The Effect of Prehospital Clinical Trial-Related Procedures on Scene Interval, Cognitive Load, and Error: A Randomized Simulation Study.

INTRODUCTION: Globally, very few settings have undertaken prehospital randomized controlled trials. Given this lack of experience, there is a risk that such trials in these settings may result in protocol deviations, increased prehospital intervals, and increased cognitive load, leading to error. Ultimately, this may affect patient safety and mortality. The aim of this study was to assess the effect of trial-related procedures on simulated scene interval, self-reported cognitive load, medical errors, and time to action. METHODS: This was a prospective simulation study. Using a cross-over design, ten teams of prehospital clinicians were allocated to three separate simulation arms in a random order. Simulations were: (1) Eligibility assessment and administration of freeze-dried plasma (FDP) and a hemoglobin-based oxygen carrier (HBOC), (2) Eligibility assessment and administration of HBOC, (3) Eligibility assessment and standard care. All simulations also required clinical management of hemorrhagic shock. Simulated scene interval, error rates, cognitive load (measured by NASA Task Load Index), and competency in clinical care (assessed using the Simulation Assessment Tool Limiting Assessment Bias (SATLAB)) were measured. Mean differences between simulations with and without trial-related procedures were sought using one-way ANOVA or Kruskal-Wallis test. A p-value of <0.05 within the 95% confidence interval was considered significant. RESULTS: Thirty simulations were undertaken, representing our powered sample size. The mean scene intervals were 00:16:56 for Simulation 1 (FDP and HBOC), 00:17:22 for Simulation 2 (HBOC only), and 00:14:24 for Simulation 3 (standard care). Scene interval did not differ between the groups (p = 0.27). There were also no significant differences in error rates (p = 0.28) or cognitive load (p = 0.67) between the simulation groups. There was no correlation between cognitive load and error rates (r = 0.15, p = 0.42). Competency was achieved in all the assessment criteria for all simulation groups. CONCLUSION: In a simulated environment, eligibility screening, performance of trial-related procedures, and clinical management of patients with hemorrhagic shock can be completed competently by prehospital advanced life support clinicians without delaying transport or emergency care. Future prehospital clinical trials may use a similar approach to help ensure graded and cautious implementation of clinical trial procedures into prehospital emergency care systems.

The risk of thromboembolic events with early intravenous 2- and 4-g bolus dosing of tranexamic acid compared to placebo in patients with severe traumatic bleeding: A secondary analysis of a randomized, double-blind, placebo-controlled, single-center trial.

BACKGROUND: Screening for the risk of thromboembolism (TE) due to tranexamic acid (TXA) in patients with severe traumatic injury has not been performed in randomized clinical trials. Our objective was to determine if TXA dose was independently-associated with thromboembolism. STUDY DESIGN AND METHODS: This is a secondary analysis of a single-center, double-blinded, randomized controlled trial comparing placebo to a 2-g or 4-g intravenous TXA bolus dose in trauma patients with severe injury. We used multivariable discrete-time Cox regression models to identify associations with risk for thromboembolic events within 30 days post-enrollment. Event curves were created using discrete-time Cox regression. RESULTS: There were 50 patients in the placebo group, 49 in the 2-g, and 50 in the 4-g TXA group. In adjusted analyses for thromboembolism, a 2-g dose of TXA had an hazard ratio (HR, 95% confidence interval [CI]) of 3.20 (1.12-9.11) (p = .029), and a 4-g dose of TXA had an HR (95% CI) of 5.33 (1.94-14.63) (p = .001). Event curves demonstrated a higher probability of thromboembolism for both doses of TXA compared to placebo. Other parameters independently associated with thromboembolism include time from injury to TXA administration, body mass index, and total blood products transfused. DISCUSSION: In patients with severe traumatic injury, there was a dose-dependent increase in the risk of at least one thromboembolic event with TXA. TXA should not be withheld, but thromboembolism screening should be considered for patients receiving a dose of at least 2-g TXA intravenously for traumatic hemorrhage.

Assessing Factor V Antigen and Degradation Products in Burn and Trauma Patients.

INTRODUCTION: Proposed mechanisms of acute traumatic coagulopathy (ATC) include decreased clotting potential due to factor consumption and proteolytic inactivation of factor V (FV) and activated factor V (FVa) by activated protein C (aPC). The role of FV/FVa depletion or inactivation in burn-induced coagulopathy is not well characterized. This study evaluates FV dynamics following burn and nonburn trauma. METHODS: Burn and trauma patients were prospectively enrolled. Western blotting was performed on admission plasma to quantitate levels of FV antigen and to assess for aPC or other proteolytically derived FV/FVa degradation products. Statistical analysis was performed with Spearman's, Chi-square, Mann-Whitney U test, and logistic regression. RESULTS: Burn (n = 60) and trauma (n = 136) cohorts showed similar degrees of FV consumption with median FV levels of 76% versus 73% (P = 0.65) of normal, respectively. Percent total body surface area (TBSA) was not correlated with FV, nor were significant differences in median FV levels observed between low and high TBSA groups. The injury severity score (ISS) in trauma patients was inversely correlated with FV (ρ = -0.26; P = 0.01) and ISS ≥ 25 was associated with a lower FV antigen level (64% versus. 93%; P = 0.009). The proportion of samples showing proteolysis-derived FV was greater in trauma than burn patients (42% versus. 16%; P = 0.0006). CONCLUSIONS: Increasing traumatic injury severity is associated with decreased FV antigen levels, and a greater proportion of trauma patient samples exhibit proteolytically degraded FV fragments. These associations are not present in burns, suggesting that mechanisms underlying FV depletion in burn and nonburn trauma are not identical.

Analysis of Nonbattle Deaths Among U.S. Service Members in the Deployed Environment.

OBJECTIVE: Describe etiologies and trends in non-battle deaths (NBD) among deployed U.S. service members to identify areas for prevention. BACKGROUND: Injuries in combat are categorized as battle (result of hostile action) or nonbattle related. Previous work found that one-third of injured US military personnel in Iraq and Afghanistan had nonbattle injuries and emphasized prevention. NBD have not yet been characterized. METHODS: U.S. military casualty data for Iraq and Afghanistan from 2001 to 2014 were obtained from the Defense Casualty Analysis System (DCAS) and the Department of Defense Trauma Registry (DoDTR). Two databases were used because DoDTR does not capture prehospital deaths, while DCAS does not contain clinical details. Nonbattle injuries and NBD were identified, etiologies classified, and NBD trends were assessed using a weighted moving average and time-series analysis with autoregressive integrated moving average. Future NBD rates were forecast. RESULTS: DCAS recorded 59,799 casualties; 21.0% (n = 1431) of all deaths (n = 6745) were NBD. DoDTR recorded 29,958 casualties; 11.5% (n = 206) of all deaths (n = 1788) were NBD. After early fluctuations, NBD rates for both Iraq and Afghanistan stabilized at approximately 21%. Leading causes of NBD were gunshot wounds and vehicle accidents, accounting for 66%. Approximately 25% was self-inflicted. A 24% NBD rate was forecasted from 2015 through 2025. CONCLUSIONS: Approximately 1 in 5 deaths were NBD. The majority were potentially preventable, including a significant proportion of self-inflicted injuries. A single comprehensive data repository would facilitate future mortality monitoring and performance improvement. These data may assist military leaders with implementing targeted safety strategies.

Evidence-Based and Clinically Relevant Outcomes for Hemorrhage Control Trauma Trials.

OBJECTIVE: To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. BACKGROUND: A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. METHODS: An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. CONCLUSIONS: For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.

Hemorrhagic shock and hemostatic resuscitation in canine trauma.

Hemorrhage is a significant cause of death among military working dogs and in civilian canine trauma. While research specifically aimed at canine trauma is limited, many principles from human trauma resuscitation apply. Trauma with significant hemorrhage results in shock and inadequate oxygen delivery to tissues. This leads to aberrations in cellular metabolism, including anaerobic metabolism, decreased energy production, acidosis, cell swelling, and eventual cell death. Considering blood and endothelium as a single organ system, blood failure is a syndrome of endotheliopathy, coagulopathy, and platelet dysfunction. In severe cases following injury, blood failure develops and is induced by inadequate oxygen delivery in the presence of hemorrhage, tissue injury, and acute stress from trauma. Severe hemorrhagic shock is best treated with hemostatic resuscitation, wherein blood products are used to restore effective circulating volume and increase oxygen delivery to tissues without exacerbating blood failure. The principles of hemostatic resuscitation have been demonstrated in severely injured people and the authors propose an algorithm for applying this to canine patients. The use of plasma and whole blood to resuscitate severely injured canines while minimizing the use of crystalloids and colloids could prove instrumental in improving both mortality and morbidity. More work is needed to understand the canine patient that would benefit from hemostatic resuscitation, as well as to determine the optimal resuscitation strategy for these patients.

Spray-dried plasma deficient in high-molecular-weight multimers of von Willebrand factor retains hemostatic properties.

BACKGROUND: Dried plasmas can overcome logistical barriers that prevent fresh frozen plasma (FFP) usage in acute resuscitation, but processing of these products can detrimentally alter the composition. Spray-dried plasma (SpDP) from single units is deficient in high-molecular-weight multimers of von Willebrand factor (vWF), a critical facilitator of platelet adhesion and thrombus formation. We hypothesized that converting high-molecular-weight multimers to smaller-molecular-weight multimers would retain vWF's capacity to mediate platelet adhesion. STUDY DESIGN AND METHODS: SpDP obtained from untreated FFP was reconstituted with glycine-hydrochloric acid (HCl) and glycine (20 mM:50 mM) or pretreated with glycine-HCl (20 mM) or glycine-glycine-HCl (20 mM:50 mM) and reconstituted with water. In vitro hemostatic potential of SpDPs versus FFP or FFP spiked with 70 mM of glycine was evaluated, leading to a more detailed in vitro study of glycine-HCl-glycine (20 mM:50 mM) pretreated SpDP. Plasmas were combined with RBCs and platelets to observe global coagulation response. RESULTS: While vWF-ristocetin cofactor activity is significantly decreased (-41.13%; p < .0001) in SpDP, a model of vWF-mediated platelet adhesion to collagen under flow showed enhanced function (+13%; p < .01). Fewer microparticles, particularly of platelet origin, were observed in SpDP versus FFP (p < .0001). Small but significant differences in thromboelastography results were observed, although SpDP and FFP were within normal ranges. CONCLUSION: Comparable coagulability was observed in FFP and SpDP. The apparent paradox between vWF-ristocetin cofactor assay and vWF-mediated platelet adhesion may be explained by the increase in smaller multimers of vWF in SpDP, producing different outcomes in these assays.

The need for dried plasma - a national issue.

Recent studies have demonstrated that early transfusion of plasma or RBCs improves survival in patients with severe trauma and hemorrhagic shock. Time to initiate transfusion is the critical factor. It is essential that transfusion begin in the prehospital environment when transport times are longer than approximately 15 to 20 minutes. Unfortunately, logistic constraints severely limit the use of blood products in the prehospital setting, especially in military, remote civilian, and mass disaster circumstances, where the need can be most acute. US military requirements for logistically supportable blood products are projected to increase dramatically in future conflicts. Although dried plasma products have been available and safely used in a number of countries for over 20 years, there is no dried plasma product commercially available in the United States. A US Food and Drug Administration-approved dried plasma is urgently needed. Considering the US military, disaster preparedness, and remote civilian trauma perspectives, this is an urgent national health care issue.

Prehospital Application of Hemostatic Agents in Iraq and Afghanistan.

INTRODUCTION: Hemorrhage is the leading cause of death on the battlefield. Development of chitosan- and kaolin-based hemostatic agents has improved hemorrhage control options. Sparse data exists on the use of these agents in the prehospital, combat setting. We describe recent use of these agents and compare patients receiving hemostatic to the baseline population. METHODS: We used a series of emergency department (ED) procedure codes to identify patients within the Department of Defense Trauma Registry (DODTR) from January 2007 to August 2016. We only included patients for whom the DODTR specified the hemostatic agent utilized (chitosan or kaolin). We defined a serious injury by body region as an Abbreviated Injury Score (AIS) of 3 or greater. RESULTS: Our predefined search codes captured 28,222 patients. Of those, 258 (0.9%) patients had documented hemostatic use: 58 chitosan, 201 kaolin, and one subject received both. Patients undergoing hemostatic agent application were more likely to be injured by gunshot wound or explosive. Patients with hemostatic application had higher median composite Injury Severity Scores (10 vs. 9, p < 0.001), and higher AIS for the abdomen, extremity and superficial body regions with higher rates of blood product utilization. Proportions of patients suffering traumatic amputations and undergoing tourniquet application were higher in the hemostatic agent group than the baseline population (11.6% vs. 6.7%, p = 0.002 and 43.4% vs. 13.8%, p < 0.001, respectively). CONCLUSIONS: Hemostatic agents were infrequently utilized to manage traumatic hemorrhage during the recent conflicts in Afghanistan and Iraq. Hemostatic agent use was more frequent in casualties with gunshot wounds, traumatic amputations, concomitant tourniquet application, and greater blood product administration."

Comprehensive US government program for dried plasma development.

Transfusion of plasma early after severe injury has been associated with improved survival. There are significant logistic factors that limit the ability to deliver plasma where needed in austere environments, such as the battlefield or during a significant civilian emergency. While some countries have access to more logistically supportable dried plasma, there is no such product approved for use in the United States. There is a clear need for a Food and Drug Administration (FDA)-approved dried plasma for military and emergency-preparedness uses, as well as for civilian use in remote or austere settings. The Department of Defense (DoD) and Biomedical Advanced Research and Development Authority are sponsoring development of three dried plasma products, incorporating different technologic approaches and business models. At the same time, the DoD is sponsoring prospective, randomized clinical studies on the prehospital use of plasma. These efforts are part of a coordinated program to provide a dried plasma for military and civilian applications and to produce additional information on plasma use so that, by the time we have an FDA-approved dried plasma, we will better understand how to use it.

Dried plasma: state of the science and recent developments.

The early transfusion of plasma is important to ensure optimal survival of patients with traumatic hemorrhage. In military and remote or austere civilian settings, it may be impossible to move patients to hospital facilities within the first few hours of injury. A dried plasma product with reduced logistical requirements is needed to enable plasma transfusion where medically needed, instead of only where freezers and other equipment are available. First developed in the 1930s, pooled lyophilized plasma was widely used by British and American forces in WWII and the Korean War. Historical dried plasma products solved the logistical problem but were abandoned because of disease transmission. Modern methods to improve blood safety have made it possible to produce safe and effective dried plasma. Dried plasma products are available in France, Germany, South Africa, and a limited number of other countries. However, no product is available in the US. Promising products are in development that employ different methods of drying, pathogen reduction, pooling, packaging, and other approaches. Although challenges exist, the in vitro and in vivo data suggest that these products have great potential to be safe and effective. The history, state of the science, and recent developments in dried plasma are reviewed.

Comparison of Rapid-, Kaolin-, and Native-TEG Parameters in Burn Patient Cohorts With Acute Burn-induced Coagulopathy and Abnormal Fibrinolytic Function.

Although use of thromboelastography (TEG) to diagnose coagulopathy and guide clinical decision-making is increasing, relative performance of different TEG methods has not been well-defined. Rapid-TEG (rTEG), kaolin-TEG (kTEG), and native-TEG (nTEG) were performed on blood samples from burn patients presenting to a regional center from admission to 21 days. Patients were categorized by burn severity, mortality, and fibrinolytic phenotypes (Shutdown [SD], Physiologic [PHYS], and Hyperfibrinolytic [HF]). Manufacturer ranges and published TEG cutoffs were examined. Concordance correlations (Rc) of TEG parameters (R, α-angle, maximum amplitude [MA], LY30) measured agreement and Cohen's Kappa (κ) determined interclass reliability. Patients (n = 121) were mostly male (n = 84; 69.4%), with median age 40 years, median TBSA burn 13%, and mortality 17% (n = 21). Severe burns (≥40% TBSA) were associated with lower admission α-angle for rTEG (P = .03) and lower MA for rTEG (P = .02) and kTEG (P = .01). MA was lower in patients who died (nTEG, P = .04; kTEG, P = .02; rTEG, P = .003). Admission HF was associated with increased mortality (OR, 10.45; 95% CI, 2.54-43.31, P = .001) on rTEG only. Delayed SD was associated with mortality using rTEG and nTEG (OR 9.46; 95% CI, 1.96-45.73; P = .005 and OR, 6.91; 95% CI, 1.35-35.48; P = .02). Admission TEGs showed poor agreement on R-time (Rc, 0.00-0.56) and α-angle (0.40 to 0.55), and moderate agreement on MA (0.67-0.81) and LY30 (0.72-0.93). Interclass reliability was lowest for R-time (κ, -0.07 to 0.01) and α-angle (-0.06 to 0.17) and highest for MA (0.22-0.51) and LY30 (0.29-0.49). Choice of TEG method may impact clinical decision-making. rTEG appeared most sensitive in parameter-specific associations with injury severity, abnormal fibrinolysis, and mortality.

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.

Tranexamic acid in remote damage control resuscitation.

With the advent of remote damage control resuscitation and far-forward surgery, a renewed emphasis has been placed on examining a variety of pharmacologic adjuncts to controlling blood loss before definitive operative intervention. In this paper, the authors review the current state of the art for tranexamic acid (TXA) and its potential benefits to those patients who are in need of a massive transfusion. Specifically addressed are its biologic and pharmacologic properties, as well the results of a number of recent studies. The 2010 CRASH-2 trial randomized in excess of 20,000 patients and demonstrated a reduction in all-cause mortality from 16.0 to 14.5% and death due to bleeding from 5.7 to 4.9%. The 2012 Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study provided a retrospective analysis of 896 wounded cared for at a military hospital in Afghanistan. This study demonstrated a 23.9%-17.4% reduction in all-cause mortality. Finally, they discuss the potential complications associated with TXA use as well as areas of future research, which are needed to solidify our knowledge of TXA and its potential beneficial effects on controlling bleeding.

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.

Immunopathology of terminal complement activation and complement C5 blockade creating a pro-survival and organ-protective phenotype in trauma.

BACKGROUND AND PURPOSE: Traumatic haemorrhage (TH) is the leading cause of potentially preventable deaths that occur during the prehospital phase of care. No effective pharmacological therapeutics are available for critical TH patients yet. Here, we identify terminal complement activation (TCA) as a therapeutic target in combat casualties and evaluate the efficacy of a TCA inhibitor (nomacopan) on organ damage and survival in vivo. EXPERIMENTAL APPROACH: Complement activation products and cytokines were analysed in plasma from 54 combat casualties. The correlations between activated complement pathway(s) and the clinical outcomes in trauma patients were assessed. Nomacopan was administered to rats subjected to lethal TH (blast injury and haemorrhagic shock). Effects of nomacopan on TH were determined using survival rate, organ damage, physiological parameters, and laboratory profiles. KEY RESULTS: Early TCA was associated with systemic inflammatory responses and clinical outcomes in this trauma cohort. Lethal TH in the untreated rats induced early TCA that correlated with the severity of tissue damage and mortality. The addition of nomacopan to a damage-control resuscitation (DCR) protocol significantly inhibited TCA, decreased local and systemic inflammatory responses, improved haemodynamics and metabolism, attenuated tissue and organ damage, and increased survival. CONCLUSION AND IMPLICATIONS: Previous findings of our and other groups revealed that early TCA represents a rational therapeutic target for trauma patients. Nomacopan as a pro-survival and organ-protective drug, could emerge as a promising adjunct to DCR that may significantly reduce the morbidity and mortality in severe TH patients while awaiting transport to critical care facilities.

Trends in Traumatic Brain Injury Among U.S. Service Members Deployed in Iraq and Afghanistan, 2002-2016.

INTRODUCTION: Traumatic brain injury (TBI) is a major health issue for service members deployed and is more common in recent conflicts; however, a thorough understanding of risk factors and trends is not well described. This study aims to characterize the epidemiology of TBI in U.S. service members and the potential impacts of changes in policy, care, equipment, and tactics over the 15 years studied. METHODS: Retrospective analysis of U.S. Department of Defense Trauma Registry data (2002-2016) was performed on service members treated for TBI at Role 3 medical treatment facilities in Iraq and Afghanistan. Risk factors and trends in TBI were examined in 2021 using Joinpoint regression and logistic regression. RESULTS: Nearly one third of 29,735 injured service members (32.4%) reaching Role 3 medical treatment facilities had TBI. The majority sustained mild (75.8%), followed by moderate (11.6%) and severe (10.6%) TBI. TBI proportion was higher in males than in females (32.6% vs 25.3%; p<0.001), in Afghanistan than in Iraq (43.8% vs 25.5%; p<0.001), and in battle than in nonbattle (38.6% vs 21.9%; p<0.001). Patients with moderate or severe TBI were more likely to have polytrauma (p<0.001). TBI proportion increased over time, primarily in mild TBI (p=0.02), slightly in moderate TBI (p=0.04), and most rapidly between 2005 and 2011, with a 2.48% annual increase. CONCLUSIONS: One third of injured service members at Role 3 medical treatment facilities experienced TBI. Findings suggest that additional preventive measures may decrease TBI frequency and severity. Clinical guidelines for field management of mild TBI may reduce the burden on evacuation and hospital systems. Additional capabilities may be needed for military field hospitals.

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects.

The use of warfarin has a well-known bleeding risk. Recombinant activated factor VII (rFVIIa) is a non-plasma-derived, rapid-acting, and rapidly infused potential treatment. This randomized, single-center, placebo-controlled, double-blinded, dose-escalation, exploratory phase 1 trial assessed safety and effects of rFVIIa in reversing warfarin-induced changes in bleeding and coagulation parameters, using a punch biopsy-induced bleeding model in healthy subjects. The effects of warfarin (experiment 1) and rFVIIa (5-80 microg/kg; experiment 2) were evaluated. Outcomes were bleeding duration, blood loss, coagulation parameters, and safety. Warfarin treatment significantly increased bleeding duration and blood loss from pretreatment (experiment 1, 12 subjects). However, these parameters after rFVIIa treatment were not significantly different from placebo (experiment 2, 85 subjects). Mean activated partial thromboplastin time, prothrombin time, and international normalized ratio were reduced from warfarin-elevated levels. rFVIIa (80 microg/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared with placebo (P < .05), and returned the thrombin generation speed to baseline. There were no thromboembolic or serious adverse events. In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation, and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated in the punch biopsy model. Trial registration is exempt (phase 1).