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Introduction: Severe COVID-19 illness can lead to thrombotic complications, organ failure, and death. Antithrombin (AT) regulates thromboinflammation and is a key component of chemical thromboprophylaxis. Our goal was to examine the link between AT activity and responsiveness to thromboprophylaxis, markers of hypercoagulability, and inflammation among severe COVID-19 patients. Methods: This was a single-center, prospective observational study enrolling SARS-CoV-2-positive patients admitted to the intensive care unit on prophylactic enoxaparin. Blood was collected daily for 7 days to assess AT activity and anti-factor Xa levels. Patient demographics, outcomes, and hospital laboratory results were collected. Continuous variables were compared using Mann-Whitney tests, and categorical variables were compared using χ2 tests. Multivariable logistic regression was used to determine the association between AT activity and mortality. Results: In 36 patients, 3 thromboembolic events occurred, and 18 (50%) patients died. Patients who died had higher fibrinogen, D-dimer, and C-reactive protein (CRP) levels and lower AT activity. Reduced AT activity was independently associated with mortality and correlated with both markers of hypercoagulability (D-dimer) and inflammation (CRP). Conclusion: Low AT activity is associated with mortality and persistent hypercoagulable and proinflammatory states in severe COVID-19 patients. The anti-thromboinflammatory properties of AT make it an appealing therapeutic target for future studies.

Malnutrition is associated with increased morbidity and mortality after trauma. The Geriatric Nutritional Risk Index (GNRI) is a validated scoring system used to predict the risk of complications related to malnutrition in nontrauma patients. We hypothesized that GNRI is predictive of worse outcomes in geriatric trauma patients.This was a single-center retrospective study of trauma patients 65 years or older admitted in 2019. Geriatric Nutritional Risk Index was calculated based on admission albumin level and ratio of actual body weight to ideal body weight. Groups were defined as major risk (GNRI82), moderate risk (GNRI 82-91), low risk (GNRI 92-98), and no risk (GNRI98). The primary outcome was mortality. Secondary outcomes included ventilator days, intensive care unit length of stay (LOS), hospital LOS, discharge home, sepsis, pneumonia, and acute respiratory distress syndrome. Bivariate and multivariable logistic regression analyses were performed to determine the association between GNRI risk category and outcomes.A total of 513 patients were identified for analysis. Median age was 78 years (71-86 years); 24 patients (4.7%) were identified as major risk, 66 (12.9%) as moderate risk, 72 (14%) as low risk, and 351 (68.4%) as no risk. Injury Severity Scores and Charlson Comorbidity Indexes were similar between all groups. Patients in the no risk group had decreased rates of death, and after adjusting for Injury Severity Score, age, and Charlson Comorbidity Index, the no risk group had decreased odds of death (odds ratio, 0.13; 95% confidence interval, 0.04-0.41) compared with the major risk group. The no risk group also had fewer infectious complications including sepsis and pneumonia, and shorter hospital LOS and were more likely to be discharged home.Major GNRI risk is associated with increased mortality and infectious complications in geriatric trauma patients. Further studies should target interventional strategies for those at highest risk based on GNRI.Prognostic and Epidemiologic; Level III.

Platelets are subcellular anucleate components of blood primarily responsible for initiating and maintaining hemostasis. After injury to a blood vessel, platelets can be activated via several pathways, resulting in changed shape, adherence to the injury site, aggregation to form a plug, degranulation to initiate activation in other nearby platelets, and acceleration of thrombin formation to convert fibrinogen to fibrin before contracting to strengthen the clot. Platelet function assays use agonists to induce and measure one or more of these processes to identify alterations in platelet function that increase the likelihood of bleeding or thrombotic events. In severe trauma, these assays have revealed that platelet dysfunction is strongly associated with poor clinical outcomes. However, to date, the mechanism(s) causing clinically significant platelet dysfunction remain poorly understood. We review the pros, cons, and evidence for use of many of the popular assays in trauma, discuss limitations of their use in this patient population, and present approaches that can be taken to develop improved functional assays capable of elucidating mechanisms of trauma-induced platelet dysfunction. Platelet dysfunction in trauma has been associated with need for transfusions and mortality; however, most of the current platelet function assays were not designed for evaluating trauma patients, and there are limited data regarding their use in this population. New or improved functional assays will help define the mechanisms by which platelet dysfunction occurs, as well as help optimize future treatment.

ImportanceIt is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies.ObjectiveTo derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies.Design, Setting, and ParticipantsThis was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022.ExposuresTEs identified by K-means clustering of plasma biomarkers collected at hospital arrival.Main Outcomes and MeasuresAn association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS.ResultsA total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001).Conclusions and RelevanceResults of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

The TRPM4 gene codes for a membrane ion channel subunit related to inflammation in the central nervous system. Recent investigation has identified an association between TRPM4 single nucleotide polymorphisms (SNPs) rs8104571 and rs150391806 and increased intracranial (ICP) pressure following traumatic brain injury (TBI). We assessed the influence of these genotypes on clinical outcomes and ICP in TBI patients. We included 292 trauma patients with TBI. DNA extraction and real-time PCR were used for TRPM4 rs8104571 and rs150391806 allele discrimination. Five participants were determined to have the rs8104571 homozygous variant genotype, and 20 participants were identified as heterozygotes; 24 of these 25 participants were African American. No participants had rs150391806 variant alleles, preventing further analysis of this SNP. Genotypes containing the rs8104571 variant allele were associated with decreased Glasgow outcome scale-extended (GOSE) score (P = 0.0231), which was also consistent within our African-American subpopulation (P = 0.0324). Regression analysis identified an association between rs8104571 variant homozygotes and mortality within our overall population (P = 0.0230) and among African Americans (P = 0.0244). Participants with rs8104571 variant genotypes exhibited an overall increase in ICP (P = 0.0077), although a greater frequency of ICP measurements > 25 mmHg was observed in wild-type participants (P =

Trauma-induced coagulopathy is a continuum ranging from hypercoagulable to hypercoagulable phenotypes. In single-center studies, the maximum amplitude (MA) to r-time (R) (MA-R) ratio has identified a phenotype of injured patients with high mortality risk. The purpose of this study was to determine the relationship between MA-R and mortality using multicenter data and to investigate fibrinogen consumption in the development of this specific coagulopathy phenotype.Using the Pragmatic Randomized Optimal Platelet and Plasma Ratios data set, patients were divided into blunt and penetrating injury cohorts. MA was divided by R time from admission thromboelastogram to calculate MA-R. MA-R was used to assess odds of early and late mortality using multivariable models. Multivariable models were used to assess thrombogram values in both cohorts. Refinement of the MA-R cut point was performed with Youden index. Repeat multivariable analysis was performed with a binary CRITICAL and NORMAL MA-R.In initial analysis, MA-R quartiles were not associated with mortality in the penetrating cohort. In the blunt cohort, there was an association between low MA-R and early and late mortality. A refined cut point of 11 was identified (CRITICAL: MA-R, ≤11; NORMAL: MA-R,11). CRITICAL MA-R was associated with mortality in both penetrating and blunt subgroups. In further injury subgroup analysis, CRITICAL patients had significantly decreased fibrinogen levels in the blunt subgroup only. In both blunt and penetrating injury, there was no difference in time to initiation of thrombin burst (lagtime). However, both endogenous thrombin potential and peak thrombin levels were significantly lower in CRITICAL patients.MA-R identifies a trauma-induced coagulopathy phenotype characterized in blunt injury by impaired thrombin generation that is associated with early and late mortality. The endotheliopathy and tissue factor release likely plays a role in the cascade of impaired thrombin burst, possible early fibrinogen consumption and the weaker clot identified by MA-R.Therapeutic/care management, level II.

Importance Emergency research is challenging to do well as it involves time sensitive interventions in unstable patients. There is limited time to obtain informed consent from the patient or their legally authorized representative (LAR). Such research is permitted under exception from informed consent (EFIC) if specific criteria are met, including notification after enrollment. Some question whether the risks of EFIC outweighs its benefits. To date, there is limited empiric information about time to notification (TTN) and rates of withdrawal in such trials. Objective To describe variation in TTN and rates of withdrawal among that patients enrolled in EFIC trials over a twelve-year period. Design We performed post hoc descriptive analyses of data from five trials conducted under EFIC. Setting Emergency medical services and receiving hospitals participating in the Resuscitation Outcomes Consortium in the United States and Canada. Participants Patients with out-of-hospital cardiac arrest or life-threatening traumatic injury. Exposures Notification strategies were specified at each site before initiation of enrollment by a local institutional review board. We monitored TTN within each site centrally throughout each study’s enrollment period. Outcomes TTN was defined as time from randomization to first-reported notification of patient or LAR of enrollment. Withdrawal was defined as patient or LAR opt out of ongoing participation at the time of notification. Results Of 35,442 patients enrolled in five trials, 33,805 had cardiac arrest; and 1636 had traumatic injury. TTN varied overall and by patient outcome. Among those with cardiac arrest, TTN ranged from median (5%ile, 95%ile) of 6 (1,27) days to 28 (2, 53) days across sites. 0.3% of notified patients with cardiac arrest withdrew. Among those with traumatic injury, TTN ranged from 0 (0, 5) days to 36 (5, 68) days across sites. 7.7% of notified patients with traumatic injury withdrew. Conclusions and Relevance There is large variation in TTN in trials conducted under EFIC for emergency research. This may be due to several factors. It may or may not be modifiable. Overall rates of withdrawal are low, which suggests current practices related to EFIC are acceptable to those who have participated in emergency research.

In trauma patients, shock-induced endotheliopathy (SHINE) is associated with a poor prognosis. We have previously identified four metabolic phenotypes in a small cohort of trauma patients (N = 20) and displayed the intracellular metabolic profile of the endothelial cell by integrating quantified plasma metabolomic profiles into a genome-scale metabolic model (iEC-GEM). A retrospective observational study of 99 trauma patients admitted to a Level 1 Trauma Center. Mass spectrometry was conducted on admission samples of plasma metabolites. Quantified metabolites were analyzed by computational network analysis of the iEC-GEM. Four plasma metabolic phenotypes (A–D) were identified, of which phenotype D was associated with an increased injury severity score (p < 0.001); 90% (91.6%) of the patients who died within 72 h possessed this phenotype. The inferred EC metabolic patterns were found to be different between phenotype A and D. Phenotype D was unable to maintain adequate redox homeostasis. We confirm that trauma patients presented four metabolic phenotypes at admission. Phenotype D was associated with increased mortality. Different EC metabolic patterns were identified between phenotypes A and D, and the inability to maintain adequate redox balance may be linked to the high mortality.

BACKGROUND: Up to 30% of severely injured patients on prophylactic anticoagulation experience venous thromboembolism (VTE). Our previous work shows that acquired antithrombin (AT) deficiency [AT

Venous thromboembolism (VTE) remains a frequent postinjury complication with well established but nonmodifiable risk factors. We hypothesized that fibrinolysis shutdown (SD) as measured by thromboelastography (TEG) would be an independent risk factor for VTE in trauma patients.A subgroup of patients enrolled in the CLOTT-2 (Consortium of Leaders in the Study of Traumatic Thromboembolism 2), multicenter prospective cohort study had kaolin TEG and tissue plasminogen activator (tPA)-TEG data at 12 and 24 hours postadmission. Patients underwent a screening duplex venous ultrasound examination during the first week unless clot was already detected on computed tomography. Injury factors associated with early fibrinolysis SD (defined as kaolin TEG Ly30 ≤0.3%) and/or tPA resistance (tPA-R) (defined as kaolin TEG with tPA 75 ng Ly302.1%) were investigated as was the association of the TEG measurements with the development of VTE.A total of 141 patients had both TEG measurements at 24 hours, and 135 had both TEG measurements at 12 hours. Shutdown was evident at 12 hours in 71 of 135 (52.6%) patients and in 62 of 141 (44%) at 24 hours. Tissue plasminogen activator resistance was found in 61 of 135 (45.2%) at 12 hours and in 49 of 141 (34.3%) at 24 hours. Factors significantly associated with SD included receiving4 U of FFP in the first 24 hours, the presence of a major brain injury or pelvic fracture, and the need for major surgery. In contrast, factors significantly associated with early tPA-R included4 U of red blood cells transfused in the first 24 hours and the presence of a major chest injury or long bone fracture. Deep vein thrombosis was detected in 15 patients and pulmonary clots in 5 (overall VTE rate, 14.2%). Tissue plasminogen activator resistance at 12 hours was found to be an independent risk factor for VTE (hazard ratio, 5.57; 95% confidence interval, 1.39-22.39).Early development of a hypercoagulable state as defined by tPA-R at 12 hours after admission represents a potentially modifiable risk factor for postinjury VTE.Therapeutic/Care Management; Level II.

BACKGROUND Low-titer group O whole blood (LTO-WB) has recently gained popularity in trauma centers for the acute resuscitation of hemorrhagic shock. However, limited supplies of Rh- product prevent implementation and strain sustainability at many trauma centers. We set out to identify whether Rh+ LTO-WB could be safely substituted for RH- product, regardless of patient's Rh status. METHODS Following Institutional Review Board approval, information on all trauma patients receiving prehospital or emergency department transfusion of uncrossed, emergency release LTO-WB (11/17-10/19) were evaluated. Patients were first divided into those who received Rh- versus Rh+ product, the assessed by Rh of the recipient. Serial hemolysis panels, transfusion reactions, and outcomes were compared. RESULTS Six hundred thirty-seven consecutive trauma patients received emergency release LTO-WB. Of these, 448 received Rh+ product, while 189 received Rh- LTO-WB. Patients receiving Rh+ product were more likely to be men (81 vs. 70%) and have lower field blood pressure (median 99 vs. 109) and GCS (median 7 vs. 12); all p < 0.05. There were no differences in blood product volume, hemolysis laboratories, transfusion reactions, complications, or survival. We then separated patients by Rh status (577 were Rh+, 70 were Rh-). Rh- patients were older (median age 54 vs. 39), more likely to be women (57 vs. 26%), and more likely to have sustained blunt trauma than their Rh+ counterparts (92 vs. 70%); all p < 0.05. There were no differences in hemolysis laboratories, transfusion reactions, complications, or survival between Rh+ and Rh- patients, regardless of Rh product received. CONCLUSION When Rh- whole blood is unavailable or in short supply, Rh+ LTO-WB appears to be a safe alternative for the resuscitation of hemorrhagic shock in both Rh+ and Rh- patients. Use of Rh+ product may help trauma centers incorporate LTO-WB into their hospital and improve sustainability of such programs. LEVEL OF EVIDENCE Therapeutic, Level III.

Background Protocols for expediting critical trauma patients directly from the helipad to the operating room tend to vary by center, rely heavily on physician gestalt, and lack supporting evidence. We evaluated a population of severely injured trauma patients with the aim of determining objective factors associated with the need for immediate surgical intervention. Methods All highest-activation trauma patients transported by air ambulance between 1/1/16 and 12/31/17 were enrolled retrospectively. Transfer, pediatric, isolated burn, and isolated head trauma patients were excluded. Patients who underwent emergency general surgery within 30 min of arrival without the aid of cross-sectional imaging were compared to the remainder of the cohort. Results Of the 863 patients who were enrolled, 85 (10%) spent less than 30 min in the emergency department (ED) before undergoing an emergency operation. The remaining 778 patients (90%) formed the comparison group. The ED ≤ 30 min group had a higher percentage of penetrating injuries, lower blood pressure, and was more likely to have a positive FAST exam. The “Direct to Operating Room” (DTOR) score is a predictive scoring system devised to identify patients most likely to benefit from bypassing the ED. The odds ratio of emergency operation within 30 min of hospital arrival increased by 2.71 (95% confidence interval 2.23-3.29; P Conclusions Trauma patients with profound hypotension or acidosis and positive FAST were more likely to require surgery within 30 min of hospital presentation. Use of a scoring system may allow early identification of these patients in the prehospital setting by nonphysician providers.

Supplemental digital content is available in the text., BACKGROUND Damage-control resuscitation (DCR) improves survival in severely bleeding patients. However, deviating from balanced transfusion ratios during a resuscitation may limit this benefit. We hypothesized that maintaining a balanced resuscitation during DCR is independently associated with improved survival. METHODS This was a secondary analysis of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients receiving >3 U of packed red blood cells (PRBCs) during any 1-hour period over the first 6 hours and surviving beyond 30 minutes were included. Linear regression assessed the effect of percent time in a high-ratio range on 24-hour survival. We identified an optimal ratio and percent of time above the target ratio threshold by Youden’s index. We compared patients with a 6-hour ratio above the target and above the percent time threshold (on-target) with all others (off-target). Kaplan-Meier analysis assessed the combined effect of blood product ratio and percent time over the target ratio on 24-hour and 30-day survival. Multivariable logistic regression identified factors independently associated with 24-hour and 30-day survival. RESULTS Of 1,245 PROMMTT patients, 524 met the inclusion criteria. Optimal targets were plasma/PRBC and platelet/PRBC of 0.75 (3:4) and ≥40% time spent over this threshold. For plasma/PRBC, on-target (n = 213) versus off-target (n = 311) patients were younger (median, 31 years; interquartile range, [22–50] vs. 40 [25–54]; p = 0.002) with similar injury burdens and presenting physiology. Similar patterns were observed for platelet/PRBC on-target (n = 116) and off-target (n = 408) patients. After adjusting for differences, on-target plasma/PRBC patients had significantly improved 24-hour (odds ratio, 2.25; 95% confidence interval, 1.20–4.23) and 30-day (odds ratio, 1.97; 95% confidence interval, 1.14–3.41) survival, while on-target platelet/PRBC patients did not. CONCLUSION Maintaining a high ratio of plasma/PRBC during DCR is independently associated with improved survival. Performance improvement efforts and prospective studies should capture time spent in a high-ratio range. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level II; Therapeutic, level IV.

Background Evidence for effective pain management and opioid minimization of intravenous ketamine in elective surgery has been extrapolated to acutely injured patients, despite limited supporting evidence in this population. This trial seeks to determine the effectiveness of the addition of sub-dissociative ketamine to a pill-based, opioid-minimizing multi-modal pain regimen (MMPR) for post traumatic pain. Methods This is a single-center, parallel-group, randomized, controlled comparative effectiveness trial comparing a MMPR to a MMPR plus a sub-dissociative ketamine infusion. All trauma patients 16 years and older admitted following a trauma which require intermediate (IMU) or intensive care unit (ICU) level of care are eligible. Prisoners, patients who are pregnant, patients not expected to survive, and those with contraindications to ketamine are excluded from this study. The primary outcome is opioid use, measured by morphine milligram equivalents (MME) per patient per day (MME/patient/day). The secondary outcomes include total MME, pain scores, morbidity, lengths of stay, opioid prescriptions at discharge, and patient centered outcomes at discharge and 6 months. Discussion This trial will determine the effectiveness of sub-dissociative ketamine infusion as part of a MMPR in reducing in-hospital opioid exposure in adult trauma patients. Furthermore, it will inform decisions regarding acute pain strategies on patient centered outcomes. Trial registration The Ketamine for Acute Pain Management After Trauma (KAPT) with registration # NCT04129086 was registered on October 16, 2019.

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>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 (ISS1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >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>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>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.

IMPORTANCE: Venous thromboembolism (VTE) affects 2% to 20% of recovering trauma patients, despite aggressive prophylaxis with enoxaparin. Antithrombin is a primary circulating anticoagulant and crucial component of enoxaparin thromboprophylaxis. Approximately 20% of trauma patients present with antithrombin deficiency (antithrombin activity

Introduction Recent in vitro data have shown that the hemostatic profile of whole blood (WB) degrades significantly after 14 days, yet the optimal storage remains debated. We hypothesized that arrival coagulation studies would be improved in patients receiving younger WB in the prehospital setting. Methods This study was approved by our institutional institutional review board. We evaluated all trauma patients who received prehospital blood products by our helicopter service between July 2017 and July 2019. "Young" WB was defined as 14 days or less. Patients who received at least 1 U of young WB were classified as YOUNG, while the remainder was classified as OLD. Continuous data are presented as medians (25th-75th interquartile range) with comparisons performed using Wilcoxon rank sum. Assessments of clinical hemostatic potential included arrival platelet cell count and rapid thrombelastography. Multivariate regression analysis was also performed (Stata 12.1; College Station, TX). Results A total of 220 patients received prehospital WB during the study period. Of these, 153 patients received YOUNG WB, while 67 were transfused only OLD WB units. There were no differences in demographics, prehospital or arrival physiology, or Injury Severity Score among the two groups. The measures of clot initiation (activated clotting time) and kinetics (k time) were improved, as were the measures of clot acceleration/fibrinogen function (angle) and platelet function (maximum amplitude). As well, arrival platelet count was higher in the YOUNG cohort. No significant differences in postarrival transfusion were noted (p = 0.220). Multivariate analysis showed the greatest differences in maximum amplitude and α angle but failed to reach significance. Conclusion Previous in vitro data have suggested deterioration of platelet function in cold-stored WB after 14 days. The current study demonstrated decreased global hemostasis by clinically available laboratory tests, especially related to fibrinogen and platelet interactions on univariate, but not multivariate analysis. This did not translate into increased transfusion requirements. Further studies are needed to determine the optimal storage duration for cold-stored WB for transfusion in the bleeding trauma patient, as well as rule out the presence of confounding variables. Level of evidence Therapeutic, level IV.

Introduction: Exsanguination remains a leading cause of preventable death in traumatically injured patients. To better treat hemorrhagic shock, hospitals have adopted massive transfusion protocols (MTPs) which accelerate the delivery of blood products to patients. There has been an increase in mass casualty events (MCE) worldwide over the past two decades. These events can overwhelm a responding hospitals supply of blood products. Using a computerized model, this study investigated the ability of US trauma centers (TCs) to meet the blood product requirements of MCEs. Methods: Cross-sectional survey data of on-hand blood products were collected from 16 US level-1 TCs. A discrete event simulation model of a TC was developed based on historic data of blood product consumption during MCEs. Each hospitals blood bank was evaluated across increasingly more demanding MCEs using modern MTPs to guide resuscitation efforts in massive transfusion (MT) patients. Results: A total of 9,000 simulations were performed on each TCs data. Under the least demanding MCE scenario, the median size MCE in which TCs failed to adequately meet blood product demand was 50 patients (IQR 20-90), considering platelets. Ten TCs exhaust their supply of platelets prior to red blood cells (RBCs) or plasma. Disregarding platelets, five TCs exhausted their supply of O- packed RBCs, six exhausted their AB plasma supply, and five had a mixed exhaustion picture. Conclusion: Assuming a TCs ability to treat patients is limited only by their supply of blood products, US level-1 TCs lack the on-hand blood products required to adequately treat patients following a MCE. Use of non-traditional blood products, which have a longer shelf life, may allow TCs to better meet the blood product requirement needs of patients following larger MCEs. Funding Agencies|Center for Translational Injury Research; John B Holmes Professorship in Clinical Sciences

BACKGROUND No Food and Drug Administration-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3-12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later. RESULTS Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only. CONCLUSION While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE Diagnostic test, level III.

BACKGROUND Recognition and clinical diagnosis of acute kidney injury (AKI) after trauma is difficult. The majority of trauma patients do not have a known true baseline creatinine, which makes application of the guidelines set forth by the international guidelines difficult to apply. Use of alternative biomarkers of renal dysfunction in trauma patients may be beneficial. We hypothesized that urinary tissue inhibitor of metalloprotease 2 (TIMP-2) × insulin-like growth factor binding protein 7 (IGFBP-7) would accurately predict AKI development in severely injured trauma patients. METHODS A prospective observational study of adult (≥16 years old) trauma intensive care unit (ICU) patients was performed between September 2018 to March 2019. Urine was collected on ICU admission and was measured for TIMP-2 × IGFBP-7. Univariate, multivariable, and receiver operating characteristic curve analyses were performed using the optimal threshold generated by a Youden index. MAIN RESULTS Of 88 included patients, 75% were male, with a median injury severity score was 27 (interquartile range [IQR], 17-34), and age of 40 years (IQR, 28-54 years). Early AKI developed in 39 patients (44%), and of those, 7 (8%) required dialysis within 48 hours. Patients without early AKI had a TIMP-2 × IGFBP-7 of 0.17 U (IQR, 0.1-0.3 U), while patients with early AKI had a TIMP-2 × IGFBP-7 of 0.46 U (IQR, 0.17-1.29 U; p < 0.001). On multivariable analyses, TIMP-2 × IGFBP-7 was associated with AKI development (p = 0.02) and need for dialysis (p = 0.03). Using the optimal threshold 0.33 U to predict AKI, the area under the receiver operating characteristic curve was 0.731, with an accuracy of 0.75, sensitivity of 0.72, and specificity of 0.78. CONCLUSION Urinary TIMP-2 × IGFBP-7 measured on ICU admission accurately predicted 48-hour AKI and was independently associated with AKI and dialysis requirement after trauma and is a promising screening tool for treatment. LEVEL OF EVIDENCE Prognostic, prospective, observational study, level III.

Background Hemorrhage is the most common cause of potentially preventable trauma deaths, but no studies have focused on all civilian traumatic deaths from hemorrhage, so we describe a year of these deaths from a large county to identify opportunities for preventing hemorrhagic deaths. Methods All trauma-related deaths in Harris County, Texas, in 2014 underwent examination by the medical examiner; patients were excluded if hemorrhage was not their primary reason for death. Deaths were then categorized as preventable/potentially preventable hemorrhage (PPH) or nonpreventable hemorrhage. These categories were compared across mechanism of injury, death location, and anatomic locations of hemorrhage to determine significant differences. Results A total of 1,848 deaths were reviewed, and 305 were from uncontrolled hemorrhage. One hundred thirty-seven (44.9%) of these deaths were PPH. Of these PPH, 49 (35.8%) occurred prehospital and an additional 28 (20.4%) died within 1 hour of arriving at an acute care setting. Of the 83 PPH who arrived at a hospital, 21 (25.3%) died at a center not designated as level 1. Isolated truncal bleeding was the source of hemorrhage in 102 (74.5%) of the PPH. Of those who died with truncal PPH, the distribution was 22 chest (21.6%), 39 chest and abdomen (38.2%), 16 abdomen (15.7%), and 25 all other combinations (24.5%). When patients who died within 1 hour of arrival to a hospital were combined with the 168 deaths that occurred prehospital, 223 (74.3%) of 300 deaths occurred before spending 1 hour in a hospital and 77 (34.5%) of 223 of these deaths were PPH. Conclusion In a well-developed, urban trauma system, 34.5% of patients died from PPH in the prehospital setting or within an hour of hospitalization. Earlier, more effective prehospital resuscitation and truncal hemorrhage control strategies are needed to decrease deaths from PPH. Level of evidence Therapeutic/Care management, level IV.

Objective To describe the current use of the ER-REBOA catheter and associated outcomes and complications. Introduction Noncompressible truncal hemorrhage is the leading cause of potentially preventable death in trauma patients. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a novel strategy to obtain earlier temporary hemorrhage control, supporting cardiac, and cerebral perfusion before definitive hemostasis. Methods Prospective, observational study conducted at 6 Level 1 Trauma Centers over 12-months. Inclusion criteria were age >15 years of age with evidence of truncal hemorrhage below the diaphragm and decision for emergent hemorrhage control intervention within 60 minutes of arrival. REBOA details, demographics, mechanism of injury, complications, and outcomes were collected. Results A total of 8166 patients were screened for enrollment. In 75, REBOA was utilized for temporary hemorrhage control. Blunt injury occurred in 80% with a median injury severity score (ISS) 34 (21, 43). Forty-seven REBOAs were placed in Zone 1 and 28 in Zone 3. REBOA inflation increased systolic blood pressure from 67 (40, 83) mm Hg to 108 (90, 128) mm Hg 5 minutes after inflation (P = 0.02). Cardiopulmonary resuscitation was ongoing during REBOA insertion in 17 patients (26.6%) and 10 patients (58.8%) had return of spontaneous circulation after REBOA inflation. The procedural complication rate was 6.6%. Overall mortality was 52%. Conclusion REBOA can be used in blunt and penetrating trauma patients, including those in arrest. Balloon inflation uniformly improved hemodynamics and was associated with a 59% rate of return of spontaneous circulation for patients in arrest. Use of the ER-REBOA catheter is technically safe with a low procedural complication rate.

Firearm homicide and suicide deaths for 2014 were examined in Harris County, Texas, for spatial variation and socio-economic correlates. Higher firearm homicide rates were found closer to central Houston than firearm suicide rates. Local hot spots were identified for both types but overlapped at only two locations. A Poisson–Gamma–Exposure regression model showed the homicide rate was associated with higher percentages of persons who are Black, aged 15 to 29 years, and living in poverty whereas the suicide rate was associated with a higher percentage of persons of non-Hispanic White ethnicity. Firearm policies that reduce homicides may also reduce suicides.

Resuscitation with human fresh frozen plasma (FFP) in hemorrhagic shock (HS) patients is associated with improved clinical outcomes. Our group has demonstrated that the beneficial effect of FFP is due to its blockade on endothelial hyperpermeability, thereby improving vascular barrier function. The current study aimed to investigate HS-induced endothelial cell apoptosis, a potential major contributor to the endothelial hyperpermeability, and to determine the effect and the key components/factors of FFP on protecting endothelial cells from apoptosis. We first measured and demonstrated an increase in apoptotic endothelial microparticles (CD146(+)AnnexinV(+)) in patients in shock compared to normal subjects, indicating the induction of endothelial cell activation and apoptosis in shock patients. We then transfused HS rats with FFP and showed that FFP blocked HS-induced endothelial cell apoptosis in gut tissue. To identify the anti-apoptotic factors in FFP, we utilized high performance liquid chromatography, fractionated FFP, and screened the fractions in vitro for the anti-apoptotic effects. We selected the most effective fractions, performed mass spectrometry, and identified fibrinogen as a potent anti-apoptotic factor. Taken together, our findings suggest that HS-induced endothelial apoptosis may constitute a major mechanism underlying the vascular hyperpermeability. Furthermore, the identified anti-apoptotic factor fibrinogen may contribute to the beneficial effects of FFP resuscitation, and therefore, may have therapeutic potential for HS.

Background Efforts to reduce opioid use in trauma patients are currently hampered by an incomplete understanding of the baseline opioid exposure and variation in United States. The purpose of this project was to obtain a global estimate of opioid exposure following injury and to quantify the variability of opioid exposure between and within United States trauma centers. Study design Prospective observational study was performed to calculate opioid exposure by converting all sources of opioids to oral morphine milligram equivalents (MMEs). To estimate variation, an intraclass correlation was calculated from a multilevel generalized linear model adjusting for the a priori selected variables Injury Severity Score and prior opioid use. Results The centers enrolled 1,731 patients. The median opioid exposure among all sites was 45 MMEs per day, equivalent to 30 mg of oxycodone or 45 mg of hydrocodone per day. Variation in opioid exposure was identified both between and within trauma centers with the vast majority of variation (93%) occurring within trauma centers. Opioid exposure increased with injury severity, in male patients, and patients suffering penetrating trauma. Conclusion The overall median opioid exposure was 45 MMEs per day. Despite significant differences in opioid exposure between trauma centers, the majority of variation was actually within centers. This suggests that efforts to minimize opioid exposure after injury should focus within trauma centers and not on high-level efforts to affect all trauma centers. Level of evidence Epidemiological, level III.

Background The high incidence of venous thromboembolism (VTE) following trauma persists in spite of aggressive thromboprophylaxis strategies. Approximately half of VTE patients do not achieve the recommended anti-FXa response to enoxaparin anticoagulation (0.1–0.4 IU/mL), however, research to explain or correct this phenomenon is lacking. We hypothesized that antithrombin III (AT) deficiency is associated with poor enoxaparin responsiveness in trauma patients that develop VTE which can be reversed through supplementation with AT. Methods and findings A retrospective cohort study was performed on plasma collected from trauma patients who did and did not develop pulmonary embolism (PE) as well as healthy volunteers. AT levels, thrombin generation, and anti-FXa levels were measured in the collected plasma at baseline and in response to supplementation with AT concentrate at 120–200% or plasma (30% volume). A total of 54 PE patients and 46 non-PE patients were enrolled in this study for analysis. Compared to healthy volunteers, trauma patients had lower levels of AT, elevated thrombin generation, and lower anti-FXa levels in response to enoxaparin. Moreover, thrombin generation was higher and responses to enoxaparin were lower in patients who developed PE compared to those who did not develop PE. We found that supplementation with AT, but not plasma, increased AT levels and improved enoxaparin-mediated inhibition of thrombin generation. Conclusions Supplementation with AT may provide a novel adjunct therapy to increase the effectiveness of enoxaparin thromboprophylaxis and reduce the incidence of VTE in the trauma population.

Objectives To evaluate the dose effects of Recombinant human Club cell 10-kDa protein (rhCC10) on lung function in a well-characterized ovine model of acute respiratory distress syndrome (ARDS) induced by smoke inhalation injury (SII); specifically, the potential of rhCC10 protein to control the inflammatory response and protect pulmonary tissue and function following SII. Design Randomized, controlled, prospective, and large animal translational studies. Setting University large animal intensive care unit. Subjects Thirty-six adult female sheep were surgically prepared and allocated into five groups (Sham (no SII), n = 6; 1 mg/kg/d CC10, n = 8; 3 mg/kg/d CC10, n = 7; 10 mg/kg/d CC10, n = 8; Control SII, n = 7). Interventions All groups except the sham group were subjected to SII with cooled cotton smoke. Then, the animals were placed on a ventilator, treated with 1, 3, and 10 mg/kg/d of intravenous rhCC10 or vehicle, divided evenly into two administrations per day every 12 h, fluid resuscitated, and monitored for 48 h in a conscious state. Measurements and main results The group treated with 10 mg/kg/d rhCC10 attenuated changes in the following variables: PaO2/FiO2 ratio, oxygenation index, and peak inspiratory pressure; neutrophil content in the airway and myeloperoxidase levels; obstruction of the large and small airways; systemic leakage of fluid and proteins, and pulmonary edema. Conclusions In this study, high-dose rhCC10 significantly attenuated ARDS progression and lung dysfunction and significantly reduced systemic extravasation of fluid and proteins, normalizing fluid balance. Based on these results, rhCC10 may be considered a novel therapeutic option for the treatment of SII-induced ARDS.