions of vascular damage after transfusion into rats with hemorrhagic shock. We expect this technology will expand the therapeutic potential of platelets.

Extracorporeal membrane oxygenation (ECMO) supplies circulatory support and gas exchange to critically ill patients. Despite the use of systemic anticoagulation, blood exposure to ECMO surfaces causes thromboembolism complications. Inhibition of biomaterial surface-mediated activation of coagulation factor XI (FXI) may prevent device-associated thrombosis. Blood was collected from healthy volunteers (n = 13) following the U.S. Army Institute of Surgical Research standard operating procedure for testing in an ex vivo ECMO circuit. A roller-pump circuit circulated either 0.5 U/ml of unfractionated heparin alone or in combination with the anti-FXI immunoglobulin G (IgG) (AB023) for 6 hours or until clot formation caused device failure. Coagulation factor activity, platelet counts, time to thrombin generation, peak thrombin, and endogenous thrombin potential were quantified. AB023 in addition to heparin sustained circuit patency in all tested circuits (5/5) after 6 hours, while 60% of circuits treated with heparin alone occluded (3/8), log-rank p < 0.03. AB023 significantly prolonged the time to clot formation as compared to heparin alone (15.5 vs . 3.3 minutes; p < 0.01) at the 3-hour time point. AB023 plus heparin significantly reduced peak thrombin compared to heparin alone (123 vs . 217 nM; p < 0.01). Inhibition of contact pathway activation of FXI may be an effective adjunct to anticoagulation in extracorporeal life support., Competing Interests: E.I.T. has financial interest in Aronora Inc., a company that may have a commercial interest in the results of this research. J.J.S. has received consulting fees from Aronora Inc. All of the remaining authors report no conflicts of interest.

Blood platelets are crucial to prevent excessive bleeding following injury to blood vessels. Platelets are crucial for the formation of clots and for clot strength. Platelet activation involves aggregation, attachment to fibrin and clot retraction. Most assays that address platelet function measure platelet aggregation, not clot retraction. Here, we describe a 96-well-based clot retraction assay that requires a relatively short runtime and small sample volume. The assay involves continuous optical density monitoring of platelet-rich plasma that is activated with thrombin. The data can be analyzed using time-series analytical tools to generate quantitative information about different phases of clot formation and clot retraction. The assay demonstrated good repeatability and reproducibility and was robust to different calcium concentrations. Impairment of platelet bioenergetics, actin polymerization, fibrin interaction, and signaling significantly affected clot retraction and was detected and showed good agreement with light transmission aggregometry, suggesting that clot retraction is predictive of platelet function. Using this microplate clot retraction assay, we showed a significant difference in platelets stored in autologous plasma compared with platelet additive solution after 7 days of room temperature storage.

Background: The beneficial effects of estrogens on survival from hemorrhage have been suggested in some preclinical models. This study investigated the effects of ethynylestradiol-3-sulfate (EE-3-S) on coagulation, metabolism and survival in pigs following traumatic hemorrhage., Methods: Twenty-six pigs were randomized into: normal saline group (NS, n = 10), EE-3-S group (EE-3, n = 11) groups, and no resuscitation group (NR, n = 5). Femur fracture was performed in each pig's left leg, followed by hemorrhage of 55% of estimated blood volume and a 10-minute shock period. Afterward, pigs were resuscitated with a small volume of either NS alone (4 mL/kg) or EE-3-S with NS (1 mL/kg at concentration of 1 mg/mL, plus NS solution of 3 mL/kg). Pigs in NR group were not resuscitated with any fluid. All pigs were then monitored for 6 hours or until death, with hemodynamics and survival times recorded. Blood samples were taken during the study for measurements of oxygen metabolism (oxygen delivery, extraction, and consumption) and coagulation function (using Rotem with Extem reagents)., Results: All baseline measurements were similar among the three groups. In the NS group, femur fracture and hemorrhage immediately reduced mean arterial pressure (MAP, 74 ± 3 mm Hg to 44 ± 4 mm Hg) and increased heart rate (97 ± 5 bpm to 218 ± 14 bpm, both p < 0.05). Similar changes in MAP and heart rate were observed in the EE-3 and NR groups. There were no differences observed in changes of Rotem ® measurements or oxygen metabolism among the groups during the study. At 6 hours, four pigs in NS, four pigs in EE-3-S, and two pigs in the NR group survived to the end of the study. The mean survival times were similar among the NS (212 ± 43 minutes), EE-3 (212 ± 39 minutes), and NR (223 ± 63 minutes) groups ( p = 0.9845)., Conclusion: Following severe traumatic hemorrhage, hypotensive resuscitation with EE-3-S did not impact coagulation, metabolism, or survival in pigs., (Copyright © 2023 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Introduction: Trauma patients are susceptible to coagulopathy and dysfunctional immune responses. Mesenchymal stromal cells (MSCs) are at the forefront of the cellular therapy revolution with profound immunomodulatory, regenerative, and therapeutic potential. Routine assays to assess immunomodulation activity examine MSC effects on proliferation of peripheral blood mononuclear cells (PBMCs) and take 3-7 days. Assays that could be done in a shorter period of time would be beneficial to allow more rapid comparison of different MSC donors. The studies presented here focused on assays for MSC suppression of mitogen-stimulated PBMC activation in time frames of 24 h or less., Methods: Three potential assays were examined-assays of apoptosis focusing on caspase activation, assays of phosphatidyl serine externalization (PS+) on PBMCs, and measurement of tumor necrosis factor alpha (TNFα) levels using rapid ELISA methods. All assays used the same initial experimental conditions: cryopreserved PBMCs from 8 to 10 pooled donors, co-culture with and without MSCs in 96-well plates, and PBMC stimulation with mitogen for 2-72 h., Results: Suppression of caspase activity in activated PBMCs by incubation with MSCs was not robust and was only significant at times after 24 h. Monitoring PS+ of live CD3+ or live CD4+/CD3+ mitogen-activated PBMCs was dose dependent, reproducible, robust, and evident at the earliest time point taken, 2 h, although no increase in the percentage of PS+ cells was seen with time. The ability of MSC in co-culture to suppress PBMC PS+ externalization compared favorably to two concomitant assays for MSC co-culture suppression of PBMC proliferation, at 72 h by ATP assay, or at 96 h by fluorescently labeled protein signal dilution. TNFα release by mitogen-activated PBMCs was dose dependent, reproducible, robust, and evident at the earliest time point taken, with accumulating signal over time. However, suppression levels with MSC co-culture was reliably seen only after 24 h., Discussion: Takeaways from these studies are as follows: (1) while early measures of PBMC activation is evident at 2-6 h, immunosuppression was only reliably detected at 24 h; (2) PS externalization at 24 h is a surrogate assay for MSC immunomodulation; and (3) rapid ELISA assay detection of TNFα release by PBMCs is a robust and sensitive assay for MSC immunomodulation at 24 h., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Herzig, Christy, Montgomery, Cantu-Garza, Barrera, Lee, Mucha, Talackine, Abaasah, Bynum and Cap.)

Abstract: Background: Hemorrhage remains the leading cause of death on the battlefield. This study aims to assess the ability of an artificial intelligence triage algorithm to automatically analyze vital-sign data and stratify hemorrhage risk in trauma patients. Methods: Here, we developed the APPRAISE-Hemorrhage Risk Index (HRI) algorithm, which uses three routinely measured vital signs (heart rate and diastolic and systolic blood pressures) to identify trauma patients at greatest risk of hemorrhage. The algorithm preprocesses the vital signs to discard unreliable data, analyzes reliable data using an artificial intelligence-based linear regression model, and stratifies hemorrhage risk into low (HRI:I), average (HRI:II), and high (HRI:III). Results: To train and test the algorithm, we used 540 h of continuous vital-sign data collected from 1,659 trauma patients in prehospital and hospital (i.e., emergency department) settings. We defined hemorrhage cases (n = 198) as those patients who received ≥1 unit of packed red blood cells within 24 h of hospital admission and had documented hemorrhagic injuries. The APPRAISE-HRI stratification yielded a hemorrhage likelihood ratio (95% confidence interval) of 0.28 (0.13-0.43) for HRI:I, 1.00 (0.85-1.15) for HRI:II, and 5.75 (3.57-7.93) for HRI:III, suggesting that patients categorized in the low-risk (high-risk) category were at least 3-fold less (more) likely to have hemorrhage than those in the average trauma population. We obtained similar results in a cross-validation analysis. Conclusions: The APPRAISE-HRI algorithm provides a new capability to evaluate routine vital signs and alert medics to specific casualties who have the highest risk of hemorrhage, to optimize decision-making for triage, treatment, and evacuation., Competing Interests: ATR has received research funding from the Nihon Kohden Corporation (Irvine, CA) to develop decision-support technology for sepsis patient management. The other authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Background: Mesenchymal stromal cells (MSCs) and other therapeutic cells show efficacy for cardiac damage, neurological disease, chronic lung disease, pediatric graft versus host disease, and several inflammatory conditions. Based on their anti-inflammatory and immune-modulatory activities, responsiveness, and secretion of beneficial factors, cellular therapeutics may provide benefits in acute and chronic traumatic injury. However, the use of live cells presents logistical challenges, especially for military trauma. MSCs are generally shipped and stored frozen but require sterile handling before infusion. This requires skilled personnel and equipment not readily available in a forward medical treatment facility or even a small community hospital., Methods: Commercial human bone marrow- and adipose-derived MSCs from multiple donors were cultured under standard conditions, harvested and stored at 4°C in solution for up to 21 days. Cell viability, ATP content, apoptosis, proliferation capability, immunomodulation activity, and responsiveness were assessed after different amounts of time., Results: Human MSCs can be stored at 4°C in MSC culture medium for 14 days while maintaining a reasonable level of viability and function. Both viability and function are reduced when MSCs are stored in crystalloid solutions., Conclusions: This approach makes it feasible to prepare cellular therapeutic agents in a laboratory or commercial facility and ship them under refrigerated conditions. Once they reach their destination, they can be stored at 4°C under conditions similar to blood products. Cells prepared and stored this way could also be used directly with minimal handling, making them more practical for both civilian and military trauma., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: The use of low-titer group O whole blood is increasing. To reduce wastage, unused units can be converted to packed red blood cells. Supernatant is currently discarded post-conversion; however, it could be a valuable transfusable product. The aim of this study was to evaluate supernatant prepared from late-storage low-titer group O whole blood being converted to red blood cells, hypothesizing it will have higher hemostatic activity compared to fresh never-frozen liquid plasma., Methods: Low-titer group O whole blood supernatant (n = 12) prepared on storage day 15 was tested on days 15, 21, and 26 and liquid plasma (n = 12) on 3, 15, 21, and 26. Same-day assays included cell counts, rotational thromboelastometry, and thrombin generation. Centrifuged plasma from units was banked for microparticle characterization, conventional coagulation, clot structure, hemoglobin, and additional thrombin generation assays., Results: Low-titer group O whole blood supernatant contained more residual platelets and microparticles compared to liquid plasma. At day 15, low-titer group O whole blood supernatant elicited a faster intrinsic clotting time compared to liquid plasma (257 ± 41 vs. 299 ± 36 s, P = 0.044), and increased clot firmness (49 ± 9 vs. 28 ± 5 mm, P < 0.0001). Low-titer group O whole blood supernatant showed more significant thrombin generation compared to liquid plasma (day 15 endogenous thrombin potential 1,071 ± 315 vs. 285 ± 221 nM·min, P < 0.0001). Flow cytometry demonstrated low-titer group O whole blood supernatant contained significantly more phosphatidylserine and CD41+ microparticles. However, thrombin generation in isolated plasma suggested residual platelets in low-titer group O whole blood supernatant were a greater contributor than microparticles. Additionally, low-titer group O whole blood supernatant and liquid plasma showed no difference in clot structure, despite higher CD61+ microparticle presence., Conclusions: Plasma supernatant produced from late-storage low-titer group O whole blood shows comparable, if not enhanced, in vitro hemostatic efficacy to liquid plasma., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Resuscitation with blood products improves survival after major hemorrhage. Blood product administration at or near the point-of-injury (POI) amplifies this benefit. Size, weight, and cold-chain management challenges all limit the amount of blood medics can carry. Warm fresh whole blood (WFWB) transfusions from a pre-screened donor within the unit represent an alternative source of blood at the POI. We measured the time required for civilian and Army technicians performing phlebotomy frequently to obtain one unit of blood to serve as a goal metric for combat medics being trained in this skill., Methods: We gathered demographic and experience data along with proportion of first intravenous cannulation attempt success, time to blood flow initiated, and time to unit draw complete., Results: We prospectively enrolled 12 civilian phlebotomy technicians and 10 Army laboratory technicians performing whole blood collections on 50 and 68 donors respectively. The mean time from setup to needle insertion was 3.7 min for civilians versus 4.2 min for Army technicians. The mean time from blood flowing to the bag being full was 10.7 min versus 8.4 min for civilians versus Army technicians respectively. The mean bag weights were 514 g versus 522 g. First-pass intravenous cannulation success was 96% versus 98% respectively., Conclusions: We found a high first intravenous cannulation attempt success among both the civilian and Army technicians. Medians times were <5 min to obtain venipuncture and <11 min to obtain one unit. These findings provide time-based benchmarks for potential use during transfusion training among military medics., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Platelets stored at room temperature (22-24°C) for transfusion purposes have a shelf life of 5-7 days, or 72 h when stored refrigerated (1-6°C). The limited shelf life of platelet products severely compromises platelet inventory. We hypothesized that cold storage of platelets in 100% plasma using xenon gas under high pressure would extend shelf life to 14 days., Study Design and Methods: Double apheresis platelet units were collected and split equally between two bags. One unit was placed in a hyperbaric chamber, pressurized to 4 bars with a xenon/oxygen gas mixture, and placed in a refrigerator for 14 days (Xe). The remaining unit was aliquoted into mini-bags (10 ml) for storage at room temperature (RTP) or in cold (CSP). Samples were assayed on days 5 (RTP) or 14 (Xe and CSP) for count, metabolism, clot strength, platelet aggregation, and activation markers., Results: The platelet count in Xe samples was lower than that of RTP but significantly higher than CSP. Despite similar levels of glucose and lactate, the pH of Xe samples was significantly lower than CSP. Glycoprotein expression was better preserved by Xe storage compared to CSP, but no differences in activation were observed. Thromboelastography and aggregometry results were comparable between all groups., Discussion: Cold storage of platelets in plasma with hyperbaric xenon provides no significant improvement in platelet function over cold storage alone. The use of a hyperbaric chamber and the slow off-gassing of Xe-stored units complicate platelet storage and delivery logistics., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Platelet concentrates (PLT) can be manufactured using a combination of apheresis collection devices and suspension media (plasma or platelet additive solution (PAS)). It is unclear how platelet quality and hemostatic function differ across the current in-use manufacturing methods in the United States. The objective of this study was therefore to compare baseline function of PLT collected using different apheresis collection platforms and storage media., Study Design and Methods: PLT were collected at two sites with identical protocols (N = 5 per site, N = 10 total per group) on the MCS® + 9000 (Haemonetics; "MCS"), the Trima Accel® 7 (Terumo; "Trima"), and the Amicus Cell Separator (Fresenius Kabi, "Amicus"). MCS PLT were collected into plasma while Trima and Amicus PLT were collected into plasma or PAS (Trima into Isoplate and Amicus into InterSol; yielding groups "TP", "TI" and "AP", "AI", respectively). PLT units were sampled 1 h after collection and assayed to compare cellular counts, biochemistry, and hemostatic function., Results: Differences in biochemistry were most evident between plasma and PAS groups, as anticipated. MCS and TP had the highest clot strength as assessed by viscoelastometry. AI had the lowest thrombin generation capacity. Both TP and TI had the highest responses on platelet aggregometry. AI had the greatest number of microparticles., Discussion: Platelet quality and function differ among collection platforms at baseline. MCS and Trima platelets overall appear to trend toward higher hemostatic function. Future investigations will assess how these differences change throughout storage, and if these in vitro measures are clinically relevant., (© 2023 AABB.)

Background: The U.S. Department of Defense (DoD) collects blood from volunteer DoD donors in U.S. Food and Drug Administration (FDA)-regulated centers, and from emergency donor panels in overseas operations. Emerging infectious diseases could reduce DoD access to blood products. In August 2016, FDA determined that Zika virus was transfusion-transmitted and advised that donated blood should be screened for Zika utilizing one of two investigational new drug (IND) applications. The Armed Services Blood Program (ASBP) tested blood using its own protocol concurrently with the IND study sponsored by Roche Molecular Systems, Inc., titled "A Prospective Study to Evaluate the Specificity of the cobas Zika test for use on the cobas 6800/8800 System for Screening of Blood Donations for the Presence of Zika virus RNA.", Study Design and Methods: This prospective clinical trial (September 2016-August 2017) evaluated the specificity of the cobas Zika 6800/8800 System. Consenting volunteers were screened for Zika by participating reference labs. Participants with positive screens were offered a follow-up study using alternative PCR and serology assays., Results: 92,618 DoD donors enrolled; four tested positive on screening (0.0043%; CI 0.001176896%, 0.01105894%). Three enrolled in follow-up testing and none were positive. These results were comparable to all U.S. donors: 3,858,114 enrolled (excluding Puerto Rico) with 459 positive screens (0.0119%; CI 0.01083582%, 0.01303962%)., Conclusion: The study demonstrated the effectiveness of the cobas Zika test. DoD donors, who are included in emergency donor panels during military operations, were at no higher risk for Zika than the overall U.S. donor population., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Data demonstrate the benefit of blood product administration near point-of-injury (POI). Fresh whole blood transfusion from a pre-screened donor provides a source of blood at the POI when resources are constrained. We captured transfusion skills data for medics performing autologous blood transfusion training., Methods: We conducted a prospective, observational study of medics with varying levels of experience. Inexperienced medics were those with minimal or no reported experience learning the autologous transfusion procedures, versus reported experience among special operations medics. When available, medics were debriefed after the procedure for qualitative feedback. We followed them for up to 7 days for adverse events., Results: The median number of attempts for inexperienced and experienced medics was 1 versus 1 (interquartile range 1-1 for both, p = .260). The inexperienced medics had a slower median time to needle venipuncture access for the donation of 7.3 versus 1.5 min, needle removal after clamping time of 0.3 versus 0.2 min, time to bag preparation of 1.9 versus 1.0 min, time to IV access for reinfusion of 6.0 versus 3.0 min, time to transfusion completion of 17.3 versus 11.0 min, and time to IV removal of 0.9 versus 0.3 min (all p < .05). We noted one administrative safety event in which an allogeneic transfusion occurred. No major adverse events occurred. Qualitative data saturated around the need for quarterly training., Conclusions: Inexperienced medics have longer procedure times when training autologous whole blood transfusion skills. This data will help establish training measures of performance for skills optimization when learning this procedure., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Platelets (PLTs) stored at 4°C exhibit equivalent or superior hemostatic function compared with 22°C PLTs, but have shorter circulation times and a decreased ability to modulate vascular permeability. These differences may be due to morphological changes and storage-induced activation. Using a proteomics-based approach, we found that 4°C-stored PLTs express decreased α-tubulin, a key PLT structural protein. PLT activation is characterized by α-tubulin deacetylation, which is regulated by histone deacetylase-6 (HDAC-6). We hypothesized that inhibition of HDAC-6 in stored PLTs will improve their ability to regulate vascular permeability through reduced activation and α-tubulin deacetylation. In an in vivo model of vascular permeability, treatment of 4°C PLTs with the HDAC-6 inhibitor tubacin enhanced the vasculoprotective properties of untreated 4°C PLTs. 4°C PLT circulation, however, was unchanged by tubacin treatment, suggesting that circulation time may not be a critical factor in determining the vasculoprotective effects of PLTs. Assessing the factor content of stored PLTs revealed that angiopoietin-1 (Ang-1) increased in 4°C PLTs over time, which was further enhanced by tubacin treatment. In addition, angiopoietin-2, an inducer of vascular leak and antagonist of Ang-1, inhibited PLT barrier protection, suggesting involvement of the Tie-2 pathway. This study demonstrates that HDAC-6 inhibition with tubacin attenuates the diminished vasculo-protective properties of 4°C PLTs, and these properties may be independent of PLT circulation time., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Special Operations Forces (SOF) medical personnel have been at the forefront of administering blood products in the austere field medicine environment. These far-forward medical providers regularly treat patients and deliver blood transfusions in some of the world's most extreme environments with minimal resources. A multitude of questions have been raised on this topic based on the unique experiences of senior providers in this field. In this paper, we analyze the available literature and present the recommendations of several experts in transfusion medicine for managing atypical field transfusion scenarios., (2023.)

Major trauma frequently occurs in the deployed, combat setting and is especially applicable in the recent conflicts with explosives dominating the combat wounded. In future near-peer conflicts, we will likely face even more profound weapons including mortars and artillery. As such, the number of severely wounded will likely increase. Hypocalcemia frequently occurs after blood transfusions, secondary to the preservatives in the blood products; however, recent data suggests major trauma in and of itself is a risk factor for hypocalcemia. Calcium is a major ion involved in heart contractility; thus, hypocalcemia can lead to poor contractility. Smaller studies have linked hypocalcemia to worse outcomes, but it remains unclear what causes hypocalcemia and if intervening could potentially save lives. The objective of this study is to determine the incidence of hypocalcemia on hospital arrival and the association with survival. We are seeking to address the following scientific questions, (1) Is hypocalcemia present following traumatic injury prior to transfusion during resuscitation? (2) Does hypocalcemia influence the amount of blood products transfused? (3) To what extent is hypocalcemia further exacerbated by transfusion? (4) What is the relationship between hypocalcemia following traumatic injury and mortality? We will conduct a multicenter, prospective, observational study. We will gather ionized calcium levels at 0, 3, 6, 12, 18, and 24 hours as part of scheduled calcium measurements. This will ensure we have accurate data to assess the early and late effects of hypocalcemia throughout the course of resuscitation and hemorrhage control. These data will be captured by a trained study team at every site. Our findings will inform clinical practice guidelines and optimize the care delivered in the combat and civilian trauma setting. We are seeking 391 patients with complete data to meet our a priori inclusion criteria. Our study will have major immediate short-term findings including risk prediction modeling to assess who is at risk for hypocalcemia, data assessing interventions associated with the incidence of hypocalcemia, and outcome data including mortality and its link to early hypocalcemia.

Background: The MARCH (Massive hemorrhage, Airway, Respirations, Circulation, and Hypothermia/Head injuries) algorithm taught to military medics includes interventions to prevent hypothermia. As possible sequelae from major trauma, hypothermia is associated with coagulopathy and lower survival. This paper sought to define hypothermia within our combat trauma population using an outcomes-based method, and determine clinical variables associated with hypothermia., Methods: This is a secondary analysis of a previously described dataset from the Department of Defense Trauma Registry focused on casualties who received prehospital care. A receiver operating curve was constructed and Youden's index was used to define hypothermia within the predetermined population based on mortality risk. A multivariable regression model was used to identify associations., Results: There were 23,243 encounters that met the inclusion criteria for this study with patients having received prehospital care and documentation of at least one emergency department temperature. An optimal threshold of 36.2° C was found to predict mortality; 3,159 casualties had temperatures below this threshold (14%). Survival to discharge was lower among casualties with hypothermia (91% versus 98%). Hypothermic casualties were less likely to undergo blanket application (38% versus 40%). However, they had higher proportions with Hypothermia Prevention and Management Kit application (11% versus 7%) and radiant warming (2% versus 1%). On multivariable regression modeling, none of the hypothermia interventions were associated with a decreased likelihood of hypothermia. Non-hypothermia interventions associated with hypothermia included prehospital intubation (OR 1.57, 95% CI 1.45-1.69) and blood product administration., Conclusions: Hypothermia, including a single recorded low temperature in the patient care record, was associated with worse outcomes in this combat trauma population. Prehospital intubation was most strongly associated with developing hypothermia. Prehospital warming interventions were not associated with a reduction in hypothermia risk. Our dataset suggests that current methods for prehospital warming are inadequate.

A perfluorocarbon (PFC) investigated for treatment of traumatic brain injury (TBI) delivers oxygen to support brain function, but causes transient thrombocytopenia. TBI can cause acute inflammation with resulting thrombocytopenia; an interaction between the PFC effects and TBI inflammation might exacerbate thrombocytopenia. Therefore, PFC effects on platelet (PLT) function and hemostasis in a lipopolysaccharide (LPS) model of inflammation in the baboon were studied. Animals were randomized to receive saline ±LPS, and ± one of two doses of PFC. PLT count, transmission electron microscopy, and microparticle populations were quantified at baseline (BL) and at 2, 24, 48, 72, and 96 hours; hemostatic parameters for aggregometry and for blood clotting were measured at baseline (BL) and days 3 and 4. Injection of vehicle and LPS caused thrombocytopenia within hours; PFCs caused delayed thrombocytopenia beginning 48 hours post-infusion. LPS+PFC produced a more prolonged PLT decline and decreased clot strength. LPS+PFC increased ADP-stimulated aggregation, but PFC alone did not. Microparticle abundance was greatest in the LPS+PFC groups. LPS+PFC caused diffuse microvascular hemorrhage and death in 2 of 5 baboons in the low dose LPS-PFC group and 2 of 2 in the high dose LPS-PFC group. Necropsy and histology suggested death was caused by shock associated with hemorrhage in multiple organs. Abnormal morphology of platelets and red blood cells were notable for PFC inclusions. In summary, PFC infusion caused clinically significant thrombocytopenia and exacerbated LPS-induced platelet activation. The interaction between these effects resulted in decreased hemostatic capacity, diffuse bleeding, shock and death., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS&gt;24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS&lt;16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb &gt;1.57 μg/ml, syndecan-1 &gt;66.6 ng/ml or D-dimer &gt;6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb&gt;1.57 µg/ml/Syndecan-1&gt;66.6 ng/ml/D-dimer&gt;6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Le, Simovic, Liu, Fraker, Cancio, Cap, Wade, DalleLucca and Li.)

Objectives: Early complementopathy and coagulopathy are shown often after trauma. However, the prevalence of any interplay between complement cascade (ComC) and coagulation cascade (CoaC) after trauma remains unclear. This study intended to explore whether complement-coagulation crosstalk exists, which may provide a reliable guide to clinical implications in trauma patients., Methods: This single-center cohort study of trauma patients enrolled 100 patients along with 20 healthy volunteers. Blood samples from patients were collected at admission, 45, 90, 135 minutes, and 18 hours after admission. Demographic characteristics were recorded, blood levels of ComC and CoaC factors, and inflammatory cytokines were measured by ELISA, clot-based assays, or luminex multiplex assay, and partial thromboplastin (PT) and partial thromboplastin time (PTT) were assessed using a Behring blood coagulation system., Results: Compared with the healthy controls, plasma levels of complement factors (C5b-9 and Bb) and 11 tested inflammatory cytokines increased in moderately and severely injured patients as early as 45 minutes after admission and sustained higher levels up to 18 hours after admission. C5b-9 correlated positively to patients' hospital stay. In parallel, the consumption of coagulation factors I, II, X, and XIII was shown throughout the first 18 hours after admission in moderately and severely injured patients, whereas PT, PTT, D-dimer, factor VII, and factor VIII values significantly increased from the admission to 135 minutes in moderately and severely injured patients. Along with an inverse correlation between plasma Bb, factors I and II, a positive correlation between C5b-9, Bb, D-dimer, PT, and PTT was evident., Conclusions: This study demonstrates trauma-induced early activation of plasma cascades including ComC, CoaC, and fibrinolytic cascade, and their correlation between plasma cascades in severe trauma patients. Our study suggests that the simultaneous modulation of plasma cascades might benefit clinical outcomes for trauma patients., Level of Evidence: Prospective study, level III., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Mass casualty incidents (MCIs) create an immediate surge in blood product demand. We hypothesize local inventories in major U.S. cities would not meet this demand., Study Design and Methods: A simulated blast in a large crowd estimated casualty numbers. Ideal resuscitation was defined as equal amounts of red blood cells (RBCs), plasma, platelets, and cryoprecipitate. Inventory was prospectively collected from six major U.S. cities at six time points between January and July 2019. City-wide blood inventories were classified as READY (>1 U/injured survivor), DEFICIENT (<10 U/severely injured survivor), or RISK (between READY and DEFICIENT), before and after resupply from local distribution centers (DC), and features of DEFICIENT cities were identified., Results: The simulated blast resulted in 2218 injured survivors including 95 with severe injuries. Balanced resuscitation would require between 950 and 2218 units each RBC, plasma, platelets and cryoprecipitate. Inventories in 88 hospitals/health systems and 10 DCs were assessed. Of 36 city-wide surveys, RISK inventories included RBCs (n = 16; 44%), plasma (n = 24; 67%), platelets (n = 6; 17%), and cryoprecipitate (n = 22; 61%) while DEFICIENT inventories included platelets (n = 30; 83%) and cryoprecipitate (n = 12; 33%). Resupply shifted most RBC and plasma inventories to READY, but some platelet and cryoprecipitate inventories remained at RISK (n = 24; 67% and n = 12; 33%, respectively) or even DEFICIENT (n = 11; 31% and n = 6; 17%, respectively). Cities with DEFICIENT inventories were smaller (p <.001) with fewer blood products per trauma bed (p <.001)., Discussion: In this simulated blast event, blood product demand exceeded local supply in some major U.S. cities. Options for closing this gap should be explored to optimize resuscitation during MCIs., (© 2022 AABB.)

Background: The United States Armed Services Blood Program (ASBP) faced complex blood supply challenges during two decades of military operations in the U.S. Central Command (CENTCOM) and through an adaptive, responsive, and agile system, gained valuable insights on blood product usage in combat casualty care., Study Design and Methods: A retrospective review of blood product introduction and utilization trends was compiled from ASBP data collected during CENTCOM operations from 2014 through 2021., Results: During the study period, several blood products were introduced to the CENTCOM area of operations including Low Titer O Whole Blood (LTOWB), Cold-Stored Platelets (CSP), Liquid Plasma (LP), and French Freeze Dried Plasma (FDP) manufactured from U.S. sourced donor plasma, all while expanding Walking Blood Bank capabilities. There was a gradual substitution of component therapy for whole blood; blood utilization peaked in 2017. Transfusion of Fresh Whole Blood (FWB) from Walking Blood Banks decreased as fully pre-tested LTOWB was supplied by the ASBP. LTOWB was initially supplied in citrate-phosphate-dextrose (CPD) anticoagulant (21-day shelf life) but was largely replaced with LTOWB in citrate-phosphate-dextrose-adenine (CPDA-1) anticoagulant (35-day shelf life) by 2019. Implementation of prehospital transfusion and expansion of surgical and resuscitation teams led to an increase in the number of sites receiving blood., Discussion: ASBP introduced new products to its inventory in order to meet changing blood product demands driven by changes in the Joint Trauma System Clinical Practice Guidelines and operational demands. These products were adopted into clinical practice with a resultant evolution in transfusion strategies., (© 2022 AABB.)

Low titer type O Rh-D + whole blood (LTO + WB) has become a first-line resuscitation medium for hemorrhagic shock in many centers around the World. Showing early effectiveness on the battlefield, LTO + WB is used in both the pre-hospital and in-hospital settings for traumatic and non-traumatic hemorrhage resuscitation. Starting in 2018, the San Antonio Whole Blood Collaborative has worked to provide LTO + WB across Southwest Texas, initially in the form of remote damage control resuscitation followed by in-hospital trauma resuscitation. This program has since expanded to include pediatric trauma resuscitation, obstetric hemorrhage, females of childbearing potential, and non-traumatic hemorrhage. The objective of this manuscript is to provide a three-year update on the successes and expansion of this system and outline resuscitation challenges in special populations., (© 2022 AABB.)

Background: Valproic acid (VPA) has been extensively used for treatment of anxiety and seizure. Recent studies have shown that VPA has cellular protective effects in preclinical models following severe hemorrhage. This study investigated the effects of VPA on coagulation and survival in pigs after traumatic hemorrhage and hypotensive resuscitation., Methods: Following baseline measurements, femur fracture was performed in 20 anesthetized and instrumented pigs (41 ± 2 kg), followed by hemorrhage of 55% of the estimated blood volume and a 10-minute shock period. Pigs were then resuscitated for 30 minutes with normal saline (NS) alone (NS group, n = 10, 4 mL/kg) or VPA solution (VPA group, n = 10, 90 mg/kg, 2 mL/kg of 45 mg VPA/mL, plus 2 mL NS/kg). All pigs were then monitored for 2 hours or until death. Hemodynamics were recorded, and blood samples were taken for blood and coagulation analysis (Rotem) at baseline, after hemorrhage, resuscitation, and 2 hours or death., Results: Femur fracture and hemorrhage caused similar reductions in mean arterial pressure and cardiac output, and increase in heart rate in both groups. Resuscitation with NS or VPA did not return these measurements to baseline. No differences were observed in hematocrit, pH, lactate, base excess, or total protein between the groups. Compared with NS, resuscitation with VPA decreased platelet counts and prolonged activated partial thromboplastin time, with no differences in fibrinogen levels, prothrombin time, or any of the Rotem measurements between the two groups. Neither survival rates (NS, 7 of 10 pigs; VPA, 7 of 10 pigs) nor survival times after resuscitation (NS, 97 ± 40 minutes; VPA, 98 ± 43 minutes) differed between the groups., Conclusion: Following traumatic hemorrhage and hypotensive resuscitation in pigs, VPA provides no benefit toward improving coagulation function or survival times., (Copyright © 2022 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)